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Watanabe-Matsui M, Kadoya S, Segawa K, Shima H, Nakagawa T, Nagasawa Y, Hayashi S, Matsumoto M, Ikeda M, Muto A, Ochiai K, Nguyen LC, Doh-Ura K, Shirouzu M, Nakayama K, Murayama K, Igarashi K. Heme regulates protein interactions and phosphorylation of BACH2 intrinsically disordered region in humoral response. iScience 2025; 28:111529. [PMID: 39758820 PMCID: PMC11699347 DOI: 10.1016/j.isci.2024.111529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 09/03/2023] [Accepted: 12/02/2024] [Indexed: 01/07/2025] Open
Abstract
Heme is known to bind to the intrinsically disordered region (IDR) to regulate protein function. The binding of heme to the IDR of transcription factor BACH2 promotes plasma cell differentiation, but the molecular basis is unknown. Heme was found to increase BACH2 IDR interaction with TANK-binding kinase 1 (TBK1). TBK1 inactivated BACH2 by phosphorylation of its IDR, whereas BACH2 repressed TBK1 gene expression. BACH2 phosphorylation by TBK1 inhibited its interaction with the co-repressor NCOR1 and promoted plasma cell differentiation. Heme also induced BACH2 binding to ubiquitin E3 ligase adaptor FBXO22, which polyubiquitinated BACH2 only in the presence of heme in vitro. Mutations of some of the TBK1-mediated phosphorylation sites promoted BACH2-FBXO22 interaction, while additional mutations abrogated their interaction, suggesting that TBK1 can both inhibit and promote BACH2-FBXO22 interaction. Therefore, heme regulates phosphorylation of BACH2 IDR by TBK1 and its interaction with NCOR1 and FBXO22, leading to de-repression of BACH2 target genes in humoral immunity.
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Affiliation(s)
- Miki Watanabe-Matsui
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
- The Japan Society for the Promotion of Science (JSPS), Tokyo, Japan
| | - Shun Kadoya
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kei Segawa
- Pharmaceutical Discovery Research Laboratories, Teijin Pharma Limited, Tokyo, Japan
| | - Hiroki Shima
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tadashi Nakagawa
- Division of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Clinical Pharmacology, Sanyo-Onoda City University, Sanyo-Onoda, Japan
| | - Yuko Nagasawa
- Division of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shuichiro Hayashi
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mitsuyo Matsumoto
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mariko Ikeda
- Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Japan
| | - Akihiko Muto
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kyoko Ochiai
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Long C. Nguyen
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Katsumi Doh-Ura
- Department of Neurochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mikako Shirouzu
- Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Japan
| | - Keiko Nakayama
- Division of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazutaka Murayama
- Division of Biomedical Measurements and Diagnostics, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan
| | - Kazuhiko Igarashi
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
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2
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Sahu V, Lu C. Metabolism-driven chromatin dynamics: Molecular principles and technological advances. Mol Cell 2025; 85:262-275. [PMID: 39824167 PMCID: PMC11750176 DOI: 10.1016/j.molcel.2024.12.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/26/2024] [Accepted: 12/11/2024] [Indexed: 01/20/2025]
Abstract
Cells integrate metabolic information into core molecular processes such as transcription to adapt to environmental changes. Chromatin, the physiological template of the eukaryotic genome, has emerged as a sensor and rheostat for fluctuating intracellular metabolites. In this review, we highlight the growing list of chromatin-associated metabolites that are derived from diverse sources. We discuss recent advances in our understanding of the mechanisms by which metabolic enzyme activities shape the chromatin structure and modifications, how specificity may emerge from their seemingly broad effects, and technologies that facilitate the study of epigenome-metabolome interplay. The recognition that metabolites are immanent components of the chromatin regulatory network has significant implications for the evolution, function, and therapeutic targeting of the epigenome.
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Affiliation(s)
- Varun Sahu
- Department of Genetics and Development and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Chao Lu
- Department of Genetics and Development and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
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3
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Li XH, Lee SH, Lu QY, Zhan CL, Lee GH, Kim JD, Sim JM, Song HJ, Cui XS. MAT2A is essential for zygotic genome activation by maintaining of histone methylation in porcine embryos. Theriogenology 2024; 230:81-90. [PMID: 39276507 DOI: 10.1016/j.theriogenology.2024.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 08/18/2024] [Accepted: 09/08/2024] [Indexed: 09/17/2024]
Abstract
Methionine adenosyltransferase 2A (MAT2A) is an essential enzyme in the methionine cycle that generates S-adenosylmethionine (SAM) by reacting with methionine and ATP. SAM acts as a methyl donors for histone and DNA methylation, which plays key roles in zygotic genome activation (ZGA). However, the effects of MAT2A on porcine ZGA remain unclear. To investigate the function of MAT2A and its underlying mechanism in porcine ZGA, MAT2A was knocked down by double-stranded RNA injection at the 1-cell stage. MAT2A is highly expressed at every stage of porcine embryo development. The percentages of four-cell-stage embryos and blastocysts were lower in the MAT2A-knockdown (KD) group than in the control group. Notably, depletion of MAT2A decreased the levels of H3K4me2, H3K9me2/3, and H3K27me3 at the four-cell stage, whereas MAT2A KD reduced the transcriptional activity of ZGA genes. MAT2A KD decreased embryonic ectoderm development (EED) and enhancer of zeste homolog 2 (EZH2) expression. Exogenous SAM supplementation rescued histone methylation levels and developmental arrest induced by MAT2A KD. Additionally, MAT2A KD significantly increased DNA damage and apoptosis. In conclusion, MAT2A is involved in regulating transcriptional activity and is essential for regulating histone methylation during porcine ZGA.
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Affiliation(s)
- Xiao-Han Li
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea
| | - Song-Hee Lee
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea
| | - Qin-Yue Lu
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea
| | - Cheng-Lin Zhan
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea
| | - Gyu-Hyun Lee
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea
| | - Ji-Dam Kim
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea
| | - Jae-Min Sim
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea
| | - Hyeon-Ji Song
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea
| | - Xiang-Shun Cui
- Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea.
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4
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Pulous FE, Steurer B, Pun FW, Zhang M, Ren F, Zhavoronkov A. MAT2A inhibition combats metabolic and transcriptional reprogramming in cancer. Drug Discov Today 2024; 29:104189. [PMID: 39306235 DOI: 10.1016/j.drudis.2024.104189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 09/05/2024] [Accepted: 09/17/2024] [Indexed: 09/26/2024]
Abstract
Metabolic and transcriptional reprogramming are crucial hallmarks of carcinogenesis that present exploitable vulnerabilities for the development of targeted anticancer therapies. Through controlling the balance of the cellular methionine (MET) metabolite pool, MET adenosyl transferase 2 alpha (MAT2A) regulates crucial steps during metabolism and the epigenetic control of transcription. The aberrant function of MAT2A has been shown to drive malignant transformation through metabolic addiction, transcriptional rewiring, and immune modulation of the tumor microenvironment (TME). Moreover, MAT2A sustains the survival of 5'-methylthioadenosine phosphorylase (MTAP)-deficient tumors, conferring synthetic lethality to cancers with MTAP loss, a genetic alteration that occurs in ∼15% of all cancers. Thus, the pharmacological inhibition of MAT2A is emerging as a desirable therapeutic strategy to combat tumor growth. Here, we review the latest insights into MAT2A biology, focusing on its roles in both metabolic addiction and gene expression modulation in the TME, outline the current landscape of MAT2A inhibitors, and highlight the most recent clinical developments and opportunities for MAT2A inhibition as a novel anti-tumor therapy.
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Affiliation(s)
- Fadi E Pulous
- Insilico Medicine US Inc, 1000 Massachusetts Avenue, Suite 126, Cambridge, MA 02138, USA
| | - Barbara Steurer
- Insilico Medicine US Inc, 1000 Massachusetts Avenue, Suite 126, Cambridge, MA 02138, USA
| | - Frank W Pun
- Insilico Medicine Hong Kong Ltd, Unit 310, 3/F, Building 8W, Hong Kong Science and Technology Park, Hong Kong SAR, China
| | - Man Zhang
- Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, China
| | - Feng Ren
- Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, China
| | - Alex Zhavoronkov
- Insilico Medicine US Inc, 1000 Massachusetts Avenue, Suite 126, Cambridge, MA 02138, USA; Insilico Medicine Hong Kong Ltd, Unit 310, 3/F, Building 8W, Hong Kong Science and Technology Park, Hong Kong SAR, China; Insilico Medicine AI Ltd, Level 6, Unit 08, Block A, IRENA HQ Building, Masdar City, Abu Dhabi, UAE.
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5
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Wan X, Zeng W, Fan H, Wang C, Han S, Sun Z, Tang M, Shao J, Liu Y, Fang Y, Jia J, Tang Y, Zhang Y, Zhao B, Fang D. MAT2B regulates the protein level of MAT2A to preserve RNA N6-methyladenosine. Cell Death Dis 2024; 15:714. [PMID: 39353892 PMCID: PMC11445541 DOI: 10.1038/s41419-024-07093-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 09/13/2024] [Accepted: 09/18/2024] [Indexed: 10/03/2024]
Abstract
MAT2B works together with MAT2A to synthesize S-Adenosyl methionine (SAM) as the primary methyl donor. MAT2B, despite lacking catalytic activity, exerts regulatory control over the enzymatic activity of MAT2A. In addition to the enzymatic activity regulation, we find that, in an NADP+-dependent manner, MAT2B binds and stabilizes MAT2A. Disruption of the cellular NADP+ remodels the protein level of MAT2A. The pentose phosphatase pathway regulates the level of MAT2A protein through the interaction of NADP+ with MAT2B. Additionally, MAT2B-MAT2A interaction regulates the mRNA m6A modification and stability. In liver tumors, the Mat2a mRNA level is elevated but the protein level is decreased by the restricted NADP+. Blocking the interaction between MAT2B and MAT2A by the keto diet can suppress liver tumor growth. These findings reveal that MAT2B is essential for regulating the protein levels of MAT2A and connecting SAM synthesis to mRNA m6A.
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Affiliation(s)
- Xinyi Wan
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Weiwu Zeng
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Haonan Fan
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Chenliang Wang
- Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Shixun Han
- Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Zhongxing Sun
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Mei Tang
- Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Juejia Shao
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Yu Liu
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Yuan Fang
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Junqi Jia
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Yin Tang
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Yanjun Zhang
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Bin Zhao
- Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Dong Fang
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou, China.
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou, China.
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6
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Hayashi Y, Kaneko J, Ito-Matsuoka Y, Takehara A, Funakoshi M, Maezawa S, Shirane K, Furuya S, Matsui Y. Control of epigenomic landscape and development of fetal male germ cells through L-serine metabolism. iScience 2024; 27:110702. [PMID: 39262797 PMCID: PMC11388182 DOI: 10.1016/j.isci.2024.110702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/02/2024] [Accepted: 08/06/2024] [Indexed: 09/13/2024] Open
Abstract
Sex-specific metabolic characteristics emerge in the mouse germ line after reaching the genital ridges around embryonic day 10.5, coinciding with sexual differentiation. However, the impact of such metabolic characteristics on germ cell development remains unclear. In this study, we observed the specific upregulation in male fetal germ cells of D-3-phosphoglycerate dehydrogenase (PHGDH), the primary enzyme in the serine-glycine-one-carbon metabolism, along with an increase in a downstream metabolite, S-adenosylmethionine (SAM), crucial for protein and nucleic acid methylation. Inhibiting PHGDH in fetal testes resulted in reduced SAM levels in germ cells, accompanied by increases in the number of mouse vasa homolog (MVH/VASA)-positive germ cells and the promyelocytic leukemia zinc finger (PLZF)-positive undifferentiated spermatogonia ratio. Furthermore, PHGDH inhibition led to a decrease in the methylation of histone H3 and DNA, resulting in aberrations in gene expression profiles. In summary, our findings underscore the significant role of certain metabolic mechanisms in the development of male germ cells.
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Affiliation(s)
- Yohei Hayashi
- Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer (IDAC), Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
- Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577, Japan
- Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Jintaro Kaneko
- School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Yumi Ito-Matsuoka
- Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer (IDAC), Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Asuka Takehara
- Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer (IDAC), Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Mayuka Funakoshi
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Yamazaki 2641, Noda, Chiba 278-8510, Japan
| | - So Maezawa
- Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Yamazaki 2641, Noda, Chiba 278-8510, Japan
| | - Kenjiro Shirane
- Department of Genome Biology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Shigeki Furuya
- Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, 744 Motooka, Fukuoka 819-0395, Japan
| | - Yasuhisa Matsui
- Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer (IDAC), Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
- Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577, Japan
- Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
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Lu Y, Fu W, Xing W, Wu H, Zhang C, Xu D. Transcriptional regulation mechanism of PARP1 and its application in disease treatment. Epigenetics Chromatin 2024; 17:26. [PMID: 39118189 PMCID: PMC11308664 DOI: 10.1186/s13072-024-00550-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 07/25/2024] [Indexed: 08/10/2024] Open
Abstract
Poly (ADP-ribose) polymerase 1 (PARP1) is a multifunctional nuclear enzyme that catalyzes poly-ADP ribosylation in eukaryotic cells. In addition to maintaining genomic integrity, this nuclear enzyme is also involved in transcriptional regulation. PARP1 can trigger and maintain changes in the chromatin structure and directly recruit transcription factors. PARP1 also prevents DNA methylation. However, most previous reviews on PARP1 have focused on its involvement in maintaining genome integrity, with less focus on its transcriptional regulatory function. This article comprehensively reviews the transcriptional regulatory function of PARP1 and its application in disease treatment, providing new ideas for targeting PARP1 for the treatment of diseases other than cancer.
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Affiliation(s)
- Yu Lu
- Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Beijing, 100850, P.R. China
- Hebei University, Baoding, Hebei, P.R. China
| | - Wenliang Fu
- Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Beijing, 100850, P.R. China
| | - Weiwei Xing
- Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Beijing, 100850, P.R. China
| | - Haowei Wu
- Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Beijing, 100850, P.R. China
| | - Chao Zhang
- Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Beijing, 100850, P.R. China.
| | - Donggang Xu
- Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Beijing, 100850, P.R. China.
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Bernasocchi T, Mostoslavsky R. Subcellular one carbon metabolism in cancer, aging and epigenetics. FRONTIERS IN EPIGENETICS AND EPIGENOMICS 2024; 2:1451971. [PMID: 39239102 PMCID: PMC11375787 DOI: 10.3389/freae.2024.1451971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/07/2024]
Abstract
The crosstalk between metabolism and epigenetics is an emerging field that is gaining importance in different areas such as cancer and aging, where changes in metabolism significantly impacts the cellular epigenome, in turn dictating changes in chromatin as an adaptive mechanism to bring back metabolic homeostasis. A key metabolic pathway influencing an organism's epigenetic state is one-carbon metabolism (OCM), which includes the folate and methionine cycles. Together, these cycles generate S-adenosylmethionine (SAM), the universal methyl donor essential for DNA and histone methylation. SAM serves as the sole methyl group donor for DNA and histone methyltransferases, making it a crucial metabolite for chromatin modifications. In this review, we will discuss how SAM and its byproduct, S-adenosylhomocysteine (SAH), along with the enzymes and cofactors involved in OCM, may function in the different cellular compartments, particularly in the nucleus, to directly regulate the epigenome in aging and cancer.
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Affiliation(s)
- Tiziano Bernasocchi
- The Krantz Family Center for Cancer Research, The Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, United States
- The Broad Institute of Harvard and MIT, Cambridge, MA, United States
| | - Raul Mostoslavsky
- The Krantz Family Center for Cancer Research, The Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, United States
- The Broad Institute of Harvard and MIT, Cambridge, MA, United States
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9
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Yu X, Li S. Specific regulation of epigenome landscape by metabolic enzymes and metabolites. Biol Rev Camb Philos Soc 2024; 99:878-900. [PMID: 38174803 DOI: 10.1111/brv.13049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 01/05/2024]
Abstract
Metabolism includes anabolism and catabolism, which play an essential role in many biological processes. Chromatin modifications are post-translational modifications of histones and nucleic acids that play important roles in regulating chromatin-associated processes such as gene transcription. There is a tight connection between metabolism and chromatin modifications. Many metabolic enzymes and metabolites coordinate cellular activities with alterations in nutrient availability by regulating gene expression through epigenetic mechanisms such as DNA methylation and histone modifications. The dysregulation of gene expression by metabolism and epigenetic modifications may lead to diseases such as diabetes and cancer. Recent studies reveal that metabolic enzymes and metabolites specifically regulate chromatin modifications, including modification types, modification residues and chromatin regions. This specific regulation has been implicated in the development of human diseases, yet the underlying mechanisms are only beginning to be uncovered. In this review, we summarise recent studies of the molecular mechanisms underlying the metabolic regulation of histone and DNA modifications and discuss how they contribute to pathogenesis. We also describe recent developments in technologies used to address the key questions in this field. We hope this will inspire further in-depth investigations of the specific regulatory mechanisms involved, and most importantly will shed lights on the development of more effective disease therapies.
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Affiliation(s)
- Xilan Yu
- State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan, Hubei 430062, China
| | - Shanshan Li
- State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan, Hubei 430062, China
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10
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Xue J, Ye C. The role of lipoylation in mitochondrial adaptation to methionine restriction. Bioessays 2024; 46:e2300218. [PMID: 38616332 DOI: 10.1002/bies.202300218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 03/12/2024] [Accepted: 04/02/2024] [Indexed: 04/16/2024]
Abstract
Dietary methionine restriction (MR) is associated with a spectrum of health-promoting benefits. Being conducive to prevention of chronic diseases and extension of life span, MR can activate integrated responses at metabolic, transcriptional, and physiological levels. However, how the mitochondria of MR influence metabolic phenotypes remains elusive. Here, we provide a summary of cellular functions of methionine metabolism and an overview of the current understanding of effector mechanisms of MR, with a focus on the aspect of mitochondria-mediated responses. We propose that mitochondria can sense and respond to MR through a modulatory role of lipoylation, a mitochondrial protein modification sensitized by MR.
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Affiliation(s)
- Jingyuan Xue
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Cunqi Ye
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
- Hainan Institute, Zhejiang University, Sanya, China
- National R&D Center for Freshwater Fish Processing, Jiangxi Normal University, Nanchang, China
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11
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Jiang Q, Lan S, Tan F, Liang Y, Guo Z, Hou Y, Zhang H, Wu G, Liu Z. Adenosylhomocysteinase plays multiple roles in maintaining the identity and pluripotency of mouse embryonic stem cells†. Biol Reprod 2024; 110:450-464. [PMID: 38035769 DOI: 10.1093/biolre/ioad165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/25/2023] [Accepted: 11/30/2023] [Indexed: 12/02/2023] Open
Abstract
Adenosylhomocysteinase (AHCY), a key enzyme in the methionine cycle, is essential for the development of embryos and the maintenance of mouse embryonic stem cells (mESCs). However, the precise underlying mechanism of Ahcy in regulating pluripotency remains unclear. As the only enzyme that can hydrolyze S-adenosylhomocysteine in mammals, AHCY plays a critical role in the metabolic homeostasis, epigenetic remodeling, and transcriptional regulation. Here, we identified Ahcy as a direct target of OCT4 and unveiled that AHCY regulates the self-renewal and differentiation potency of mESCs through multiple mechanisms. Our study demonstrated that AHCY is required for the metabolic homeostasis of mESCs. We revealed the dual role of Ahcy in both transcriptional activation and inhibition, which is accomplished via the maintenance of H3K4me3 and H3K27me3, respectively. We found that Ahcy is required for H3K4me3-dependent transcriptional activation in mESCs. We also demonstrated that AHCY interacts with polycomb repressive complex 2 (PRC2), thereby maintaining the pluripotency of mESCs by sustaining the H3K27me3-regulated transcriptional repression of related genes. These results reveal a previously unrecognized OCT4-AHCY-PRC2 axis in the regulation of mESCs' pluripotency and provide insights into the interplay between transcriptional factors, cellular metabolism, chromatin dynamics and pluripotency regulation.
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Affiliation(s)
- Qi Jiang
- College of Life Science, Northeast Agricultural University, Harbin, China
- Basic Research Department, Guangzhou National Laboratory, Guangzhou, China
- Key Laboratory of Animal Cellular and Genetic Engineering of Heilongjiang Province, College of Life Science, Northeast Agricultural University, Harbin, China
| | - Shubing Lan
- Basic Research Department, Guangzhou National Laboratory, Guangzhou, China
| | - Fancheng Tan
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China
| | - Yiping Liang
- Basic Research Department, Guangzhou National Laboratory, Guangzhou, China
| | - Zhencheng Guo
- Basic Research Department, Guangzhou National Laboratory, Guangzhou, China
| | - Yanlin Hou
- Basic Research Department, Guangzhou National Laboratory, Guangzhou, China
| | - Hui Zhang
- Basic Research Department, Guangzhou National Laboratory, Guangzhou, China
- The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Guangming Wu
- Basic Research Department, Guangzhou National Laboratory, Guangzhou, China
- Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhonghua Liu
- College of Life Science, Northeast Agricultural University, Harbin, China
- Key Laboratory of Animal Cellular and Genetic Engineering of Heilongjiang Province, College of Life Science, Northeast Agricultural University, Harbin, China
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12
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Jevtic Z, Schwaller J. First mouse model of infant acute myeloid leukemia with t(7;12)(q36;p17). Haematologica 2024; 109:712-714. [PMID: 37584296 PMCID: PMC10905090 DOI: 10.3324/haematol.2023.283659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 08/08/2023] [Indexed: 08/17/2023] Open
Affiliation(s)
| | - J. Schwaller
- University Children’s Hospital Basel, Department of Biomedicine, University of Basel, Basel, Switzerland
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13
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He H, Wang Z, Peng X, Qing L, Zhang Y, Fu S, Xu J, Li Y, Zhang S. Identification of a Sonically Activated Degrader of Methionine Adenosyltransferase 2A by an in Silico Approach Assisted with the Hole-Electron Analysis. J Med Chem 2024; 67:543-554. [PMID: 38166392 DOI: 10.1021/acs.jmedchem.3c01770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2024]
Abstract
Small molecules capable of modulating methionine adenosyltransferase 2A (MAT2A) are of significant interest in precise cancer therapeutics. Herein, we raised the hole-electron Coulombic attraction as a reliable molecular descriptor for predicting the reactive oxygen generation capacity of MAT2A inhibitors, based on which we discovered compound H3 as a sonically activated degrader of MAT2A. Upon sonication, H3 can generate reactive oxygen species to specifically degrade cellular MAT2A via rapid oxidative reactions. Combination of H3 and sonication induced 87% MAT2A depletion in human colon cancer cells, thus elevating its antiproliferation effects by 8-folds. In vivo, H3 had a favorable pharmacokinetic profile (bioavailability = 77%) and ADME properties. Owing to the MAT2A degradation merits, H3 at a dosage of 10 mg/kg induced 31% tumor regression in xenograft colon tumor models. The significantly boosted antitumor potency can potentially alleviate the toxicity of high-dose MAT2A inhibitors to normal cells and tissues, especially to the liver.
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Affiliation(s)
- Huan He
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, P. R. China
- Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, P. R. China
| | - Ziwei Wang
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, P. R. China
- Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, P. R. China
| | - Xueke Peng
- Guiyang Healthcare Vocational University, Guiyang 550081, P. R. China
| | - Luolong Qing
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, P. R. China
- Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, P. R. China
| | - Yu Zhang
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, P. R. China
- Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, P. R. China
| | - Shaojuan Fu
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, P. R. China
| | - Juan Xu
- College of Chemistry and Chemical Engineering, Hubei Polytechnic University, Huangshi 435003, P. R. China
| | - Yuanyuan Li
- School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, P. R. China
| | - Silong Zhang
- Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, P. R. China
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14
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Ikeda M, Kato H, Shima H, Matsumoto M, Furukawa E, Yan Y, Liao R, Xu J, Muto A, Fujiwara T, Harigae H, Bresnick EH, Igarashi K. Heme-dependent induction of mitophagy program during differentiation of murine erythroid cells. Exp Hematol 2023; 118:21-30. [PMID: 36481429 PMCID: PMC10161131 DOI: 10.1016/j.exphem.2022.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 11/25/2022] [Accepted: 11/26/2022] [Indexed: 12/12/2022]
Abstract
Although establishment and maintenance of mitochondria are essential for the production of massive amounts of heme in erythroblasts, mitochondria must be degraded upon terminal differentiation to red blood cells (RBCs), thus creating a biphasic regulatory process. Previously, we reported that iron deficiency in mice promotes mitochondrial retention in RBCs, suggesting that a proper amount of iron and/or heme is necessary for the degradation of mitochondria during erythroblast maturation. Because the transcription factor GATA1 regulates autophagy in erythroid cells, which involves mitochondrial clearance (mitophagy), we investigated the relationship between iron or heme and mitophagy by analyzing the expression of genes related to GATA1 and autophagy and the impact of iron or heme restriction on the amount of mitochondria. We found that heme promotes the expression of GATA1-regulated mitophagy-related genes and the induction of mitophagy. GATA1 might induce the expression of the autophagy-related genes Atg4d and Stk11 for mitophagy through a heme-dependent mechanism in murine erythroleukemia (MEL) cells and a genetic rescue system with G1E-ER-GATA1 erythroblast cells derived from Gata1-null murine embryonic stem cells. These results provide evidence for a biphasic mechanism in which mitochondria are essential for heme generation, and the heme generated during differentiation promotes mitophagy and mitochondrial disposal. This mechanism provides a molecular framework for understanding this fundamentally important cell biological process.
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Affiliation(s)
- Masatoshi Ikeda
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan
| | - Hiroki Kato
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan; Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan
| | - Hiroki Shima
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan
| | - Mitsuyo Matsumoto
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan; Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan
| | - Eijiro Furukawa
- Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan
| | - Yan Yan
- Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan
| | - Ruiqi Liao
- Department of Cell and Regenerative Biology, Wisconsin Blood Cancer Research Institute, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Jian Xu
- Children's Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
| | - Akihiko Muto
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan
| | - Tohru Fujiwara
- Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan
| | - Hideo Harigae
- Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan
| | - Emery H Bresnick
- Department of Cell and Regenerative Biology, Wisconsin Blood Cancer Research Institute, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Kazuhiko Igarashi
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan; Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan.
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15
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Cai S, Quan S, Yang G, Zeng X, Wang X, Ye C, Li H, Wang G, Zeng X, Qiao S. DDIT3 regulates key enzymes in the methionine cycle and flux during embryonic development. J Nutr Biochem 2023; 111:109176. [PMID: 36220527 DOI: 10.1016/j.jnutbio.2022.109176] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 08/14/2022] [Accepted: 08/19/2022] [Indexed: 11/09/2022]
Abstract
One-carbon metabolism is a key metabolic network that integrates nutritional signals with embryonic development. However, the response of one-carbon metabolism to methionine status and the regulatory mechanisms are poorly understood. Herein, we found that methionine supplementation during pregnancy significantly increased fetal number and average fetal weight. In addition, methionine modulated one-carbon metabolism primarily through 2 metabolic enzymes, cystathionine β-synthase (CBS) and methionine adenosyltransferase 2A (MAT2A), which were significantly increased in fetal liver tissues and porcine trophoblast (pTr) cells in response to proper methionine supplementation. CBS and MAT2A overexpression enhanced the DNA synthesis in pTr cells. More importantly, we identified a transcription factor, DNA damage-inducible transcript 3 (DDIT3), that was the primary regulator of CBS and MAT2A, which bound directly to promoters and negatively regulated the expression of CBS and MAT2A. Taken together, our findings identified that DDIT3 targeting CBS and MAT2A was a novel regulatory pathway that mediated cellular one-carbon metabolism in response to methionine signal and provided promising targets to improve pregnancy health.
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Affiliation(s)
- Shuang Cai
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China; Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Shuang Quan
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China; Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Guangxin Yang
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China; Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Xiangzhou Zeng
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China; Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Xinyu Wang
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China; Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Changchuan Ye
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China; Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Huan Li
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China; Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Gang Wang
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China; Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Xiangfang Zeng
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China; Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China.
| | - Shiyan Qiao
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, Beijing, China; Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
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16
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Lin JMG, Kourtis S, Ghose R, Pardo Lorente N, Kubicek S, Sdelci S. Metabolic modulation of transcription: The role of one-carbon metabolism. Cell Chem Biol 2022; 29:S2451-9456(22)00415-9. [PMID: 36513079 DOI: 10.1016/j.chembiol.2022.11.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 10/05/2022] [Accepted: 11/18/2022] [Indexed: 12/15/2022]
Abstract
While it is well known that expression levels of metabolic enzymes regulate the metabolic state of the cell, there is mounting evidence that the converse is also true, that metabolite levels themselves can modulate gene expression via epigenetic modifications and transcriptional regulation. Here we focus on the one-carbon metabolic pathway, which provides the essential building blocks of many classes of biomolecules, including purine nucleotides, thymidylate, serine, and methionine. We review the epigenetic roles of one-carbon metabolic enzymes and their associated metabolites and introduce an interactive computational resource that places enzyme essentiality in the context of metabolic pathway topology. Therefore, we briefly discuss examples of metabolic condensates and higher-order complexes of metabolic enzymes downstream of one-carbon metabolism. We speculate that they may be required to the formation of transcriptional condensates and gene expression control. Finally, we discuss new ways to exploit metabolic pathway compartmentalization to selectively target these enzymes in cancer.
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Affiliation(s)
- Jung-Ming G Lin
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Vienna 1090, Austria
| | - Savvas Kourtis
- Centre for Genomic Regulation (CRG), the Barcelona Institute of Science and Technology, Barcelona, Catalonia 08003, Spain
| | - Ritobrata Ghose
- Centre for Genomic Regulation (CRG), the Barcelona Institute of Science and Technology, Barcelona, Catalonia 08003, Spain
| | - Natalia Pardo Lorente
- Centre for Genomic Regulation (CRG), the Barcelona Institute of Science and Technology, Barcelona, Catalonia 08003, Spain
| | - Stefan Kubicek
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Vienna 1090, Austria
| | - Sara Sdelci
- Centre for Genomic Regulation (CRG), the Barcelona Institute of Science and Technology, Barcelona, Catalonia 08003, Spain.
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17
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Impact of Nuclear De Novo NAD + Synthesis via Histone Dynamics on DNA Repair during Cellular Senescence To Prevent Tumorigenesis. Mol Cell Biol 2022; 42:e0037922. [PMID: 36278823 PMCID: PMC9670974 DOI: 10.1128/mcb.00379-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
NAD+ synthesis is a fundamental process in living cells. The effects of local metabolite production on chromatin influence the epigenetic status of chromatin in DNA metabolism. We have previously shown that K5 acetylation of H2AX by TIP60 is required for the ADP ribosylation activity of PARP-1, for histone H2AX exchange at DNA damage sites. However, the detailed molecular mechanism has remained unclear. Here, we identified de novo NAD synthetase 1 (NAD syn1) as a novel binding partner to H2AX. The enzymatic activity of NAD syn1 is crucial for the ADP ribosylation activity of PARP-1 for the H2AX dynamics at sites of DNA damage. Inhibition of the NAD synthetase activity in the cell nucleus decreased the overall cellular NAD+ concentration, leading to cellular senescence. Accordingly, the acetylation-dependent H2AX dynamics and homologous recombination repair were suppressed, leading to increased tumorigenesis. Our findings have revealed the importance of de novo NAD+ production in the cell nucleus for protection against the decreased DNA repair capacity caused by cellular senescence and thus against tumorigenesis.
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18
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Ahuja M, Kaidery NA, Dutta D, Attucks OC, Kazakov EH, Gazaryan I, Matsumoto M, Igarashi K, Sharma SM, Thomas B. Harnessing the Therapeutic Potential of the Nrf2/Bach1 Signaling Pathway in Parkinson's Disease. Antioxidants (Basel) 2022; 11:antiox11091780. [PMID: 36139853 PMCID: PMC9495572 DOI: 10.3390/antiox11091780] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 09/03/2022] [Accepted: 09/05/2022] [Indexed: 11/16/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative movement disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although a complex interplay of multiple environmental and genetic factors has been implicated, the etiology of neuronal death in PD remains unresolved. Various mechanisms of neuronal degeneration in PD have been proposed, including oxidative stress, mitochondrial dysfunction, neuroinflammation, α-synuclein proteostasis, disruption of calcium homeostasis, and other cell death pathways. While many drugs individually targeting these pathways have shown promise in preclinical PD models, this promise has not yet translated into neuroprotective therapies in human PD. This has consequently spurred efforts to identify alternative targets with multipronged therapeutic approaches. A promising therapeutic target that could modulate multiple etiological pathways involves drug-induced activation of a coordinated genetic program regulated by the transcription factor, nuclear factor E2-related factor 2 (Nrf2). Nrf2 regulates the transcription of over 250 genes, creating a multifaceted network that integrates cellular activities by expressing cytoprotective genes, promoting the resolution of inflammation, restoring redox and protein homeostasis, stimulating energy metabolism, and facilitating repair. However, FDA-approved electrophilic Nrf2 activators cause irreversible alkylation of cysteine residues in various cellular proteins resulting in side effects. We propose that the transcriptional repressor of BTB and CNC homology 1 (Bach1), which antagonizes Nrf2, could serve as a promising complementary target for the activation of both Nrf2-dependent and Nrf2-independent neuroprotective pathways. This review presents the current knowledge on the Nrf2/Bach1 signaling pathway, its role in various cellular processes, and the benefits of simultaneously inhibiting Bach1 and stabilizing Nrf2 using non-electrophilic small molecules as a novel therapeutic approach for PD.
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Affiliation(s)
- Manuj Ahuja
- Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29406, USA
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29406, USA
| | - Navneet Ammal Kaidery
- Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29406, USA
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29406, USA
| | - Debashis Dutta
- Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29406, USA
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29406, USA
| | | | | | - Irina Gazaryan
- Pace University, White Plains, NY 10601, USA
- Department of Chemical Enzymology, School of Chemistry, M.V. Lomonosov Moscow State University, 111401 Moscow, Russia
- Faculty of Biology and Biotechnologies, Higher School of Economics, 111401 Moscow, Russia
| | - Mitsuyo Matsumoto
- Department of Biochemistry, Graduate School of Medicine, Tohoku University, Sendai 980-8576, Japan
| | - Kazuhiko Igarashi
- Department of Biochemistry, Graduate School of Medicine, Tohoku University, Sendai 980-8576, Japan
| | - Sudarshana M. Sharma
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29406, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29406, USA
| | - Bobby Thomas
- Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29406, USA
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29406, USA
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29406, USA
- Department of Drug Discovery, Medical University of South Carolina, Charleston, SC 29406, USA
- Correspondence:
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19
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Yang PW, Jiao JY, Chen Z, Zhu XY, Cheng CS. Keep a watchful eye on methionine adenosyltransferases, novel therapeutic opportunities for hepatobiliary and pancreatic tumours. Biochim Biophys Acta Rev Cancer 2022; 1877:188793. [PMID: 36089205 DOI: 10.1016/j.bbcan.2022.188793] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/31/2022] [Accepted: 08/30/2022] [Indexed: 11/18/2022]
Abstract
Methionine adenosyltransferases (MATs) synthesize S-adenosylmethionine (SAM) from methionine, which provides methyl groups for DNA, RNA, protein, and lipid methylation. MATs play a critical role in cellular processes, including growth, proliferation, and differentiation, and have been implicated in tumour development and progression. The expression of MATs is altered in hepatobiliary and pancreatic (HBP) cancers, which serves as a rare biomarker for early diagnosis and prognosis prediction of HBP cancers. Independent of SAM depletion in cells, MATs are often dysregulated at the transcriptional, post-transcriptional, and post-translational levels. Dysregulation of MATs is involved in carcinogenesis, chemotherapy resistance, T cell exhaustion, activation of tumour-associated macrophages, cancer stemness, and activation of tumourigenic pathways. Targeting MATs both directly and indirectly is a potential therapeutic strategy. This review summarizes the dysregulations of MATs, their proposed mechanism, diagnostic and prognostic roles, and potential therapeutic effects in context of HBP cancers.
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Affiliation(s)
- Pei-Wen Yang
- Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ju-Ying Jiao
- Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhen Chen
- Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiao-Yan Zhu
- Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Chien-Shan Cheng
- Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
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20
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Zong W, Gong Y, Sun W, Li T, Wang ZQ. PARP1: Liaison of Chromatin Remodeling and Transcription. Cancers (Basel) 2022; 14:cancers14174162. [PMID: 36077699 PMCID: PMC9454564 DOI: 10.3390/cancers14174162] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/18/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
Poly(ADP-ribosyl)ation (PARylation) is a covalent post-translational modification and plays a key role in the immediate response of cells to stress signals. Poly(ADP-ribose) polymerase 1 (PARP1), the founding member of the PARP superfamily, synthesizes long and branched polymers of ADP-ribose (PAR) onto acceptor proteins, thereby modulating their function and their local surrounding. PARP1 is the most prominent of the PARPs and is responsible for the production of about 90% of PAR in the cell. Therefore, PARP1 and PARylation play a pleotropic role in a wide range of cellular processes, such as DNA repair and genomic stability, cell death, chromatin remodeling, inflammatory response and gene transcription. PARP1 has DNA-binding and catalytic activities that are important for DNA repair, yet also modulate chromatin conformation and gene transcription, which can be independent of DNA damage response. PARP1 and PARylation homeostasis have also been implicated in multiple diseases, including inflammation, stroke, diabetes and cancer. Studies of the molecular action and biological function of PARP1 and PARylation provide a basis for the development of pharmaceutic strategies for clinical applications. This review focuses primarily on the role of PARP1 in the regulation of chromatin remodeling and transcriptional activation.
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Affiliation(s)
- Wen Zong
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China
- Correspondence: (W.Z.); or (Z.-Q.W.)
| | - Yamin Gong
- Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), 07745 Jena, Germany
- College of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen 518055, China
| | - Wenli Sun
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China
| | - Tangliang Li
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China
| | - Zhao-Qi Wang
- Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), 07745 Jena, Germany
- Faculty of Biological Sciences, Friedrich-Schiller-University of Jena, 07743 Jena, Germany
- Correspondence: (W.Z.); or (Z.-Q.W.)
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21
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Zhao T, Lum JJ. Methionine cycle-dependent regulation of T cells in cancer immunity. Front Oncol 2022; 12:969563. [PMID: 36033438 PMCID: PMC9399763 DOI: 10.3389/fonc.2022.969563] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022] Open
Abstract
The methionine cycle comprises a series of reactions that catabolizes and regenerates methionine. This process is crucial to many cellular functions, including polyamine synthesis, DNA synthesis, redox balance, and DNA and histone methylation. In response to antigens, T cells activate the methionine cycle to support proliferation and differentiation, indicating the importance of the methionine cycle to T cell immunity. In cancer, T cells serve as important effectors of adaptive immunity by directly killing cancerous cells. However, the tumor microenvironment can induce a state of T cell exhaustion by regulating the methionine metabolism of T cells, posing a barrier to both endogenous T cell responses and T cell immunotherapy. Here we review the role of methionine cycle metabolites in regulating the activation and effector function of T cells and explore the mechanism by which tumor cells exploit the methionine pathway as a means of immune evasion. Finally, we discuss new perspectives on reprogramming the methionine cycle of T cells to enhance anti-tumor immunotherapy.
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Affiliation(s)
- Tian Zhao
- Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, BC, Canada
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
| | - Julian J Lum
- Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, BC, Canada
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
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22
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Erichsen L, Thimm C, Santourlidis S. Methyl Group Metabolism in Differentiation, Aging, and Cancer. Int J Mol Sci 2022; 23:8378. [PMID: 35955511 PMCID: PMC9369357 DOI: 10.3390/ijms23158378] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 07/21/2022] [Accepted: 07/26/2022] [Indexed: 12/04/2022] Open
Abstract
Methyl group metabolism belongs to a relatively understudied field of research. Its importance lies in the fact that methyl group metabolic pathways are crucial for the successful conversion of dietary nutrients into the basic building blocks to carry out any cellular methylation reaction. Methyl groups play essential roles in numerous cellular functions such as DNA methylation, nucleotide- and protein biosynthesis. Especially, DNA methylation is responsible for organizing the genome into transcriptionally silent and active regions. Ultimately, it is this proper annotation that determines the quality of expression patterns required to ensure and shape the phenotypic integrity and function of a highly specialized cell type. Life is characterized by constantly changing environmental conditions, which are addressed by changes in DNA methylation. This relationship is increasingly coming into focus as it is of fundamental importance for differentiation, aging, and cancer. The stability and permanence of these metabolic processes, fueling the supplementation of methyl groups, seem to be important criteria to prevent deficiencies and erosion of the methylome. Alterations in the metabolic processes can lead to epigenetic and genetic perturbations, causative for diverse disorders, accelerated aging, and various age-related diseases. In recent decades, the intake of methyl group compounds has changed significantly due to, e.g., environmental pollution and food additives. Based on the current knowledge, this review provides a brief overview of the highly interconnected relationship between nutrition, metabolism, changes in epigenetic modifications, cancer, and aging. One goal is to provide an impetus to additionally investigate changes in DNA methylation as a possible consequence of an impaired methyl group metabolism.
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Affiliation(s)
- Lars Erichsen
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany;
| | - Chantelle Thimm
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany;
| | - Simeon Santourlidis
- Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany;
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23
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Musabyimana JP, Distler U, Sassmannshausen J, Berks C, Manti J, Bennink S, Blaschke L, Burda PC, Flammersfeld A, Tenzer S, Ngwa CJ, Pradel G. Plasmodium falciparum S-Adenosylmethionine Synthetase Is Essential for Parasite Survival through a Complex Interaction Network with Cytoplasmic and Nuclear Proteins. Microorganisms 2022; 10:1419. [PMID: 35889137 PMCID: PMC9320499 DOI: 10.3390/microorganisms10071419] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/01/2022] [Accepted: 07/11/2022] [Indexed: 11/16/2022] Open
Abstract
S-adenosylmethionine synthetase (SAMS) is a key enzyme for the synthesis of the lone methyl donor S-adenosyl methionine (SAM), which is involved in transmethylation reactions and hence required for cellular processes such as DNA, RNA, and histone methylation, but also polyamine biosynthesis and proteostasis. In the human malaria parasite Plasmodium falciparum, PfSAMS is encoded by a single gene and has been suggested to be crucial for malaria pathogenesis and transmission; however, to date, PfSAMS has not been fully characterized. To gain deeper insight into the function of PfSAMS, we generated a conditional gene knockdown (KD) using the glmS ribozyme system. We show that PfSAMS localizes to the cytoplasm and the nucleus of blood-stage parasites. PfSAMS-KD results in reduced histone methylation and leads to impaired intraerythrocytic growth and gametocyte development. To further determine the interaction network of PfSAMS, we performed a proximity-dependent biotin identification analysis. We identified a complex network of 1114 proteins involved in biological processes such as cell cycle control and DNA replication, or transcription, but also in phosphatidylcholine and polyamine biosynthesis and proteasome regulation. Our findings highlight the diverse roles of PfSAMS during intraerythrocytic growth and sexual stage development and emphasize that PfSAMS is a potential drug target.
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Affiliation(s)
- Jean Pierre Musabyimana
- Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany; (J.P.M.); (J.S.); (C.B.); (J.M.); (S.B.); (L.B.); (A.F.); (C.J.N.)
| | - Ute Distler
- Proteomics Core Facility, Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (U.D.); (S.T.)
| | - Juliane Sassmannshausen
- Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany; (J.P.M.); (J.S.); (C.B.); (J.M.); (S.B.); (L.B.); (A.F.); (C.J.N.)
| | - Christina Berks
- Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany; (J.P.M.); (J.S.); (C.B.); (J.M.); (S.B.); (L.B.); (A.F.); (C.J.N.)
| | - Janice Manti
- Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany; (J.P.M.); (J.S.); (C.B.); (J.M.); (S.B.); (L.B.); (A.F.); (C.J.N.)
| | - Sandra Bennink
- Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany; (J.P.M.); (J.S.); (C.B.); (J.M.); (S.B.); (L.B.); (A.F.); (C.J.N.)
| | - Lea Blaschke
- Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany; (J.P.M.); (J.S.); (C.B.); (J.M.); (S.B.); (L.B.); (A.F.); (C.J.N.)
| | - Paul-Christian Burda
- Centre for Structural Systems Biology (CSSB) c/o DESY, Bernhard Nocht Institute, University of Hamburg, Notkestraße 85, Building 15, 22607 Hamburg, Germany;
| | - Ansgar Flammersfeld
- Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany; (J.P.M.); (J.S.); (C.B.); (J.M.); (S.B.); (L.B.); (A.F.); (C.J.N.)
| | - Stefan Tenzer
- Proteomics Core Facility, Institute of Immunology, University Medical Center of the Johannes-Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (U.D.); (S.T.)
| | - Che Julius Ngwa
- Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany; (J.P.M.); (J.S.); (C.B.); (J.M.); (S.B.); (L.B.); (A.F.); (C.J.N.)
| | - Gabriele Pradel
- Division of Cellular and Applied Infection Biology, Institute of Zoology, RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany; (J.P.M.); (J.S.); (C.B.); (J.M.); (S.B.); (L.B.); (A.F.); (C.J.N.)
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24
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Li C, Gui G, Zhang L, Qin A, Zhou C, Zha X. Overview of Methionine Adenosyltransferase 2A (MAT2A) as an Anticancer Target: Structure, Function, and Inhibitors. J Med Chem 2022; 65:9531-9547. [PMID: 35796517 DOI: 10.1021/acs.jmedchem.2c00395] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Methionine adenosyltransferase 2A (MAT2A) is a rate-limiting enzyme in the methionine cycle that primarily catalyzes the synthesis of S-adenosylmethionine (SAM) from methionine and adenosine triphosphate (ATP). MAT2A has been recognized as a therapeutic target for the treatment of cancers. Recently, a few MAT2A inhibitors have been reported, and three entered clinical trials to treat solid tumorsor lymphoma with MTAP loss. This review aims to summarize the current understanding of the roles of MAT2A in cancer and the discovery of MAT2A inhibitors. Furthermore, a perspective on the use of MAT2A inhibitors for the treatment of cancer is also discussed. We hope to provide guidance for future drug design and optimization via analysis of the binding modes of known MAT2A inhibitors.
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Affiliation(s)
- Chunzheng Li
- Department of Pharmaceutical Engineering, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Gang Gui
- Department of Pharmaceutical Engineering, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Li Zhang
- Department of Pharmaceutical Engineering, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Anqi Qin
- Department of Pharmaceutical Engineering, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Chen Zhou
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
| | - Xiaoming Zha
- Department of Pharmaceutical Engineering, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
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25
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Topoisomerase VI participates in an insulator-like function that prevents H3K9me2 spreading. Proc Natl Acad Sci U S A 2022; 119:e2001290119. [PMID: 35759655 PMCID: PMC9271158 DOI: 10.1073/pnas.2001290119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The organization of the genome into transcriptionally active and inactive chromatin domains requires well-delineated chromatin boundaries and insulator functions in order to maintain the identity of adjacent genomic loci with antagonistic chromatin marks and functionality. In plants that lack known chromatin insulators, the mechanisms that prevent heterochromatin spreading into euchromatin remain to be identified. Here, we show that DNA Topoisomerase VI participates in a chromatin boundary function that safeguards the expression of genes in euchromatin islands within silenced heterochromatin regions. While some transposable elements are reactivated in mutants of the Topoisomerase VI complex, genes insulated in euchromatin islands within heterochromatic regions of the Arabidopsis thaliana genome are specifically down-regulated. H3K9me2 levels consistently increase at euchromatin island loci and decrease at some transposable element loci. We further show that Topoisomerase VI physically interacts with S-adenosylmethionine synthase methionine adenosyl transferase 3 (MAT3), which is required for H3K9me2. A Topoisomerase VI defect affects MAT3 occupancy on heterochromatic elements and its exclusion from euchromatic islands, thereby providing a possible mechanistic explanation to the essential role of Topoisomerase VI in the delimitation of chromatin domains.
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26
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Kitano A, Norikura T, Matsui-Yuasa I, Shimakawa H, Kamezawa M, Kojima-Yuasa A. Black carrot extract protects against hepatic injury through epigenetic modifications. J Food Biochem 2022; 46:e14292. [PMID: 35762419 DOI: 10.1111/jfbc.14292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 04/10/2022] [Accepted: 06/17/2022] [Indexed: 11/29/2022]
Abstract
We studied the epigenetic regulation of how black carrot extract (BCE) protects against ethanol-induced hepatic damage. We have shown that the butanol-extracted fraction of BCE (BCE-BuOH) increased intracellular cyclic adenosine monophosphate (cAMP) levels by suppressing the expression of phosphodiesterase 4b (PDE4b); however, the detailed mechanism remains to be elucidated. We focused on changes in histone modifications involved in the suppression of pde4 expression. The methylation level of histone H3 lysine 9 (H3K9), which regulates gene expression of PDE4b, decreased after treatment with 100 mM ethanol but was significantly increased by treatment with 400 μg/ml BCE-BuOH. In contrast, ethanol induced an increase in H3K9 acetylation. However, treatment with BCE-BuOH inhibited the increase in acetylation through an increase in Sirtuin 1 (Sirt1), a histone deacetylase. Furthermore, BCE-BuOH treatment increased the level of methionine adenosyltransferase (MAT) 2a mRNA and increased intracellular S-adenosylmethionine. The present results indicate that BCE-BuOH is useful for protection against alcohol-induced hepatic injury. PRACTICAL APPLICATIONS: We have reported that black carrot extract (BCE) suppressed liver steatosis and liver fibrosis on a rat alcoholic liver disease model. The results from this study have shown that BCE regulated the alcoholic-induced hepatic injury at the level of epigenetic modifications. These results suggested that BCE is useful for protection against alcoholic-induced hepatic injury.
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Affiliation(s)
- Atsuko Kitano
- Department of Food and Human Health Sciences, Graduate School of Human Life Science, Osaka City University, Osaka, Japan
| | - Toshio Norikura
- Department of Nutrition, Aomori University of Health and Welfare, Aomori, Japan
| | - Isao Matsui-Yuasa
- Department of Food and Human Health Sciences, Graduate School of Human Life Science, Osaka City University, Osaka, Japan
| | | | | | - Akiko Kojima-Yuasa
- Department of Food and Human Health Sciences, Graduate School of Human Life Science, Osaka City University, Osaka, Japan
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27
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Alam M, Shima H, Matsuo Y, Long NC, Matsumoto M, Ishii Y, Sato N, Sugiyama T, Nobuta R, Hashimoto S, Liu L, Kaneko MK, Kato Y, Inada T, Igarashi K. mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine. J Biol Chem 2022; 298:102084. [PMID: 35636512 PMCID: PMC9243181 DOI: 10.1016/j.jbc.2022.102084] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 05/19/2022] [Accepted: 05/20/2022] [Indexed: 11/21/2022] Open
Abstract
Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine (SAM). As the sole methyl-donor for methylation of DNA, RNA, and proteins, SAM levels affect gene expression by changing methylation patterns. Expression of MAT2A, the catalytic subunit of isozyme MAT2, is positively correlated with proliferation of cancer cells; however, how MAT2A promotes cell proliferation is largely unknown. Given that the protein synthesis is induced in proliferating cells and that RNA and protein components of translation machinery are methylated, we tested here whether MAT2 and SAM are coupled with protein synthesis. By measuring ongoing protein translation via puromycin labeling, we revealed that MAT2A depletion or chemical inhibition reduced protein synthesis in HeLa and Hepa1 cells. Furthermore, overexpression of MAT2A enhanced protein synthesis, indicating that SAM is limiting under normal culture conditions. In addition, MAT2 inhibition did not accompany reduction in mechanistic target of rapamycin complex 1 activity but nevertheless reduced polysome formation. Polysome-bound RNA sequencing revealed that MAT2 inhibition decreased translation efficiency of some fraction of mRNAs. MAT2A was also found to interact with the proteins involved in rRNA processing and ribosome biogenesis; depletion or inhibition of MAT2 reduced 18S rRNA processing. Finally, quantitative mass spectrometry revealed that some translation factors were dynamically methylated in response to the activity of MAT2A. These observations suggest that cells possess an mTOR-independent regulatory mechanism that tunes translation in response to the levels of SAM. Such a system may acclimate cells for survival when SAM synthesis is reduced, whereas it may support proliferation when SAM is sufficient.
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Affiliation(s)
- Mahabub Alam
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Animal Science and Nutrition, Faculty of Veterinary Medicine, Chattogram Veterinary and Animal Sciences University, Chattogram, Bangladesh
| | - Hiroki Shima
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshitaka Matsuo
- Division of RNA and Gene Regulation, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Nguyen Chi Long
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mitsuyo Matsumoto
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yusho Ishii
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Nichika Sato
- Division of RNA and Gene Regulation, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takato Sugiyama
- Laboratory of Gene Regulation, Department of Molecular Biopharmacy and Genetics, Tohoku University Graduate School of Pharmaceutical Science, Sendai, Japan
| | - Risa Nobuta
- Laboratory of Gene Regulation, Department of Molecular Biopharmacy and Genetics, Tohoku University Graduate School of Pharmaceutical Science, Sendai, Japan
| | - Satoshi Hashimoto
- Laboratory of Gene Regulation, Department of Molecular Biopharmacy and Genetics, Tohoku University Graduate School of Pharmaceutical Science, Sendai, Japan
| | - Liang Liu
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toshifumi Inada
- Division of RNA and Gene Regulation, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| | - Kazuhiko Igarashi
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
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28
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Barrero MJ, Cejas P, Long HW, Ramirez de Molina A. Nutritional Epigenetics in Cancer. Adv Nutr 2022; 13:1748-1761. [PMID: 35421212 PMCID: PMC9526851 DOI: 10.1093/advances/nmac039] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 03/11/2022] [Accepted: 04/09/2022] [Indexed: 01/28/2023] Open
Abstract
Alterations in the epigenome are well known to affect cancer development and progression. Epigenetics is highly influenced by the environment, including diet, which is a source of metabolic substrates that influence the synthesis of cofactors or substrates for chromatin and RNA modifying enzymes. In addition, plants are a common source of bioactives that can directly modify the activity of these enzymes. Here, we review and discuss the impact of diet on epigenetic mechanisms, including chromatin and RNA regulation, and its potential implications for cancer prevention and treatment.
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Affiliation(s)
| | - Paloma Cejas
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA,Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA,Translational Oncology Laboratory, Hospital La Paz Institute for Health Research, Madrid, Spain
| | - Henry W Long
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA,Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
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29
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Wang H, Wu Y, Tang W. Methionine cycle in nonalcoholic fatty liver disease and its potential applications. Biochem Pharmacol 2022; 200:115033. [PMID: 35395242 DOI: 10.1016/j.bcp.2022.115033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/31/2022] [Accepted: 03/31/2022] [Indexed: 11/25/2022]
Abstract
As a chronic metabolic disease affecting epidemic proportions worldwide, the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD) is not clear yet. There is also a lack of precise biomarkers and specific medicine for the diagnosis and treatment of NAFLD. Methionine metabolic cycle, which is critical for the maintaining of cellular methylation and redox state, is involved in the pathophysiology of NAFLD. However, the molecular basis and mechanism of methionine metabolism in NAFLD are not completely understood. Here, we mainly focus on specific enzymes that participates in methionine cycle, to reveal their interconnections with NAFLD, in order to recognize the pathogenesis of NAFLD from a new angle and at the same time, explore the clinical characteristics and therapeutic strategies.
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Affiliation(s)
- Haoyu Wang
- University of Chinese Academy of Sciences, Beijing, 100049, PR China; Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China
| | - Yanwei Wu
- Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China
| | - Wei Tang
- University of Chinese Academy of Sciences, Beijing, 100049, PR China; Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
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30
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Ajoolabady A, Aslkhodapasandhokmabad H, Zhou Y, Ren J. Epigenetic modification in alcohol‐related liver diseases. Med Res Rev 2022; 42:1463-1491. [DOI: 10.1002/med.21881] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/21/2022] [Accepted: 01/30/2022] [Indexed: 12/13/2022]
Affiliation(s)
- Amir Ajoolabady
- School of Pharmacy University of Wyoming College of Health Sciences Laramie Wyoming USA
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai China
| | | | - Yuan Zhou
- Department of Biomedical Informatics, School of Basic Medical Sciences Peking University Beijing China
| | - Jun Ren
- School of Pharmacy University of Wyoming College of Health Sciences Laramie Wyoming USA
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital Fudan University Shanghai China
- Department of Laboratory Medicine and Pathology University of Washington Seattle Washington USA
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31
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Unconventional metabolites in chromatin regulation. Biosci Rep 2022; 42:230604. [PMID: 34988581 PMCID: PMC8777195 DOI: 10.1042/bsr20211558] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 01/04/2022] [Accepted: 01/04/2022] [Indexed: 11/17/2022] Open
Abstract
Chromatin, the complex of DNA and histone proteins, serves as a main integrator of cellular signals. Increasing evidence links cellular functional to chromatin state. Indeed, different metabolites are emerging as modulators of chromatin function and structure. Alterations in chromatin state are decisive for regulating all aspects of genome function and ultimately have the potential to produce phenotypic changes. Several metabolites such as acetyl-CoA, S-adenosylmethionine (SAM) or adenosine triphosphate (ATP) have now been well characterized as main substrates or cofactors of chromatin-modifying enzymes. However, there are other metabolites that can directly interact with chromatin influencing its state or that modulate the properties of chromatin regulatory factors. Also, there is a growing list of atypical enzymatic and nonenzymatic chromatin modifications that originate from different cellular pathways that have not been in the limelight of chromatin research. Here, we summarize different properties and functions of uncommon regulatory molecules originating from intermediate metabolism of lipids, carbohydrates and amino acids. Based on the various modes of action on chromatin and the plethora of putative, so far not described chromatin-regulating metabolites, we propose that there are more links between cellular functional state and chromatin regulation to be discovered. We hypothesize that these connections could provide interesting starting points for interfering with cellular epigenetic states at a molecular level.
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32
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Adhikari S, Guha D, Mohan C, Mukherjee S, Tyler JK, Das C. Reprogramming Carbohydrate Metabolism in Cancer and Its Role in Regulating the Tumor Microenvironment. Subcell Biochem 2022; 100:3-65. [PMID: 36301490 PMCID: PMC10760510 DOI: 10.1007/978-3-031-07634-3_1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Altered metabolism has become an emerging feature of cancer cells impacting their proliferation and metastatic potential in myriad ways. Proliferating heterogeneous tumor cells are surrounded by other resident or infiltrating cells, along with extracellular matrix proteins, and other secretory factors constituting the tumor microenvironment. The diverse cell types of the tumor microenvironment exhibit different molecular signatures that are regulated at their genetic and epigenetic levels. The cancer cells elicit intricate crosstalks with these supporting cells, exchanging essential metabolites which support their anabolic processes and can promote their survival, proliferation, EMT, angiogenesis, metastasis and even therapeutic resistance. In this context, carbohydrate metabolism ensures constant energy supply being a central axis from which other metabolic and biosynthetic pathways including amino acid and lipid metabolism and pentose phosphate pathway are diverged. In contrast to normal cells, increased glycolytic flux is a distinguishing feature of the highly proliferative cancer cells, which supports them to adapt to a hypoxic environment and also protects them from oxidative stress. Such rewired metabolic properties are often a result of epigenetic alterations in the cancer cells, which are mediated by several factors including, DNA, histone and non-histone protein modifications and non-coding RNAs. Conversely, epigenetic landscapes of the cancer cells are also dictated by their diverse metabolomes. Altogether, this metabolic and epigenetic interplay has immense potential for the development of efficient anti-cancer therapeutic strategies. In this book chapter we emphasize upon the significance of reprogrammed carbohydrate metabolism in regulating the tumor microenvironment and cancer progression, with an aim to explore the different metabolic and epigenetic targets for better cancer treatment.
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Affiliation(s)
- Swagata Adhikari
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India
- Homi Bhaba National Institute, Mumbai, India
| | - Deblina Guha
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India
| | - Chitra Mohan
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Shravanti Mukherjee
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India
| | - Jessica K Tyler
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Chandrima Das
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India.
- Homi Bhaba National Institute, Mumbai, India.
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33
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Mishra P, Beura S, Ghosh R, Modak R. Nutritional Epigenetics: How Metabolism Epigenetically Controls Cellular Physiology, Gene Expression and Disease. Subcell Biochem 2022; 100:239-267. [PMID: 36301497 DOI: 10.1007/978-3-031-07634-3_8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
The regulation of gene expression is a dynamic process that is influenced by both internal and external factors. Alteration in the epigenetic profile is a key mechanism in the regulation process. Epigenetic regulators, such as enzymes and proteins involved in posttranslational modification (PTM), use different cofactors and substrates derived from dietary sources. For example, glucose metabolism provides acetyl CoA, S-adenosylmethionine (SAM), α- ketoglutarate, uridine diphosphate (UDP)-glucose, adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD+), and fatty acid desaturase (FAD), which are utilized by chromatin-modifying enzymes in many intermediary metabolic pathways. Any alteration in the metabolic status of the cell results in the alteration of these metabolites, which causes dysregulation in the activity of chromatin regulators, resulting in the alteration of the epigenetic profile. Such long-term or repeated alteration of epigenetic profile can lead to several diseases, like cancer, insulin resistance and diabetes, cognitive impairment, neurodegenerative disease, and metabolic syndromes. Here we discuss the functions of key nutrients that contribute to epigenetic regulation and their role in pathophysiological conditions.
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Affiliation(s)
- Pragyan Mishra
- Infection and Epigenetics Group, School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar, Odisha, India
| | - Shibangini Beura
- Infection and Epigenetics Group, School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar, Odisha, India
| | - Ritu Ghosh
- Infection and Epigenetics Group, School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar, Odisha, India
| | - Rahul Modak
- Infection and Epigenetics Group, School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar, Odisha, India.
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34
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Polar Interactions at the Dimer-Dimer Interface of Methionine Adenosyltransferase MAT I Control Tetramerization. Int J Mol Sci 2021; 22:ijms222413206. [PMID: 34948004 PMCID: PMC8703375 DOI: 10.3390/ijms222413206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/29/2021] [Accepted: 12/06/2021] [Indexed: 11/17/2022] Open
Abstract
Catalytic MATα1 subunits associate into kinetically distinct homo-dimers (MAT III) and homo-tetramers (MAT I) that synthesize S-adenosylmethionine in the adult liver. Pathological reductions in S-adenosylmethionine levels correlate with MAT III accumulation; thus, it is important to know the determinants of dimer–dimer associations. Here, polar interactions (<3.5 Å) at the rat MAT I dimer–dimer interface were disrupted by site-directed mutagenesis. Heterologous expression rendered decreased soluble mutant MATα1 levels that appeared mostly as dimers. Substitutions at the B1–B2 or B3–C1 β-strand loops, or changes in charge on helix α2 located behind, induced either MAT III or MAT I accumulation. Notably, double mutants combining neutral changes on helix α2 with substitutions at either β-strand loop further increased MAT III content. Mutations had negligible impact on secondary or tertiary protein structure, but induced changes of 5–10 °C in thermal stability. All mutants preserved tripolyphosphatase activity, although AdoMet synthesis was only detected in single mutants. Kinetic parameters were altered in all purified proteins, their AdoMet synthesis Vmax and methionine affinities correlating with the association state induced by the corresponding mutations. In conclusion, polar interactions control MATα1 tetramerization and kinetics, diverse effects being induced by changes on opposite β-sheet loops putatively leading to subtle variations in central domain β-sheet orientation.
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35
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Bailey J, Douglas H, Masino L, de Carvalho LPS, Argyrou A. Human Mat2A Uses an Ordered Kinetic Mechanism and Is Stabilized but Not Regulated by Mat2B. Biochemistry 2021; 60:3621-3632. [PMID: 34780697 PMCID: PMC8638259 DOI: 10.1021/acs.biochem.1c00672] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Methionine adenosyltransferase (MAT) catalyzes the adenosine 5'-triphosphate (ATP) and l-methionine (l-Met) dependent formation of S-adenosyl-l-methionine (SAM), the principal methyl donor of most biological transmethylation reactions. We carried out in-depth kinetic studies to further understand its mechanism and interaction with a potential regulator, Mat2B. The initial velocity pattern and results of product inhibition by SAM, phosphate, and pyrophosphate, and dead-end inhibition by the l-Met analog cycloleucine (l-cLeu) suggest that Mat2A follows a strictly ordered kinetic mechanism where ATP binds before l-Met and with SAM released prior to random release of phosphate and pyrophosphate. Isothermal titration calorimetry (ITC) showed binding of ATP to Mat2A with a Kd of 80 ± 30 μM, which is close to the Km(ATP) of 50 ± 10 μM. In contrast, l-Met or l-cLeu showed no binding to Mat2A in the absence of ATP; however, binding to l-cLeu was observed in the presence of ATP. The ITC results are fully consistent with the product and dead-inhibition results obtained. We also carried out kinetic studies in the presence of the physiological regulator Mat2B. Under conditions where all Mat2A is found in complex with Mat2B, no significant change in the kinetic parameters was observed despite confirmation of a very high binding affinity of Mat2A to Mat2B (Kd of 6 ± 1 nM). Finally, we found that while Mat2A is unstable at low concentrations (<100 nM), rapidly losing activity at 37 °C, it retained full activity for at least 2 h when Mat2B was present at the known 2:1 Mat2A/Mat2B stoichiometry.
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Affiliation(s)
- Jonathan Bailey
- Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, London NW1 1AT, United Kingdom.,Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
| | - Holly Douglas
- Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, London NW1 1AT, United Kingdom
| | - Laura Masino
- Structural Biology Scientific Technology Platform, The Francis Crick Institute, London NW1 1AT, United Kingdom
| | - Luiz Pedro Sorio de Carvalho
- Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, London NW1 1AT, United Kingdom
| | - Argyrides Argyrou
- Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
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36
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Boon R. Metabolic Fuel for Epigenetic: Nuclear Production Meets Local Consumption. Front Genet 2021; 12:768996. [PMID: 34804127 PMCID: PMC8595138 DOI: 10.3389/fgene.2021.768996] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 10/20/2021] [Indexed: 12/28/2022] Open
Abstract
Epigenetic modifications are responsible for finetuning gene expression profiles to the needs of cells, tissues, and organisms. To rapidly respond to environmental changes, the activity of chromatin modifiers critically depends on the concentration of a handful of metabolites that act as substrates and co-factors. In this way, these enzymes act as metabolic sensors that directly link gene expression to metabolic states. Although metabolites can easily diffuse through the nuclear pore, molecular mechanisms must be in place to regulate epigenetic marker deposition in specific nuclear subdomains or even on single loci. In this review, I explore the possible subcellular sites of metabolite production that influence the epigenome. From the relationship between cytoplasmic metabolism and nuclear metabolite deposition, I converse to the description of a compartmentalized nuclear metabolism. Last, I elaborate on the possibility of metabolic enzymes to operate in phase-separated nuclear microdomains formed by multienzyme and chromatin-bound protein complexes.
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Affiliation(s)
- Ruben Boon
- The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, United States.,The Broad Institute of Harvard and MIT, Cambridge, MA, United States.,Laboratory for Functional Epigenetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
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37
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Pan C, Li B, Simon MC. Moonlighting functions of metabolic enzymes and metabolites in cancer. Mol Cell 2021; 81:3760-3774. [PMID: 34547237 DOI: 10.1016/j.molcel.2021.08.031] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/17/2021] [Accepted: 08/23/2021] [Indexed: 12/18/2022]
Abstract
The growing field of tumor metabolism has greatly expanded our knowledge of metabolic reprogramming in cancer. Apart from their established roles, various metabolic enzymes and metabolites harbor non-canonical ("moonlighting") functions to support malignant transformation. In this article, we intend to review the current understanding of moonlighting functions of metabolic enzymes and related metabolites broadly existing in cancer cells by dissecting each major metabolic pathway and its regulation of cellular behaviors. Understanding these non-canonical functions may broaden the horizon of the cancer metabolism field and uncover novel therapeutic vulnerabilities in cancer.
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Affiliation(s)
- Chaoyun Pan
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Bo Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510080, China; Center for Precision Medicine, Sun Yat-sen University, Guangzhou 510080, China.
| | - M Celeste Simon
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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38
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Chen L, Liu X, Zhou H, Li G, Huang F, Zhang J, Xia T, Lei W, Zhao J, Li C, Chen M. Activating transcription factor 4 regulates angiogenesis under lipid overload via methionine adenosyltransferase 2A-mediated endothelial epigenetic alteration. FASEB J 2021; 35:e21612. [PMID: 33948996 DOI: 10.1096/fj.202100233r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/19/2021] [Accepted: 04/06/2021] [Indexed: 02/05/2023]
Abstract
Lipid overload is intimately connected with the change of endothelial epigenetic status which impacts cellular signaling activities and endothelial function. Activating transcription factor 4 (ATF4) is involved in the regulation of lipid metabolism and meanwhile an epigenetic modifier. However, the role of ATF4 in the angiogenesis under lipid overload is not well understood. Here, to induce lipid overload status, we employed high-fat diet (HFD)-induced obese mouse model in vivo and palmitic acid (PA) to stimulate endothelial cells in vitro. Compared with mice fed with normal chow diet (NCD), HFD-induced obese mice showed angiogenic defects evidenced by decline in (1) blood flow recovery after hind limb ischemia, (2) wound healing speed after skin injury, (3) capillary density in injured tissues and matrigel plugs, and (4) endothelial sprouts of aortic ring. ATF4 deficiency aggravated above angiogenic defects in mice while ATF4 overexpression improved the blunted angiogenic response. Mechanistically, lipid overload lowered the H3K4 methylation levels at the regulatory regions of NOS3 and ERK1 genes, leading to reduced angiogenic signaling activity. Methionine adenosyltransferase 2A (MAT2A) is identified as a target of ATF4 and formed complex with ATF4 to direct lysine methyltransferase 2A (MLL1) to the regulatory regions of both genes for the maintenance of the H3K4 methylation level and angiogenic signaling activity. Here, we uncovered a novel metabolic-epigenetic coupling orchestrated by the ATF4-MAT2A axis for angiogenesis. The ATF4-MAT2A axis links lipid overload milieu to altered epigenetic status of relevant angiogenic signaling in endothelial cells, suggesting a potential therapeutic target for angiogenesis impaired by lipid overload.
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Affiliation(s)
- Li Chen
- Laboratory of Cardiovascular Disease, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Xiaojing Liu
- Laboratory of Cardiovascular Disease, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Hao Zhou
- Laboratory of Cardiovascular Disease, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Guoyong Li
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Fangyang Huang
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Jialiang Zhang
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Tianli Xia
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Wenhua Lei
- Laboratory of Cardiovascular Disease, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, P.R. China.,Department of Cardiology, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Jiahao Zhao
- Laboratory of Cardiovascular Disease, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Changming Li
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Mao Chen
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, P.R. China
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Sun L, Zhang H, Gao P. Metabolic reprogramming and epigenetic modifications on the path to cancer. Protein Cell 2021; 13:877-919. [PMID: 34050894 PMCID: PMC9243210 DOI: 10.1007/s13238-021-00846-7] [Citation(s) in RCA: 287] [Impact Index Per Article: 71.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023] Open
Abstract
Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolism- and epigenetic modification-based therapeutic prospects in cancer.
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Affiliation(s)
- Linchong Sun
- Guangzhou First People's Hospital, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, 510006, China.
| | - Huafeng Zhang
- The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230027, China. .,CAS Centre for Excellence in Cell and Molecular Biology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
| | - Ping Gao
- Guangzhou First People's Hospital, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, 510006, China. .,School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, China. .,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510005, China.
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40
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MAT2A Localization and Its Independently Prognostic Relevance in Breast Cancer Patients. Int J Mol Sci 2021; 22:ijms22105382. [PMID: 34065390 PMCID: PMC8161225 DOI: 10.3390/ijms22105382] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/02/2021] [Accepted: 05/13/2021] [Indexed: 02/07/2023] Open
Abstract
(1) Background: methionine cycle is not only essential for cancer cell proliferation but is also critical for metabolic reprogramming, a cancer hallmark. Hepatic and extrahepatic tissues methionine adenosyltransferases (MATs) are products of two genes, MAT1A and MAT2A that catalyze the formation of S-adenosylmethionine (SAM), the principal biological methyl donor. Glycine N-methyltransferase (GNMT) further utilizes SAM for sarcosine formation, thus it regulates the ratio of SAM:S-adenosylhomocysteine (SAH). (2) Methods: by analyzing the TCGA/GTEx datasets available within GEPIA2, we discovered that breast cancer patients with higher MAT2A had worse survival rate (p = 0.0057). Protein expression pattern of MAT1AA, MAT2A and GNMT were investigated in the tissue microarray in our own cohort (n = 252) by immunohistochemistry. MAT2A C/N expression ratio and cell invasion activity were further investigated in a panel of breast cancer cell lines. (3) Results: GNMT and MAT1A were detected in the cytoplasm, whereas MAT2A showed both cytoplasmic and nuclear immunoreactivity. Neither GNMT nor MAT1A protein expression was associated with patient survival rate in our cohort. Kaplan–Meier survival curves showed that a higher cytoplasmic/nuclear (C/N) MAT2A protein expression ratio correlated with poor overall survival (5 year survival rate: 93.7% vs. 83.3%, C/N ratio ≥ 1.0 vs. C/N ratio < 1.0, log-rank p = 0.004). Accordingly, a MAT2A C/N expression ratio ≥ 1.0 was determined as an independent risk factor by Cox regression analysis (hazard ratio = 2.771, p = 0.018, n = 252). In vitro studies found that breast cancer cell lines with a higher MAT2A C/N ratio were more invasive. (4) Conclusions: the subcellular localization of MAT2A may affect its functions, and elevated MAT2A C/N ratio in breast cancer cells is associated with increased invasiveness. MAT2A C/N expression ratio determined by IHC staining could serve as a novel independent prognostic marker for breast cancer.
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41
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Niland CN, Ghosh A, Cahill SM, Schramm VL. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. Biochemistry 2021; 60:791-801. [PMID: 33656855 DOI: 10.1021/acs.biochem.0c00998] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
S-Adenosyl-l-methionine (AdoMet) is synthesized by the MAT2A isozyme of methionine adenosyltransferase in most human tissues and in cancers. Its contribution to epigenetic control has made it a target for anticancer intervention. A recent kinetic isotope effect analysis of MAT2A demonstrated a loose nucleophilic transition state. Here we show that MAT2A has a sequential mechanism with a rate-limiting step of formation of AdoMet, followed by rapid hydrolysis of the β-γ bond of triphosphate, and rapid release of phosphate and pyrophosphate. MAT2A catalyzes the slow hydrolysis of both ATP and triphosphate in the absence of other reactants. Positional isotope exchange occurs with 18O as the 5'-oxygen of ATP. Loss of the triphosphate is sufficiently reversible to permit rotation and recombination of the α-phosphoryl group of ATP. Adenosine (α-β or β-γ)-imido triphosphates are slow substrates, and the respective imido triphosphates are inhibitors. The hydrolytically stable (α-β, β-γ)-diimido triphosphate (PNPNP) is a nanomolar inhibitor. The MAT2A protein structure is highly stabilized against denaturation by binding of PNPNP. A crystal structure of MAT2A with 5'-methylthioadenosine and PNPNP shows the ligands arranged appropriately in the ATP binding site. Two magnesium ions chelate the α- and γ-phosphoryl groups of PNPNP. The β-phosphoryl oxygen is in contact with an essential potassium ion. Imidophosphate derivatives provide contact models for the design of catalytic site ligands for MAT2A.
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Affiliation(s)
- Courtney N Niland
- Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, United States
| | - Agnidipta Ghosh
- Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, United States
| | - Sean M Cahill
- Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, United States
| | - Vern L Schramm
- Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, United States
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42
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Xu D, Shao F, Bian X, Meng Y, Liang T, Lu Z. The Evolving Landscape of Noncanonical Functions of Metabolic Enzymes in Cancer and Other Pathologies. Cell Metab 2021; 33:33-50. [PMID: 33406403 DOI: 10.1016/j.cmet.2020.12.015] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Key pathological, including oncogenic, signaling pathways regulate the canonical functions of metabolic enzymes that serve the cellular metabolic needs. Importantly, these signaling pathways also confer a large number of metabolic enzymes to have noncanonical or nonmetabolic functions that are referred to as "moonlighting" functions. In this review, we highlight how aberrantly regulated metabolic enzymes with such activities play critical roles in the governing of a wide spectrum of instrumental cellular activities, including gene expression, cell-cycle progression, DNA repair, cell proliferation, survival, apoptosis, and tumor microenvironment remodeling, thereby promoting the pathologic progression of disease, including cancer.
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Affiliation(s)
- Daqian Xu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China
| | - Fei Shao
- The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, Shandong 266003, China
| | - Xueli Bian
- The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, Shandong 266003, China
| | - Ying Meng
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China
| | - Tingbo Liang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China
| | - Zhimin Lu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China; Zhejiang University Cancer Center, Hangzhou 310029, China.
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43
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Greco CM, Cervantes M, Fustin JM, Ito K, Ceglia N, Samad M, Shi J, Koronowski KB, Forne I, Ranjit S, Gaucher J, Kinouchi K, Kojima R, Gratton E, Li W, Baldi P, Imhof A, Okamura H, Sassone-Corsi P. S-adenosyl-l-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling. SCIENCE ADVANCES 2020; 6:eabc5629. [PMID: 33328229 PMCID: PMC7744083 DOI: 10.1126/sciadv.abc5629] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 10/30/2020] [Indexed: 05/03/2023]
Abstract
Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocysteinase (AHCY) cyclically associates to CLOCK-BMAL1 at chromatin sites and promotes circadian transcriptional activity. SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)-dependent methyltransferases, and timely hydrolysis of SAH by AHCY is critical to sustain methylation reactions. We show that AHCY is essential for cyclic H3K4 trimethylation, genome-wide recruitment of BMAL1 to chromatin, and subsequent circadian transcription. Depletion or targeted pharmacological inhibition of AHCY in mammalian cells markedly decreases the amplitude of circadian gene expression. In mice, pharmacological inhibition of AHCY in the hypothalamus alters circadian locomotor activity and rhythmic transcription within the suprachiasmatic nucleus. These results reveal a previously unappreciated connection between cellular metabolism, chromatin dynamics, and circadian regulation.
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Affiliation(s)
- Carolina Magdalen Greco
- Center for Epigenetics and Metabolism; U1233 INSERM; Department of Biological Chemistry, School of Medicine, University of California, Irvine (UCI), Irvine, CA, USA.
| | - Marlene Cervantes
- Center for Epigenetics and Metabolism; U1233 INSERM; Department of Biological Chemistry, School of Medicine, University of California, Irvine (UCI), Irvine, CA, USA
| | - Jean-Michel Fustin
- Graduate School of Pharmaceutical Sciences, Department of Systems Biology, Kyoto University, Kyoto 606-8501, Japan
| | - Kakeru Ito
- Graduate School of Pharmaceutical Sciences, Department of Systems Biology, Kyoto University, Kyoto 606-8501, Japan
| | - Nicholas Ceglia
- Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California Irvine (UCI), Irvine, CA, USA
| | - Muntaha Samad
- Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California Irvine (UCI), Irvine, CA, USA
| | - Jiejun Shi
- Department of Biological Chemistry, School of Medicine, University of California Irvine (UCI), Irvine, CA, USA
- Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Kevin Brian Koronowski
- Center for Epigenetics and Metabolism; U1233 INSERM; Department of Biological Chemistry, School of Medicine, University of California, Irvine (UCI), Irvine, CA, USA
| | - Ignasi Forne
- Biomedical Center, Protein Analysis Unit, Faculty of Medicine, Ludwig-Maximilians-Universität München, Großhaderner Strasse 9, 82152 Planegg-Martinsried, Germany
| | - Suman Ranjit
- Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California Irvine (UCI), Irvine, CA, USA
| | - Jonathan Gaucher
- Center for Epigenetics and Metabolism; U1233 INSERM; Department of Biological Chemistry, School of Medicine, University of California, Irvine (UCI), Irvine, CA, USA
| | - Kenichiro Kinouchi
- Center for Epigenetics and Metabolism; U1233 INSERM; Department of Biological Chemistry, School of Medicine, University of California, Irvine (UCI), Irvine, CA, USA
| | - Rika Kojima
- Graduate School of Pharmaceutical Sciences, Department of Systems Biology, Kyoto University, Kyoto 606-8501, Japan
| | - Enrico Gratton
- Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California Irvine (UCI), Irvine, CA, USA
| | - Wei Li
- Department of Biological Chemistry, School of Medicine, University of California Irvine (UCI), Irvine, CA, USA
- Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Pierre Baldi
- Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California Irvine (UCI), Irvine, CA, USA
| | - Axel Imhof
- Biomedical Center, Protein Analysis Unit, Faculty of Medicine, Ludwig-Maximilians-Universität München, Großhaderner Strasse 9, 82152 Planegg-Martinsried, Germany
| | - Hitoshi Okamura
- Graduate School of Pharmaceutical Sciences, Department of Systems Biology, Kyoto University, Kyoto 606-8501, Japan
| | - Paolo Sassone-Corsi
- Center for Epigenetics and Metabolism; U1233 INSERM; Department of Biological Chemistry, School of Medicine, University of California, Irvine (UCI), Irvine, CA, USA.
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44
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Yang Z, Jiang H. A chromatin perspective on metabolic and genotoxic impacts on hematopoietic stem and progenitor cells. Cell Mol Life Sci 2020; 77:4031-4047. [PMID: 32318759 PMCID: PMC7541408 DOI: 10.1007/s00018-020-03522-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/17/2020] [Accepted: 04/06/2020] [Indexed: 02/07/2023]
Abstract
Fate determination in self-renewal and differentiation of hematopoietic stem and progenitor cells (HSCs and HPCs) is ultimately controlled by gene expression, which is profoundly influenced by the global and local chromatin state. Cellular metabolism directly influences the chromatin state through the dynamic regulation of the enzymatic activities that modify DNA and histones, but also generates genotoxic metabolites that can damage DNA and thus pose threat to the genome integrity. On the other hand, mechanisms modulating the chromatin state impact metabolism by regulating the expression and activities of key metabolic enzymes. Moreover, through regulating either DNA damage response directly or expression of genes involved in this process, chromatin modulators play active and crucial roles in guarding the genome integrity, breaching of which results in defective HSPC function. Therefore, HSPC function is regulated by the dynamic and two-way interactions between metabolism and chromatin. Here, we review recent advances that provide a chromatin perspective on the major impacts the metabolic and genotoxic factors can have on HSPC function and fate determination.
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Affiliation(s)
- Zhenhua Yang
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Hao Jiang
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
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45
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Linnerbauer M, Wheeler MA, Quintana FJ. Astrocyte Crosstalk in CNS Inflammation. Neuron 2020; 108:608-622. [PMID: 32898475 DOI: 10.1016/j.neuron.2020.08.012] [Citation(s) in RCA: 538] [Impact Index Per Article: 107.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/12/2020] [Accepted: 08/14/2020] [Indexed: 12/22/2022]
Abstract
Astrocytes control multiple processes in the nervous system in health and disease. It is now clear that specific astrocyte subsets or activation states are associated with specific genomic programs and functions. The advent of novel genomic technologies has enabled rapid progress in the characterization of astrocyte heterogeneity and its control by astrocyte interactions with other cells in the central nervous system (CNS). In this review, we provide an overview of the multifaceted roles of astrocytes in the context of CNS inflammation, highlighting recent discoveries on astrocyte subsets and their regulation. We explore mechanisms of crosstalk between astrocytes and other cells in the CNS in the context of neuroinflammation and neurodegeneration and discuss how these interactions shape pathological outcomes.
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Affiliation(s)
- Mathias Linnerbauer
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Michael A Wheeler
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Francisco J Quintana
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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46
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Fourier N, Zolty M, Azriel A, Tedesco D, Levi BZ. MafK Mediates Chromatin Remodeling to Silence IRF8 Expression in Non-immune Cells in a Cell Type-SpecificManner. J Mol Biol 2020; 432:4544-4560. [PMID: 32534063 DOI: 10.1016/j.jmb.2020.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 06/02/2020] [Accepted: 06/05/2020] [Indexed: 11/17/2022]
Abstract
The regulation of gene expression is a result of a complex interplay between chromatin remodeling, transcription factors, and signaling molecules. Cell differentiation is accompanied by chromatin remodeling of specific loci to permanently silence genes that are not essential for the differentiated cell activity. The molecular cues that recruit the chromatin remodeling machinery are not well characterized. IRF8 is an immune-cell specific transcription factor and its expression is augmented by interferon-γ. Therefore, it serves as a model gene to elucidate the molecular mechanisms governing its silencing in non-immune cells. Ahigh-throughput shRNA library screen in IRF8 expression-restrictive cells enabled the identification of MafK as modulator of IRF8 silencing, affecting chromatin architecture. ChIP-Seq analysis revealed three MafK binding regions (-25 kb, -20 kb, and IRF8 6th intron) within the IRF8 locus. These MafK binding sites are sufficient to repress a reporter gene when cloned in genome-integrated lentiviral reporter constructs in only expression-restrictive cells. Conversely, plasmid-based constructs do not demonstrate such repressive effect. These results highlight the role of these MafK binding sites in mediating repressed chromatin assembly. Finally, a more thorough genomic analysis was performed, using CRISPR-Cas9 to delete MafK-int6 binding region in IRF8 expression-restrictive cells. Deleted clones exhibited an accessible chromatin conformation within the IRF8 locus that was accompanied by a significant increase in basal expression of IRF8 that was further induced by interferon-γ. Taken together, we identified and characterized several MafK binding elements within the IRF8 locus that mediate repressive chromatin conformation resulting in the silencing of IRF8 expression in a celltype-specific manner.
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Affiliation(s)
- Nitsan Fourier
- Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | - Maya Zolty
- Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | - Aviva Azriel
- Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | | | - Ben-Zion Levi
- Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
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47
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Portillo F, Vázquez J, Pajares MA. Protein-protein interactions involving enzymes of the mammalian methionine and homocysteine metabolism. Biochimie 2020; 173:33-47. [DOI: 10.1016/j.biochi.2020.02.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 02/20/2020] [Indexed: 12/16/2022]
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48
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Sun H, Kang J, Su J, Zhang J, Zhang L, Liu X, Zhang J, Wang F, Lu Z, Xing X, Chen H, Zhang Y. Methionine adenosyltransferase 2A regulates mouse zygotic genome activation and morula to blastocyst transition†. Biol Reprod 2020; 100:601-617. [PMID: 30265288 DOI: 10.1093/biolre/ioy194] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 07/26/2018] [Accepted: 09/26/2018] [Indexed: 01/02/2023] Open
Abstract
Methionine adenosyltransferase II (MAT2A) is essential to the synthesis of S-adenosylmethionine, a major methyl donor, from L-methionine and ATP. Upon fertilization, zygotic genome activation (ZGA) marks the period that transforms the genome from transcriptional quiescence to robust transcriptional activity. During this period, embryonic epigenome undergoes extensive modifications, including histone methylation changes. However, whether MAT2A participates in histone methylation at the ZGA stage is unknown. Herein, we identified that MAT2A is a pivotal factor for ZGA in mouse embryos. Mat2a knockdown exhibited 2-cell embryo arrest and reduced transcriptional activity but did not affect H3K4me2/3 and H3K9me2/3. When the cycloleucine, a selective inhibitor of MAT2A catalytic activity, was added to a culture medium, embryos were arrested at the morula stage in the same manner as the embryos cultured in an L-methionine-deficient medium. Under these two culture conditions, H3K4me3 levels of morula and blastocyst were much lower than those cultured under normal medium. Furthermore, cycloleucine treatment or methionine starvation apparently reduced the developmental potential of blastocysts. Thus, Mat2a is indispensable for ZGA and morula-to-blastocyst transition.
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Affiliation(s)
- Hongzheng Sun
- College of Veterinary Medicine, Northwest A&F University, Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Yangling, Shaanxi Province, China
| | - Jian Kang
- College of Veterinary Medicine, Northwest A&F University, Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Yangling, Shaanxi Province, China
| | - Jianmin Su
- College of Veterinary Medicine, Northwest A&F University, Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Yangling, Shaanxi Province, China
| | - Jinjing Zhang
- College of Veterinary Medicine, Northwest A&F University, Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Yangling, Shaanxi Province, China
| | - Lei Zhang
- College of Veterinary Medicine, Northwest A&F University, Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Yangling, Shaanxi Province, China
| | - Xin Liu
- College of Veterinary Medicine, Northwest A&F University, Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Yangling, Shaanxi Province, China
| | - Jingcheng Zhang
- College of Veterinary Medicine, Northwest A&F University, Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Yangling, Shaanxi Province, China
| | - Fengyu Wang
- College of Veterinary Medicine, Northwest A&F University, Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Yangling, Shaanxi Province, China
| | - Zhenzhen Lu
- College of Veterinary Medicine, Northwest A&F University, Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Yangling, Shaanxi Province, China
| | - Xupeng Xing
- College of Veterinary Medicine, Northwest A&F University, Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Yangling, Shaanxi Province, China
| | - HuanHuan Chen
- College of Veterinary Medicine, Northwest A&F University, Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Yangling, Shaanxi Province, China
| | - Yong Zhang
- College of Veterinary Medicine, Northwest A&F University, Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Yangling, Shaanxi Province, China
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49
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Haws SA, Yu D, Ye C, Wille CK, Nguyen LC, Krautkramer KA, Tomasiewicz JL, Yang SE, Miller BR, Liu WH, Igarashi K, Sridharan R, Tu BP, Cryns VL, Lamming DW, Denu JM. Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence. Mol Cell 2020; 78:210-223.e8. [PMID: 32208170 PMCID: PMC7191556 DOI: 10.1016/j.molcel.2020.03.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 02/05/2020] [Accepted: 02/28/2020] [Indexed: 12/12/2022]
Abstract
S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate epigenetic states and subsequent gene expression. This metabolism-epigenome link sensitizes chromatin methylation to altered SAM abundance, yet the mechanisms that allow organisms to adapt and protect epigenetic information during life-experienced fluctuations in SAM availability are unknown. We identified a robust response to SAM depletion that is highlighted by preferential cytoplasmic and nuclear mono-methylation of H3 Lys 9 (H3K9) at the expense of broad losses in histone di- and tri-methylation. Under SAM-depleted conditions, H3K9 mono-methylation preserves heterochromatin stability and supports global epigenetic persistence upon metabolic recovery. This unique chromatin response was robust across the mouse lifespan and correlated with improved metabolic health, supporting a significant role for epigenetic adaptation to SAM depletion in vivo. Together, these studies provide evidence for an adaptive response that enables epigenetic persistence to metabolic stress.
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Affiliation(s)
- Spencer A Haws
- Department of Biomolecular Chemistry, SMPH, University of Wisconsin-Madison, Madison, WI 53706, USA; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA
| | - Deyang Yu
- William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular & Environmental Toxicology Center, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Cunqi Ye
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Coral K Wille
- Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA
| | - Long C Nguyen
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Kimberly A Krautkramer
- Department of Biomolecular Chemistry, SMPH, University of Wisconsin-Madison, Madison, WI 53706, USA; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA
| | - Jay L Tomasiewicz
- William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA
| | - Shany E Yang
- William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Blake R Miller
- William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Wallace H Liu
- Department of Biomolecular Chemistry, SMPH, University of Wisconsin-Madison, Madison, WI 53706, USA; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA
| | - Kazuhiko Igarashi
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Rupa Sridharan
- Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Benjamin P Tu
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Vincent L Cryns
- Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular & Environmental Toxicology Center, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA; University of Wisconsin Carbone Cancer Center, Madison, WI 53792, USA
| | - Dudley W Lamming
- William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular & Environmental Toxicology Center, SMPH, University of Wisconsin-Madison, Madison, WI 53705, USA; University of Wisconsin Carbone Cancer Center, Madison, WI 53792, USA
| | - John M Denu
- Department of Biomolecular Chemistry, SMPH, University of Wisconsin-Madison, Madison, WI 53706, USA; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
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50
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Herr P, Boström J, Rullman E, Rudd SG, Vesterlund M, Lehtiö J, Helleday T, Maddalo G, Altun M. Cell Cycle Profiling Reveals Protein Oscillation, Phosphorylation, and Localization Dynamics. Mol Cell Proteomics 2020; 19:608-623. [PMID: 32051232 PMCID: PMC7124475 DOI: 10.1074/mcp.ra120.001938] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/07/2020] [Indexed: 11/06/2022] Open
Abstract
The cell cycle is a highly conserved process involving the coordinated separation of a single cell into two daughter cells. To relate transcriptional regulation across the cell cycle with oscillatory changes in protein abundance and activity, we carried out a proteome- and phospho-proteome-wide mass spectrometry profiling. We compared protein dynamics with gene transcription, revealing many transcriptionally regulated G2 mRNAs that only produce a protein shift after mitosis. Integration of CRISPR/Cas9 survivability studies further highlighted proteins essential for cell viability. Analyzing the dynamics of phosphorylation events and protein solubility dynamics over the cell cycle, we characterize predicted phospho-peptide motif distributions and predict cell cycle-dependent translocating proteins, as exemplified by the S-adenosylmethionine synthase MAT2A. Our study implicates this enzyme in translocating to the nucleus after the G1/S-checkpoint, which enables epigenetic histone methylation maintenance during DNA replication. Taken together, this data set provides a unique integrated resource with novel insights on cell cycle dynamics.
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Affiliation(s)
- Patrick Herr
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden; Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, S10 2RX Sheffield, England
| | - Johan Boström
- Science for Life Laboratory, Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Eric Rullman
- Science for Life Laboratory, Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Sean G Rudd
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden
| | - Mattias Vesterlund
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden
| | - Janne Lehtiö
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden
| | - Thomas Helleday
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden; Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, S10 2RX Sheffield, England
| | - Gianluca Maddalo
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Mikael Altun
- Science for Life Laboratory, Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
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