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Geiger LT, Balouek JAR, Barrett MR, Thompson JM, Fang LZ, Farrelly LA, Chen AS, Tang M, Bennett SN, Garcia BA, Maze I, Creed MC, Peña CJ. Early-life stress alters chromatin modifications in VTA to prime stress sensitivity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.03.14.584631. [PMID: 38559030 PMCID: PMC10980038 DOI: 10.1101/2024.03.14.584631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Early-life stress increases sensitivity to subsequent stress, which has been observed at behavioral, neural activity, and gene expression levels. However, the molecular mechanisms underlying such long-lasting sensitivity are poorly understood. We tested the hypothesis that persistent changes in transcription and transcriptional potential were maintained at the level of the epigenome, through changes in chromatin. We used a combination of bottom-up mass spectrometry, viral-mediated epigenome-editing, RNA-sequencing, patch clamp electrophysiology of dopamine neurons, and behavioral quantification in a mouse model of early-life stress, focusing on the ventral tegmental area (VTA), a dopaminergic brain region critically implicated in motivation, reward learning, stress response, and mood and drug disorders. We found that early-life stress alters histone dynamics in VTA, including enrichment of histone-3 lysine-4 monomethylation - associated with open chromatin and primed or active enhancers - and the H3K4 monomethylase Setd7. Mimicking early-life stress through postnatal overexpression of Setd7 and enrichment of H3K4me1 in VTA sensitizes transcriptional, physiological, and behavioral response to adult stress. These findings link early-life stress experience to long-term stress hypersensitivity within the brain's dopaminergic circuitry, providing a mechanism by which early-life stress increases risk for mood and anxiety disorders later in life.
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Manea SA, Vlad ML, Lazar AG, Muresian H, Simionescu M, Manea A. SET7 lysine methyltransferase mediates the up-regulation of NADPH oxidase expression, oxidative stress, and NLRP3 inflammasome priming in atherosclerosis. J Transl Med 2025; 23:339. [PMID: 40098010 PMCID: PMC11912627 DOI: 10.1186/s12967-025-06338-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 03/01/2025] [Indexed: 03/19/2025] Open
Abstract
BACKGROUND Dysregulation of histone methylation-based epigenetic mechanisms leads to either transient or long-lasting transcriptomic alterations in vascular and immune cells with important consequences on atherosclerotic plaque development and stability. We hypothesized that the epigenetic enzyme SET7 lysine methyltransferase contributes to the up-regulation of NADPH oxidase (Nox) and NLRP3 inflammasome expression in atherosclerosis. METHODS To test this hypothesis, we examined human non-atherosclerotic and atherosclerotic tissue samples, apolipoprotein E-deficient (ApoE-/-) mice, and human macrophages (Mac) employing real-time PCR, Western blot, immunofluorescence microscopy, and histological techniques. Male ApoE-/- mice with established atherosclerosis were randomized to receive concomitant with the high-fat diet, 5 mg/kg (R)-PFI-2, a selective SET7 pharmacological inhibitor, or its vehicle, every other day for 4 weeks. RESULTS The results revealed that SET7 mRNA and protein, and H3K4me1 levels were significantly elevated in human carotid atherosclerotic lesions, aorta of atherosclerotic mice, and in cultured pro-inflammatory Mac. In the atherosclerotic mice, pharmacological blockade of SET7 catalytic activity with the specific inhibitor, significantly reduced atherosclerotic plaque development, decreased the aortic up-regulation of mRNA and protein levels of Nox catalytic subunits, mitigated the formation of NT-/4HNE-protein adducts, attenuated NLRP3 gene and protein expression, and reduced pro-caspase-1 and pro-IL18 cleavage. In polarized pro-inflammatory human M1-Mac, SET7-oriented pharmacological intervention reduced the transcriptional up-regulation of Nox catalytic subunits, NLRP3, caspase-1, IL1β, and IL18, and the secretion IL1β and TNFα. Transient overexpression of SET7 in human endothelial cells enhanced mRNA levels of Nox1, Nox2, Nox4, Nox5, and p22phox. CONCLUSION The novel results show that SET7 regulates important mechanisms leading to enhanced formation of reactive oxygen species and pro-inflammatory cytokines release in atherosclerosis. The data recommend SET7 as a promising target for pharmacological interventions and as supportive therapeutic strategy in atherosclerotic cardiovascular diseases.
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Affiliation(s)
- Simona-Adriana Manea
- Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8, B.P. Hasdeu Street, Bucharest, 050568, Romania
| | - Mihaela-Loredana Vlad
- Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8, B.P. Hasdeu Street, Bucharest, 050568, Romania
| | - Alexandra-Gela Lazar
- Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8, B.P. Hasdeu Street, Bucharest, 050568, Romania
| | - Horia Muresian
- Cardiovascular Surgery Department, University Hospital Bucharest, Bucharest, Romania
| | - Maya Simionescu
- Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8, B.P. Hasdeu Street, Bucharest, 050568, Romania
| | - Adrian Manea
- Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8, B.P. Hasdeu Street, Bucharest, 050568, Romania.
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Mimura I, Chen Z, Natarajan R. Epigenetic alterations and memory: key players in the development/progression of chronic kidney disease promoted by acute kidney injury and diabetes. Kidney Int 2025; 107:434-456. [PMID: 39725223 DOI: 10.1016/j.kint.2024.10.031] [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: 02/25/2024] [Revised: 09/20/2024] [Accepted: 10/08/2024] [Indexed: 12/28/2024]
Abstract
Chronic kidney disease (CKD) is a highly prevalent global public health issue and can progress to kidney failure. Survivors of acute kidney injury (AKI) have an increased risk of progressing to CKD by 8.8-fold and kidney failure by 3.1-fold. Further, 20% to 40% of individuals with diabetes will develop CKD, also known as diabetic kidney disease (DKD). Thus, preventing these kidney diseases can positively impact quality-of-life and life-expectancy outcomes for affected individuals. Frequent episodes of hyperglycemia and renal hypoxia are implicated in the pathophysiology of CKD. Prior periods of hyperglycemia/uncontrolled diabetes can result in development/progression of DKD even after achieving normoglycemia, a phenomenon known as metabolic memory or legacy effect. Similarly, in AKI, hypoxic memory is stored in renal cells even after recovery from the initial AKI episode and can transition to CKD. Epigenetic mechanisms involving DNA methylation, chromatin histone post-translational modifications, and noncoding RNAs are implicated in both metabolic and hypoxic memory, collectively known as "epigenetic memory." This epigenetic memory is generally reversible and provides a therapeutic avenue to ameliorate persistent disease progression due to hyperglycemia and hypoxia and prevent/ameliorate CKD progression. Indeed, therapeutic strategies targeting epigenetic memory are effective at preventing CKD development/progression in experimental models of AKI and DKD. Here, we review the latest in-depth evidence for epigenetic features in DKD and AKI, and in epigenetic memories of AKI-to-CKD transition or DKD development and progression, followed by translational and clinical implications of these epigenetic changes for the treatment of these widespread kidney disorders.
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Affiliation(s)
- Imari Mimura
- Division of Nephrology and Endocrinology, the University of Tokyo School of Medicine, Tokyo Japan.
| | - Zhuo Chen
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, USA.
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Yang Y, Xie W, Qiao X, Yang J, Yao D, Zhu D. ZKSCAN5 activates LAPTM5 expression by recruiting SETD7 to promote metastasis in pancreatic ductal adenocarcinoma. Histol Histopathol 2024; 39:747-760. [PMID: 38018874 DOI: 10.14670/hh-18-678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2023]
Abstract
Lysosomal-associated transmembrane protein 5 (LAPTM5) has been associated with poor prognosis in cancer patients. Its role in regulating metastasis in pancreatic ductal adenocarcinoma (PDAC), however, remains vague. The study here aimed to expound the metastasis-promoting properties of LAPTM5 in PDAC and the detailed mechanism. LAPTM5 was overexpressed in metastatic PDAC cells and was related to the dismal prognosis of patients in GEO datasets. By using lentiviral vectors harboring short hairpin RNA, we found that LAPTM5 downregulation reduced PDAC cell viability, proliferation, and aggressiveness in vitro and liver metastasis in vivo. Zinc finger with KRAB and SCAN domains 5 (ZKSCAN5) was predicted and verified to mediate LAPTM5 transcription in PDAC cells. Both ZKSCAN5 and SET domains, containing lysine methyltransferase 7 (SETD7) bound to the LAPTM5 promoter, and ZKSCAN5 recruited SETD7 to form a complex promoting LAPTM5 transcription. LAPTM5 knockdown reversed the promoting effect of ZKSCAN5 on the metastasis of PDAC cells. Thus, our findings on the ZKSCAN5/SETD7/LAPTM5 axis provide insights into the underlying mechanism of liver metastasis dissemination in PDAC.
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Affiliation(s)
- Yong Yang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China
- Department of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Wei Xie
- Department of General Surgery, Jurong Hospital Affiliated to Jiangsu University, Zhenjiang, Jiangsu, PR China
| | - Xuan Qiao
- Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Jun Yang
- Department of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Dan Yao
- Department of Gastrointestinal Surgery, Huai'an Second People's Hospital, the Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, PR China
| | - Dongming Zhu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China.
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Talukdar PD, Chatterji U. Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases. Signal Transduct Target Ther 2023; 8:427. [PMID: 37953273 PMCID: PMC10641101 DOI: 10.1038/s41392-023-01651-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: 04/18/2023] [Revised: 08/27/2023] [Accepted: 09/10/2023] [Indexed: 11/14/2023] Open
Abstract
Specific cell states in metazoans are established by the symphony of gene expression programs that necessitate intricate synergic interactions between transcription factors and the co-activators. Deregulation of these regulatory molecules is associated with cell state transitions, which in turn is accountable for diverse maladies, including developmental disorders, metabolic disorders, and most significantly, cancer. A decade back most transcription factors, the key enablers of disease development, were historically viewed as 'undruggable'; however, in the intervening years, a wealth of literature validated that they can be targeted indirectly through transcriptional co-activators, their confederates in various physiological and molecular processes. These co-activators, along with transcription factors, have the ability to initiate and modulate transcription of diverse genes necessary for normal physiological functions, whereby, deregulation of such interactions may foster tissue-specific disease phenotype. Hence, it is essential to analyze how these co-activators modulate specific multilateral processes in coordination with other factors. The proposed review attempts to elaborate an in-depth account of the transcription co-activators, their involvement in transcription regulation, and context-specific contributions to pathophysiological conditions. This review also addresses an issue that has not been dealt with in a comprehensive manner and hopes to direct attention towards future research that will encompass patient-friendly therapeutic strategies, where drugs targeting co-activators will have enhanced benefits and reduced side effects. Additional insights into currently available therapeutic interventions and the associated constraints will eventually reveal multitudes of advanced therapeutic targets aiming for disease amelioration and good patient prognosis.
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Affiliation(s)
- Priyanka Dey Talukdar
- Cancer Research Laboratory, Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, 700019, West Bengal, India
| | - Urmi Chatterji
- Cancer Research Laboratory, Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, 700019, West Bengal, India.
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Scisciola L, Taktaz F, Fontanella RA, Pesapane A, Surina, Cataldo V, Ghosh P, Franzese M, Puocci A, Paolisso P, Rafaniello C, Marfella R, Rizzo MR, Barbato E, Vanderheyden M, Barbieri M. Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors. Cardiovasc Diabetol 2023; 22:24. [PMID: 36732760 PMCID: PMC9896756 DOI: 10.1186/s12933-023-01754-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 01/24/2023] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Sodium-glucose co-transporters (SGLT) inhibitors (SGLT2i) showed many beneficial effects at the cardiovascular level. Several mechanisms of action have been identified. However, no data on their capability to act via epigenetic mechanisms were reported. Therefore, this study aimed to investigate the ability of SGLT2 inhibitors (SGLT2i) to induce protective effects at the cardiovascular level by acting on DNA methylation. METHODS To better clarify this issue, the effects of empagliflozin (EMPA) on hyperglycemia-induced epigenetic modifications were evaluated in human ventricular cardiac myoblasts AC16 exposed to hyperglycemia for 7 days. Therefore, the effects of EMPA on DNA methylation of NF-κB, SOD2, and IL-6 genes in AC16 exposed to high glucose were analyzed by pyrosequencing-based methylation analysis. Modifications of gene expression and DNA methylation of NF-κB and SOD2 were confirmed in response to a transient SGLT2 gene silencing in the same cellular model. Moreover, chromatin immunoprecipitation followed by quantitative PCR was performed to evaluate the occupancy of TET2 across the investigated regions of NF-κB and SOD2 promoters. RESULTS Seven days of high glucose treatment induced significant demethylation in the promoter regions of NF-kB and SOD2 with a consequent high level in mRNA expression of both genes. The observed DNA demethylation was mediated by increased TET2 expression and binding to the CpGs island in the promoter regions of analyzed genes. Indeed, EMPA prevented the HG-induced demethylation changes by reducing TET2 binding to the investigated promoter region and counteracted the altered gene expression. The transient SGLT2 gene silencing prevented the DNA demethylation observed in promoter regions, thus suggesting a role of SGLT2 as a potential target of the anti-inflammatory and antioxidant effect of EMPA in cardiomyocytes. CONCLUSIONS In conclusion, our results demonstrated that EMPA, mainly acting on SGLT2, prevented DNA methylation changes induced by high glucose and provided evidence of a new mechanism by which SGLT2i can exert cardio-beneficial effects.
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Affiliation(s)
- Lucia Scisciola
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Fatemeh Taktaz
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Rosaria Anna Fontanella
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Ada Pesapane
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Surina
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Vittoria Cataldo
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Puja Ghosh
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Martina Franzese
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Armando Puocci
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Pasquale Paolisso
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
- Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium
| | - Concetta Rafaniello
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
- Mediterranea Cardiocentro, Naples, Italy
| | - Maria Rosaria Rizzo
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Emanuele Barbato
- Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy
| | | | - Michelangela Barbieri
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
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7
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Yang S, Wang X, Bai J, Duan B. The role of SET domain containing lysine methyltransferase 7 in tumorigenesis and development. Cell Cycle 2023; 22:269-275. [PMID: 36101480 PMCID: PMC9851238 DOI: 10.1080/15384101.2022.2122257] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 04/22/2022] [Accepted: 09/05/2022] [Indexed: 01/22/2023] Open
Abstract
SET domain containing lysine methyltransferase 7 (SETD7) belongs to the protein lysine methyltransferase family and can catalyze the monomethylation of histone H3K4, which plays a vital role in the regulation of cell cycle, cell differentiation, DNA damage response and chromatin remodeling through K/R-S/T-K (K is lysine residue) sites and the recognition of substrates mediated by SET, i-SET, and n-SET domains and electrostatic action. SETD7 also can regulate the transcription of several genes including β-catenin, Cullin l and lin-28 homolog A (LIN28A), etc. In addition, the abnormal expression of SETD7 can promote the proliferation, migration, invasion of tumor cells, predict the poor prognosis of tumor patients, and may be a potential target for tumor therapy. This paper reviews the structure of SETD7, its role in tumor genesis and development, and the current research progress of relevant targeted drugs to explore its regulatory mechanism in tumor genesis and development and the prospect of targeted therapy.
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Affiliation(s)
- Shangzhen Yang
- Department of Medical Oncology of Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
- Xi’an Medical University, Xi’an, Shaanxi, China
| | - Xi Wang
- Department of Medical Oncology of Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
| | - Jun Bai
- Department of Medical Oncology of Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
| | - Baojun Duan
- Department of Medical Oncology of Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
- Department of Medical Oncology of Baoji Central Hospital, Baoji Central Hospital, Baoji, Shaanxi, China
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8
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Set7 methyltransferase roles in myocardial protection from chronic stressors. Clin Sci (Lond) 2023; 137:105-108. [PMID: 36601782 DOI: 10.1042/cs20220773] [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: 12/13/2022] [Revised: 12/20/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023]
Abstract
Epigenome changes in chronic states of cardiovascular stress including diabetes, pressure overload and cardiomyopathies frequently involve changes in open chromatin and post-translation modifications of histone lysine residues at specific amino acid positions by acetylation, methylation and phosphorylation. Since the discovery of Set7 as an important regulator of histone H3 lysine 4 methylation state, there has been wide interest in its role in cardiovascular remodeling and cardiac dysfunction. Recent transcriptome and Fourier transform infrared spectroscopy analyses and in vivo assessments of cardiac function by Lunardon and colleagues now reveal a clear role of Set7 in the regulation of the extracellular matrix composition and cardiac hypertrophy in response to chronic isoproterenol induced cardiac stress.
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Zhang F, Duan B, Zhou Z, Han L, Huang P, Ye Y, Wang Q, Huang F, Li J. Integration of metabolomics and transcriptomics to reveal anti-chronic myocardial ischemia mechanism of Gualou Xiebai decoction. JOURNAL OF ETHNOPHARMACOLOGY 2022; 297:115530. [PMID: 35830899 DOI: 10.1016/j.jep.2022.115530] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 07/05/2022] [Accepted: 07/07/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Gualou Xiebai decoction (GLXB), a well-known classic traditional Chinese medicine formula, is a recorded and proven therapy for the management of cardiac diseases. However, its pharmacological characteristics and mechanism of action are unclear. MATERIALS AND METHODS The effects of GLXB and its mechanism of action in an isoprenaline-induced rat model of chronic myocardial ischemia (CMI) were investigated by incorporating metabonomics and transcriptomics. Meanwhile, the echocardiographic evaluation, histopathological analysis, serum biochemistry assay, TUNEL assay and western blot analysis were detected to revealed the protective effects of GLXB on CMI. RESULTS The results of echocardiographic evaluation, histopathological analysis and serum biochemistry assay revealed that GLXB had a significantly cardioprotective performance by reversing echocardiographic abnormalities, restoring pathological disorders and converting the serum biochemistry perturbations. Further, the omics analysis indicated that many genes and metabolites were regulated after modeling and GLXB administration, and maintained the marked "high-low" or "low-high" trends. Meanwhile, the results from integrated bioinformatics analysis suggested that the interaction network mainly consisted of amino acid and organic acid metabolism. The results of TUNEL assay and western blot analysis complemented the findings of integrated analysis of metabolomics and transcriptomics. CONCLUSION These findings suggested that GLXB has a curative effect in isoproterenol-induced CMI in rats. Integrated analysis based on transcriptomics and metabolomics studies revealed that the mechanism of GLXB in alleviating CMI was principally by the regulation of energy homeostasis and apoptosis, which was through a multi-component and multi-target treatment modality.
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Affiliation(s)
- Fengyun Zhang
- Pharmacy School, Hubei University of Chinese Medicine, Wuhan, 430065, China; Key Laboratory of Traditional Chinese Medicine Resource and Prescription, Ministry of Education, Wuhan, Hubei, 430061, China
| | - Bailu Duan
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China.
| | - Zhenxiang Zhou
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Lintao Han
- Pharmacy School, Hubei University of Chinese Medicine, Wuhan, 430065, China; Key Laboratory of Traditional Chinese Medicine Resource and Prescription, Ministry of Education, Wuhan, Hubei, 430061, China
| | - Ping Huang
- Key Laboratory of Traditional Chinese Medicine Resource and Prescription, Ministry of Education, Wuhan, Hubei, 430061, China; College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Yan Ye
- Pharmacy School, Hubei University of Chinese Medicine, Wuhan, 430065, China; Key Laboratory of Traditional Chinese Medicine Resource and Prescription, Ministry of Education, Wuhan, Hubei, 430061, China
| | - Qiong Wang
- Key Laboratory of Traditional Chinese Medicine Resource and Prescription, Ministry of Education, Wuhan, Hubei, 430061, China; College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Fang Huang
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Jingjing Li
- College of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China.
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Usher ET, Showalter SA. Biophysical insights into glucose-dependent transcriptional regulation by PDX1. J Biol Chem 2022; 298:102623. [PMID: 36272648 PMCID: PMC9691942 DOI: 10.1016/j.jbc.2022.102623] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/22/2022] Open
Abstract
The pancreatic and duodenal homeobox 1 (PDX1) is a central regulator of glucose-dependent transcription of insulin in pancreatic β cells. PDX1 transcription factor activity is integral to the development and sustained health of the pancreas; accordingly, deciphering the complex network of cellular cues that lead to PDX1 activation or inactivation is an important step toward understanding the etiopathologies of pancreatic diseases and the development of novel therapeutics. Despite nearly 3 decades of research into PDX1 control of Insulin expression, the molecular mechanisms that dictate the function of PDX1 in response to glucose are still elusive. The transcriptional activation functions of PDX1 are regulated, in part, by its two intrinsically disordered regions, which pose a barrier to its structural and biophysical characterization. Indeed, many studies of PDX1 interactions, clinical mutations, and posttranslational modifications lack molecular level detail. Emerging methods for the quantitative study of intrinsically disordered regions and refined models for transactivation now enable us to validate and interrogate the biochemical and biophysical features of PDX1 that dictate its function. The goal of this review is to summarize existing PDX1 studies and, further, to generate a comprehensive resource for future studies of transcriptional control via PDX1.
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Affiliation(s)
- Emery T Usher
- Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Scott A Showalter
- Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, USA; Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania, USA.
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11
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Gorica E, Mohammed SA, Ambrosini S, Calderone V, Costantino S, Paneni F. Epi-Drugs in Heart Failure. Front Cardiovasc Med 2022; 9:923014. [PMID: 35911511 PMCID: PMC9326055 DOI: 10.3389/fcvm.2022.923014] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/17/2022] [Indexed: 11/13/2022] Open
Abstract
Unveiling the secrets of genome's flexibility does not only foster new research in the field, but also gives rise to the exploration and development of novel epigenetic-based therapies as an approach to alleviate disease phenotypes. A better understanding of chromatin biology (DNA/histone complexes) and non-coding RNAs (ncRNAs) has enabled the development of epigenetic drugs able to modulate transcriptional programs implicated in cardiovascular diseases. This particularly applies to heart failure, where epigenetic networks have shown to underpin several pathological features, such as left ventricular hypertrophy, fibrosis, cardiomyocyte apoptosis and microvascular dysfunction. Targeting epigenetic signals might represent a promising approach, especially in patients with heart failure with preserved ejection fraction (HFpEF), where prognosis remains poor and breakthrough therapies have yet to be approved. In this setting, epigenetics can be employed for the development of customized therapeutic approaches thus paving the way for personalized medicine. Even though the beneficial effects of epi-drugs are gaining attention, the number of epigenetic compounds used in the clinical practice remains low suggesting that more selective epi-drugs are needed. From DNA-methylation changes to non-coding RNAs, we can establish brand-new regulations for drug targets with the aim of restoring healthy epigenomes and transcriptional programs in the failing heart. In the present review, we bring the timeline of epi-drug discovery and development, thus highlighting the emerging role of epigenetic therapies in heart failure.
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Affiliation(s)
- Era Gorica
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | - Shafeeq A. Mohammed
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | - Samuele Ambrosini
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | | | - Sarah Costantino
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Cardiology, University Heart Center, Zurich, Switzerland
| | - Francesco Paneni
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Cardiology, University Heart Center, Zurich, Switzerland
- Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
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12
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Studying Epigenetics of Cardiovascular Diseases on Chip Guide. CARDIOGENETICS 2022. [DOI: 10.3390/cardiogenetics12030021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Epigenetics is defined as the study of inheritable changes in the gene expressions and phenotypes that occurs without altering the normal DNA sequence. These changes are mainly due to an alteration in chromatin or its packaging, which changes the DNA accessibility. DNA methylation, histone modification, and noncoding or microRNAs can best explain the mechanism of epigenetics. There are various DNA methylated enzymes, histone-modifying enzymes, and microRNAs involved in the cause of various CVDs (cardiovascular diseases) such as cardiac hypertrophy, heart failure, and hypertension. Moreover, various CVD risk factors such as diabetes mellitus, hypoxia, aging, dyslipidemia, and their epigenetics are also discussed together with CVDs such as CHD (coronary heart disease) and PAH (pulmonary arterial hypertension). Furthermore, different techniques involved in epigenetic chromatin mapping are explained. Among these techniques, the ChIP-on-chip guide is explained with regard to its role in cardiac hypertrophy, a final form of heart failure. This review focuses on different epigenetic factors that are involved in causing cardiovascular diseases.
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Chiang C, Yang H, Zhu L, Chen C, Chen C, Zuo Y, Zheng D. The Epigenetic Regulation of Nonhistone Proteins by SETD7: New Targets in Cancer. Front Genet 2022; 13:918509. [PMID: 35812730 PMCID: PMC9256981 DOI: 10.3389/fgene.2022.918509] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/27/2022] [Indexed: 11/23/2022] Open
Abstract
Epigenetic modifications are essential mechanism by which to ensure cell homeostasis. One such modification is lysine methylation of nonhistone proteins by SETD7, a mono-methyltransferase containing SET domains. SETD7 methylates over 30 proteins and is thus involved in various classical pathways. As such, SETD7 has been implicated in both the basic functions of normal tissues but also in several pathologies, such as cancers. In this review, we summarize the current knowledge of SETD7 substrates, especially transcriptional-related proteins and enzymes, and their putative roles upon SETD7-mediated methylation. We focus on the role of SETD7 in cancers, and speculate on the possible points of intervention and areas for future research.
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Affiliation(s)
- Chengyao Chiang
- Southern University of Science and Technology, Yantian Hospital, Shenzhen, China
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Cell Biology and Genetics, Department of Pharmacy, Shenzhen University International Cancer Center, School of Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital (Shenzhen Institute of Translational Medicine), Shenzhen University, Shenzhen, China
| | - Heng Yang
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Cell Biology and Genetics, Department of Pharmacy, Shenzhen University International Cancer Center, School of Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital (Shenzhen Institute of Translational Medicine), Shenzhen University, Shenzhen, China
| | - Lizhi Zhu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Cell Biology and Genetics, Department of Pharmacy, Shenzhen University International Cancer Center, School of Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital (Shenzhen Institute of Translational Medicine), Shenzhen University, Shenzhen, China
| | - Chunlan Chen
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Cell Biology and Genetics, Department of Pharmacy, Shenzhen University International Cancer Center, School of Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital (Shenzhen Institute of Translational Medicine), Shenzhen University, Shenzhen, China
| | - Cheng Chen
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Cell Biology and Genetics, Department of Pharmacy, Shenzhen University International Cancer Center, School of Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital (Shenzhen Institute of Translational Medicine), Shenzhen University, Shenzhen, China
| | - You Zuo
- Southern University of Science and Technology, Yantian Hospital, Shenzhen, China
- *Correspondence: You Zuo, ; Duo Zheng,
| | - Duo Zheng
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Cell Biology and Genetics, Department of Pharmacy, Shenzhen University International Cancer Center, School of Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital (Shenzhen Institute of Translational Medicine), Shenzhen University, Shenzhen, China
- *Correspondence: You Zuo, ; Duo Zheng,
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14
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Keating ST, El-Osta A. Metaboloepigenetics in cancer, immunity and cardiovascular disease. Cardiovasc Res 2022; 119:357-370. [PMID: 35389425 PMCID: PMC10064843 DOI: 10.1093/cvr/cvac058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 01/12/2022] [Accepted: 02/02/2022] [Indexed: 11/14/2022] Open
Abstract
The influence of cellular metabolism on epigenetic pathways are well documented but misunderstood. Scientists have long known of the metabolic impact on epigenetic determinants. More often than not, that title role for DNA methylation was portrayed by the metabolite SAM or S-adenosylmethionine. Technically speaking there are many other metabolites that drive epigenetic processes that instruct seemingly distant - yet highly connect pathways - and none more so than our understanding of the cancer epigenome. Recent studies have shown that available energy link the extracellular environment to influence cellular responses. This focused review examines the recent interest in epigenomics and casts cancer, metabolism and immunity in unfamiliar roles - cooperating. There are not only language lessons from cancer research, we have come round to appreciate that reaching into areas previously thought of as too distinct are also object lessons in understanding health and disease. The Warburg effect is one such signature of how glycolysis influences metabolic shift during oncogenesis. That shift in metabolism - now recognised as central to proliferation in cancer biology - influence core enzymes that not only control gene expression but are also central to replication, condensation and the repair of nucleic acid. These nuclear processes rely on metabolism and with glucose at center stage the role of respiration and oxidative metabolism are now synonymous with the mitochondria as the powerhouses of metaboloepigenetics. The emerging evidence for metaboloepigenetics in trained innate immunity has revealed recognisable signalling pathways with antecedent extracellular stimulation. With due consideration to immunometabolism we discuss the striking signalling similarities influencing these core pathways. The immunometabolic-epigenetic axis in cardiovascular disease has deeply etched connections with inflammation and we examine the chromatin template as a carrier of epigenetic indices that determine the expression of genes influencing atherosclerosis and vascular complications of diabetes.
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Affiliation(s)
- Samuel T Keating
- Department of Biology, University of Copenhagen, Copenhagen DK-2200, Denmark
| | - Assam El-Osta
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia.,Epigenetics in Human Health and Disease Laboratory, Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR.,Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, 3/F Lui Che Woo Clinical Sciences Building, 30-32 Ngan Shing Street, Sha Tin, Hong Kong SAR.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR.,University College Copenhagen, Faculty of Health, Department of Technology, Biomedical Laboratory Science, Copenhagen, Denmark
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15
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Liu Z, Chen B, Chang J, Feng L, Zhao X. Melatonin regulates trophoblast pyroptosis, invasion and migration in preeclampsia by inhibiting HtrA1 transcription through the microRNA-520c-3p/SETD7 axis. Am J Reprod Immunol 2022; 87:e13523. [PMID: 35137483 DOI: 10.1111/aji.13523] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 01/16/2022] [Accepted: 01/31/2022] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Melatonin has an inhibitory effect on preeclampsia (PE). This study was launched to explore the way that melatonin regulated trophoblast migration, invasion, and pyroptosis in PE and to provide new ideas for the diagnosis and treatment of PE. METHODS Expression levels of melatonin receptors (MT1 and MT2), microRNA (miR)-520c-3p, SETD7, and HtrA1 in placental tissues and HTR8/SVneo cells were measured by RT-qPCR and Western blot. Scratch, Transwell, and Western blot assays were performed to detect migration, invasion, and pyroptosis of hypoxia/reoxygenation (H/R)-treated HTR8/SVneo cells. Dual-luciferase reporter assay was utilized to verify the targeting relationship between miR-520c-3p and SETD7. ChIP experiment was conducted to detect the enrichment of H3K4me3 and SETD7 in HtrA1 promoter. RESULTS Low expression of MT1, MT2, and miR-520c-3p and high expression of SETD7 and HtrA1 were observed in the placental tissues of PE patients and H/R-treated HTR8/Svneo cells. A high concentration of melatonin promoted migration and invasion and inhibited pyroptosis of PE cell models. Knockdown of miR-520c-3p, overexpression of SETD7, or overexpression of HtrA1 impaired migration and invasion and accelerated pyroptosis of H/R-treated HTR8/SVneo cells, but these outcomes could be reversed by treatment with 1000 μM melatonin. miR-520c-3p targeted SETD7 which promoted histone methylation in the promoter region of HtrA1. CONCLUSION Melatonin may inhibit HtrA1 transcription through the miR-520c-3p/SETD7 axis to promote trophoblast invasion and migration and reduce trophoblast pyroptosis in PE.
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Affiliation(s)
- Zhaochun Liu
- Department of Obstetrics, the First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, P.R. China
| | - Bin Chen
- Department of Obstetrics, the First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, P.R. China
| | - Jing Chang
- Department of Obstetrics, the First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, P.R. China
| | - Lulu Feng
- Department of Obstetrics, the First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, P.R. China
| | - Xia Zhao
- Department of Obstetrics, the First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, P.R. China
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16
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Pan S, Cesarek M, Godoy C, Co CM, Schindler C, Padilla K, Haskell A, Barreda H, Story C, Poole R, Dabney A, Gregory CA. Morpholino-driven blockade of Dkk-1 in osteosarcoma inhibits bone damage and tumour expansion by multiple mechanisms. Br J Cancer 2022; 127:43-55. [PMID: 35277659 PMCID: PMC9276700 DOI: 10.1038/s41416-022-01764-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 02/02/2022] [Accepted: 02/15/2022] [Indexed: 11/09/2022] Open
Abstract
Abstract
Background
Osteosarcoma (OS) is the most common primary bone malignancy. Chemotherapy plays an essential role in OS treatment, potentially doubling 5-year event-free survival if tumour necrosis can be stimulated. The canonical Wnt inhibitor Dickkopf-1 (Dkk-1) enhances OS survival in part through upregulation of aldehyde-dehydrogenase-1A1 which neutralises reactive oxygen species originating from nutritional stress and chemotherapeutic challenge.
Methods
A vivo morpholino (DkkMo) was employed to block the expression of Dkk-1 in OS cells. Cell mitosis, gene expression and bone destruction were measured in vitro and in vivo in the presence and absence of doxorubicin (DRB).
Results
DkkMo reduced the expression of Dkk-1 and Aldh1a1, reduced expansion of OS tumours, preserved bone volume and architecture and stimulated tumour necrosis. This was observed in the presence or absence of DRB.
Conclusion
These results indicate that administration of DkkMo with or without chemotherapeutics can substantially improve OS outcome with respect to tumour expansion and osteolytic corruption of bone in experimental OS model.
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17
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Daks A, Vasileva E, Fedorova O, Shuvalov O, Barlev NA. The Role of Lysine Methyltransferase SET7/9 in Proliferation and Cell Stress Response. Life (Basel) 2022; 12:life12030362. [PMID: 35330113 PMCID: PMC8949485 DOI: 10.3390/life12030362] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/25/2022] [Accepted: 02/26/2022] [Indexed: 12/14/2022] Open
Abstract
Lysine-specific methyltransferase 7 (KMT7) SET7/9, aka Set7, Set9, or SetD7, or KMT5 was discovered 20 years ago, yet its biological role remains rather enigmatic. In this review, we analyze the particularities of SET7/9 enzymatic activity and substrate specificity with respect to its biological importance, mostly focusing on its two well-characterized biological functions: cellular proliferation and stress response.
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Affiliation(s)
- Alexandra Daks
- Institute of Cytology RAS, 194064 St. Petersburg, Russia; (A.D.); (E.V.); (O.F.); (O.S.)
| | - Elena Vasileva
- Institute of Cytology RAS, 194064 St. Petersburg, Russia; (A.D.); (E.V.); (O.F.); (O.S.)
- Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA
| | - Olga Fedorova
- Institute of Cytology RAS, 194064 St. Petersburg, Russia; (A.D.); (E.V.); (O.F.); (O.S.)
| | - Oleg Shuvalov
- Institute of Cytology RAS, 194064 St. Petersburg, Russia; (A.D.); (E.V.); (O.F.); (O.S.)
| | - Nickolai A. Barlev
- Institute of Cytology RAS, 194064 St. Petersburg, Russia; (A.D.); (E.V.); (O.F.); (O.S.)
- Correspondence:
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18
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Yang Y, Luan Y, Feng Q, Chen X, Qin B, Ren KD, Luan Y. Epigenetics and Beyond: Targeting Histone Methylation to Treat Type 2 Diabetes Mellitus. Front Pharmacol 2022; 12:807413. [PMID: 35087408 PMCID: PMC8788853 DOI: 10.3389/fphar.2021.807413] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/24/2021] [Indexed: 12/30/2022] Open
Abstract
Diabetes mellitus is a global public health challenge with high morbidity. Type 2 diabetes mellitus (T2DM) accounts for 90% of the global prevalence of diabetes. T2DM is featured by a combination of defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. However, the pathogenesis of this disease is complicated by genetic and environmental factors, which needs further study. Numerous studies have demonstrated an epigenetic influence on the course of this disease via altering the expression of downstream diabetes-related proteins. Further studies in the field of epigenetics can help to elucidate the mechanisms and identify appropriate treatments. Histone methylation is defined as a common histone mark by adding a methyl group (-CH3) onto a lysine or arginine residue, which can alter the expression of downstream proteins and affect cellular processes. Thus, in tthis study will discuss types and functions of histone methylation and its role in T2DM wilsed. We will review the involvement of histone methyltransferases and histone demethylases in the progression of T2DM and analyze epigenetic-based therapies. We will also discuss the potential application of histone methylation modification as targets for the treatment of T2DM.
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Affiliation(s)
- Yang Yang
- Department of Translational Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ying Luan
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Qi Feng
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
| | - Xing Chen
- Department of Translational Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bo Qin
- Department of Translational Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kai-Di Ren
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Yi Luan
- Department of Translational Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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19
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Daks A, Shuvalov O, Fedorova O, Petukhov A, Lezina L, Zharova A, Baidyuk E, Khudiakov A, Barlev NA. p53-Independent Effects of Set7/9 Lysine Methyltransferase on Metabolism of Non-Small Cell Lung Cancer Cells. Front Oncol 2021; 11:706668. [PMID: 34692483 PMCID: PMC8528242 DOI: 10.3389/fonc.2021.706668] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 09/14/2021] [Indexed: 11/13/2022] Open
Abstract
Set7/9 is a lysine-specific methyltransferase, which regulates the functioning of both the histone and non-histone substrates, thereby significantly affecting the global gene expression landscape. Using microarray expression profiling, we have identified several key master regulators of metabolic networks, including c-Myc, that were affected by Set7/9 status. Consistent with this observation, c-Myc transcriptional targets-genes encoding the glycolytic enzymes hexokinase (HK2), aldolase (ALDOB), and lactate dehydrogenase (LDHA)-were upregulated upon Set7/9 knockdown (Set7/9KD). Importantly, we showed the short hairpin RNA (shRNA)-mediated attenuation of Set7/9 augmented c-Myc, GLUT1, HK2, ALDOA, and LDHA expression in non-small cell lung cancer (NSCLC) cell lines, not only at the transcriptional but also at the protein level. In line with this observation, Set7/9KD significantly augmented the membrane mitochondrial potential (MMP), glycolysis, respiration, and the proliferation rate of NSCLC cells. Importantly, all these effects of Set7/9 on cell metabolism were p53-independent. Bioinformatic analysis has shown a synergistic impact of Set7/9 together with either GLUT1, HIF1A, HK2, or LDHA on the survival of lung cancer patients. Based on these evidence, we hypothesize that Set7/9 can be an important regulator of energy metabolism in NSCLC.
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Affiliation(s)
- Alexandra Daks
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia
| | - Oleg Shuvalov
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia
| | - Olga Fedorova
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia
| | - Alexey Petukhov
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia.,Institute of Molecular Biology and Genetics, Almazov National Medical Research Centre, St Petersburg, Russia
| | - Larissa Lezina
- Regulation of Cell Signaling Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Arsenia Zharova
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia
| | - Ekaterina Baidyuk
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia
| | - Alexander Khudiakov
- Institute of Molecular Biology and Genetics, Almazov National Medical Research Centre, St Petersburg, Russia
| | - Nickolai A Barlev
- Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia.,Regulation of Cell Signaling Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
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20
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Masi S, Ambrosini S, Mohammed SA, Sciarretta S, Lüscher TF, Paneni F, Costantino S. Epigenetic Remodeling in Obesity-Related Vascular Disease. Antioxid Redox Signal 2021; 34:1165-1199. [PMID: 32808539 DOI: 10.1089/ars.2020.8040] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Significance: The prevalence of obesity and cardiometabolic phenotypes is alarmingly increasing across the globe and is associated with atherosclerotic vascular complications and high mortality. In spite of multifactorial interventions, vascular residual risk remains high in this patient population, suggesting the need for breakthrough therapies. The mechanisms underpinning obesity-related vascular disease remain elusive and represent an intense area of investigation. Recent Advances: Epigenetic modifications-defined as environmentally induced chemical changes of DNA and histones that do not affect DNA sequence-are emerging as a potent modulator of gene transcription in the vasculature and might significantly contribute to the development of obesity-induced endothelial dysfunction. DNA methylation and histone post-translational modifications cooperate to build complex epigenetic signals, altering transcriptional networks that are implicated in redox homeostasis, mitochondrial function, vascular inflammation, and perivascular fat homeostasis in patients with cardiometabolic disturbances. Critical Issues: Deciphering the epigenetic landscape in the vasculature is extremely challenging due to the complexity of epigenetic signals and their function in regulating transcription. An overview of the most important epigenetic pathways is required to identify potential molecular targets to treat or prevent obesity-related endothelial dysfunction and atherosclerotic disease. This would enable the employment of precision medicine approaches in this setting. Future Directions: Current and future research efforts in this field entail a better definition of the vascular epigenome in obese patients as well as the unveiling of novel, cell-specific chromatin-modifying drugs that are able to erase specific epigenetic signals that are responsible for maladaptive transcriptional alterations and vascular dysfunction in obese patients. Antioxid. Redox Signal. 34, 1165-1199.
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Affiliation(s)
- Stefano Masi
- Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Pisa, Italy
| | - Samuele Ambrosini
- Center for Molecular Cardiology, University of Zürich, Zurich, Switzerland
| | - Shafeeq A Mohammed
- Center for Molecular Cardiology, University of Zürich, Zurich, Switzerland
| | - Sebastiano Sciarretta
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.,Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zürich, Zurich, Switzerland.,Heart Division, Royal Brompton and Harefield Hospital Trust, National Heart & Lung Institute, Imperial College, London, United Kingdom
| | - Francesco Paneni
- Center for Molecular Cardiology, University of Zürich, Zurich, Switzerland.,Department of Cardiology, University Heart Center, University Hospital Zurich, Switzerland.,Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
| | - Sarah Costantino
- Center for Molecular Cardiology, University of Zürich, Zurich, Switzerland
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21
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Keating ST, Groh L, van der Heijden CDCC, Rodriguez H, Dos Santos JC, Fanucchi S, Okabe J, Kaipananickal H, van Puffelen JH, Helder L, Noz MP, Matzaraki V, Li Y, de Bree LCJ, Koeken VACM, Moorlag SJCFM, Mourits VP, Domínguez-Andrés J, Oosting M, Bulthuis EP, Koopman WJH, Mhlanga M, El-Osta A, Joosten LAB, Netea MG, Riksen NP. The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by β-Glucan. Cell Rep 2021; 31:107548. [PMID: 32320649 PMCID: PMC7184679 DOI: 10.1016/j.celrep.2020.107548] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 01/31/2020] [Accepted: 03/31/2020] [Indexed: 12/25/2022] Open
Abstract
Trained immunity confers a sustained augmented response of innate immune cells to a secondary challenge, via a process dependent on metabolic and transcriptional reprogramming. Because of its previous associations with metabolic and transcriptional memory, as well as the importance of H3 histone lysine 4 monomethylation (H3K4me1) to innate immune memory, we hypothesize that the Set7 methyltransferase has an important role in trained immunity induced by β-glucan. Using pharmacological studies of human primary monocytes, we identify trained immunity-specific immunometabolic pathways regulated by Set7, including a previously unreported H3K4me1-dependent plasticity in the induction of oxidative phosphorylation. Recapitulation of β-glucan training in vivo additionally identifies Set7-dependent changes in gene expression previously associated with the modulation of myelopoiesis progenitors in trained immunity. By revealing Set7 as a key regulator of trained immunity, these findings provide mechanistic insight into sustained metabolic changes and underscore the importance of characterizing regulatory circuits of innate immune memory.
Set7 regulates enhanced cytokine production in trained immunity in vitro Set7 knockout mice are unable to mount trained immunity against endotoxin challenge Set7 modulates cellular respiration in β-glucan-trained macrophages Set7-dependent histone methylation regulates MDH2 and SDHB in trained cells
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Affiliation(s)
- Samuel T Keating
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Laszlo Groh
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Charlotte D C C van der Heijden
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Hanah Rodriguez
- Epigenetics in Human Health and Disease, Department of Diabetes, Monash University, Melbourne, VIC, Australia
| | - Jéssica C Dos Santos
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Stephanie Fanucchi
- Division of Chemical, Systems and Synthetic Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Gene Expression and Biophysics Group, CSIR Biosciences, Pretoria, South Africa
| | - Jun Okabe
- Epigenetics in Human Health and Disease, Department of Diabetes, Monash University, Melbourne, VIC, Australia
| | - Harikrishnan Kaipananickal
- Epigenetics in Human Health and Disease, Department of Diabetes, Monash University, Melbourne, VIC, Australia; Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia
| | - Jelmer H van Puffelen
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands; Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Leonie Helder
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Marlies P Noz
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Vasiliki Matzaraki
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Yang Li
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands; Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine, Helmholtz Centre for Infection Research, Hannover Medical School, 30625 Hannover, Germany
| | - L Charlotte J de Bree
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands; Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Odense, Denmark
| | - Valerie A C M Koeken
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Simone J C F M Moorlag
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Vera P Mourits
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Jorge Domínguez-Andrés
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Marije Oosting
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Elianne P Bulthuis
- Department of Biochemistry, Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Werner J H Koopman
- Department of Biochemistry, Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands
| | - Musa Mhlanga
- Division of Chemical, Systems and Synthetic Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Assam El-Osta
- Epigenetics in Human Health and Disease, Department of Diabetes, Monash University, Melbourne, VIC, Australia; Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia; Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong City, Hong Kong SAR
| | - Leo A B Joosten
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands; Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
| | - Niels P Riksen
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands.
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22
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Liu B, Nie J, Liang H, Liang Z, Huang J, Yu W, Wen S. Pharmacological inhibition of SETD7 by PFI-2 attenuates renal fibrosis following folic acid and obstruction injury. Eur J Pharmacol 2021; 901:174097. [PMID: 33848540 DOI: 10.1016/j.ejphar.2021.174097] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 04/01/2021] [Accepted: 04/07/2021] [Indexed: 01/19/2023]
Abstract
Renal fibrosis is the common pathological hallmark of chronic kidney disease, and SET domain containing lysine methyltransferase 7 (SETD7) promote considerably renal fibrosis. However, the signaling mechanisms underlying SETD7 driving renal fibrosis are not fully understood. Here, we investigated the role of SETD7 in M2 macrophages-myofibroblasts transition and the myeloid fibroblasts activation in folic acid and obstruction-induced renal fibrosis. Mice treated with PFI-2, an inhibitor of SETD7, presented less bone marrow-derived myofibroblasts, fewer CD206+/α-smooth muscle actin + cells and developed less renal fibrosis (P＜0.01). Furthermore, SETD7 inhibition reduced the infiltration of inflammatory cells and decreased the production of pro-inflammatory cytokines and chemokines in the kidneys after folic acid treatment (P＜0.01). Finally, SETD7 inhibition suppressed the accumulation of NF-κB p65+ cells in folic acid nephropathy (P＜0.01). Taken together, SETD7 mediates M2 macrophages-myofibroblasts transition, bone marrow-derived myofibroblasts activation, and inflammation response in the development of renal fibrosis.
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Affiliation(s)
- Benquan Liu
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, China
| | - Jiayi Nie
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, China
| | - Hua Liang
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, China; Translational Medicine Institute of Anesthesiology and Perioperative Medicine, The First People's Hospital of Foshan, Foshan, 528000, China.
| | - Zijie Liang
- Department of Nephrology, The First People's Hospital of Foshan, Foshan, 528000, China
| | - Jiangju Huang
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, China
| | - Wenqiang Yu
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, 528000, China
| | - Shihong Wen
- Department of Anesthesiology, The First Affiliated Hospital of SUN YAT-SEN University, Guangzhou, 510080, China
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23
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Francis M, Gopinathan G, Salapatas A, Nares S, Gonzalez M, Diekwisch T, Luan X. SETD1 and NF-κB Regulate Periodontal Inflammation through H3K4 Trimethylation. J Dent Res 2020; 99:1486-1493. [PMID: 32762504 PMCID: PMC7684838 DOI: 10.1177/0022034520939029] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The inflammatory response to periodontal pathogens is dynamically controlled by the chromatin state on inflammatory gene promoters. In the present study, we have focused on the effect of the methyltransferase SETD1B on histone H3 lysine K4 (H3K4) histone trimethylation on inflammatory gene promoters. Experiments were based on 3 model systems: 1) an in vitro periodontal ligament (PDL) cell culture model for the study of SETD1 function as it relates to histone methylation and inflammatory gene expression using Porphyromonas gingivalis lipopolysaccharide (LPS) as a pathogen, 2) a subcutaneous implantation model to determine the relationship between SETD1 and nuclear factor κB (NF-κB) through its activation inhibitor BOT-64, and 3) a mouse periodontitis model to test whether the NF-κB activation inhibitor BOT-64 reverses the inflammatory tissue destruction associated with periodontal disease. In our PDL progenitor cell culture model, P. gingivalis LPS increased H3K4me3 histone methylation on IL-1β, IL-6, and MMP2 gene promoters, while SETD1B inhibition decreased H3K4me3 enrichment and inflammatory gene expression in LPS-treated PDL cells. LPS also increased SETD1 nuclear localization in a p65-dependent fashion and the nuclear translocation of p65 as mediated through SETD1, suggestive of a synergistic effect between SETD1 and p65 in the modulation of inflammation. Confirming the role of SETD1 in p65-mediated periodontal inflammation, BOT-64 reduced the number of SETD1-positive cells in inflamed periodontal tissues, restored periodontal tissue integrity, and enhanced osteogenesis in a periodontal inflammation model in vivo. Together, these results have established the histone lysine methyltransferase SETD1 as a key factor in the opening of the chromatin on inflammatory gene promoters through histone H3K4 trimethylation. Our studies also confirmed the role of BOT-64 as a potent molecular therapeutic for the restoration of periodontal health through the inhibition of NF-κB activity and the amelioration of SETD1-induced chromatin relaxation.
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Affiliation(s)
- M. Francis
- Department of Oral Biology, UIC College of Dentistry, Chicago, IL, USA
| | - G. Gopinathan
- Department of Periodontics and Center for Craniofacial Research and Diagnosis, Texas A&M University College of Dentistry, Dallas, TX, USA
| | - A. Salapatas
- Department of Oral Biology, UIC College of Dentistry, Chicago, IL, USA
| | - S. Nares
- Department of Periodontics, UIC College of Dentistry, Chicago, IL, USA
| | - M. Gonzalez
- Department of Periodontics and Center for Craniofacial Research and Diagnosis, Texas A&M University College of Dentistry, Dallas, TX, USA
| | - T.G.H. Diekwisch
- Department of Oral Biology, UIC College of Dentistry, Chicago, IL, USA
- Department of Periodontics and Center for Craniofacial Research and Diagnosis, Texas A&M University College of Dentistry, Dallas, TX, USA
| | - X. Luan
- Department of Oral Biology, UIC College of Dentistry, Chicago, IL, USA
- Department of Periodontics and Center for Craniofacial Research and Diagnosis, Texas A&M University College of Dentistry, Dallas, TX, USA
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24
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Targeting post-translational modification of transcription factors as cancer therapy. Drug Discov Today 2020; 25:1502-1512. [DOI: 10.1016/j.drudis.2020.06.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/19/2020] [Accepted: 06/08/2020] [Indexed: 12/17/2022]
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25
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Hou Z, Min W, Zhang R, Niu A, Li Y, Cao L, Han J, Luo C, Yang P, Ding H. Lead discovery, chemical optimization, and biological evaluation studies of novel histone methyltransferase SET7 small-molecule inhibitors. Bioorg Med Chem Lett 2020; 30:127061. [PMID: 32173197 DOI: 10.1016/j.bmcl.2020.127061] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 02/14/2020] [Accepted: 02/22/2020] [Indexed: 10/24/2022]
Abstract
The post-translational modifications of histones, including histone methylation and demethylation, control the expression switch of multiple genes. SET domain-containing lysine methyltransferase 7 (SET7) is the only methyltransferase, which can specifically monomethylate lysine-4 of histone H3 (H3K4me1) and play critical roles in various diseases, including breast cancer, hepatitis C virus (HCV), atherosclerotic vascular disease, diabetes, prostate cancer, hepatocellular carcinoma, and obesity. However, several known SET7 inhibitors exhibit weak activity or poor selectivity. Therefore, the development of novel SET7 inhibitors is highly desirable and of great clinical value. In this study, we identified 2-79 as a new hit compound by structure-based virtual screening and further AlphaLISA-based biochemical evaluation. Via chemical optimization, the synthesized compound DC21 was confirmed as a potent SET7 inhibitor with an IC50 value of 15.93 μM. The interaction between DC21 and SET7 was also validated through SPR experiment. Especially, DC21 retarded proliferation of MCF7 cells with an IC50 value of 25.84 μM in cellular level. In addition, DC21 has good selectivity for several other epigenetic targets, such as SUV39H1, G9a, NSD1, DOT1L and MOF. DC21 can serve as a lead compound to develop more potential SET7 inhibitors and as a chemical probe for SET7 biological function studies.
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Affiliation(s)
- Zeng Hou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
| | - Wenjian Min
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Rukang Zhang
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Ao Niu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
| | - Yuanqing Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
| | - Liyuan Cao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Jie Han
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
| | - Cheng Luo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
| | - Peng Yang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Hong Ding
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
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26
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Computational discovery and biological evaluation of novel inhibitors targeting histone-lysine N-methyltransferase SET7. Bioorg Med Chem 2020; 28:115372. [DOI: 10.1016/j.bmc.2020.115372] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 02/05/2020] [Accepted: 02/06/2020] [Indexed: 12/11/2022]
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27
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Mahesh A, Khan MIK, Govindaraju G, Verma M, Awasthi S, Chavali PL, Chavali S, Rajavelu A, Dhayalan A. SET7/9 interacts and methylates the ribosomal protein, eL42 and regulates protein synthesis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118611. [DOI: 10.1016/j.bbamcr.2019.118611] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 10/21/2019] [Accepted: 11/13/2019] [Indexed: 12/14/2022]
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28
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Basuroy T, de la Serna IL. SETD7 in cardiomyocyte differentiation and cardiac function. Stem Cell Investig 2019; 6:29. [PMID: 31620476 DOI: 10.21037/sci.2019.08.01] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 07/30/2019] [Indexed: 11/06/2022]
Affiliation(s)
- Tupa Basuroy
- Center for Cancer Research, Massachusetts General Hospital Cancer Center, Charlestown, MA, USA
| | - Ivana L de la Serna
- University of Toledo College of Medicine and Life Sciences, Department of Cancer Biology, Toledo, OH, USA
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29
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Bultman SJ. SETD7 interacts with other chromatin-modifying factors to regulate cardiac development. Stem Cell Investig 2019; 6:14. [PMID: 31304180 DOI: 10.21037/sci.2019.05.03] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 05/20/2019] [Indexed: 11/06/2022]
Affiliation(s)
- Scott J Bultman
- Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
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30
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Nayak A, Lopez-Davila AJ, Kefalakes E, Holler T, Kraft T, Amrute-Nayak M. Regulation of SETD7 Methyltransferase by SENP3 Is Crucial for Sarcomere Organization and Cachexia. Cell Rep 2019; 27:2725-2736.e4. [DOI: 10.1016/j.celrep.2019.04.107] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 03/20/2019] [Accepted: 04/24/2019] [Indexed: 12/16/2022] Open
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31
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Bhujbalrao R, Anand R. Deciphering Determinants in Ribosomal Methyltransferases That Confer Antimicrobial Resistance. J Am Chem Soc 2019; 141:1425-1429. [PMID: 30624914 DOI: 10.1021/jacs.8b10277] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Post-translational methylation of rRNA at select positions is a prevalent resistance mechanism adopted by pathogens. In this work, KsgA, a housekeeping ribosomal methyltransferase (rMtase) involved in ribosome biogenesis, was exploited as a model system to delineate the specific targeting determinants that impart substrate specificity to rMtases. With a combination of evolutionary and structure-guided approaches, a set of chimeras were created that altered the targeting specificity of KsgA such that it acted similarly to erythromycin-resistant methyltransferases (Erms), rMtases found in multidrug-resistant pathogens. The results revealed that specific loop embellishments on the basic Rossmann fold are key determinants in the selection of the cognate RNA. Moreover, in vivo studies confirmed that chimeric constructs are competent in imparting macrolide resistance. This work explores the factors that govern the emergence of resistance and paves the way for the design of specific inhibitors useful in reversing antibiotic resistance.
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Affiliation(s)
- Ruchika Bhujbalrao
- Department of Chemistry , Indian Institute of Technology Bombay , Powai, Mumbai 400076 , India
| | - Ruchi Anand
- Department of Chemistry , Indian Institute of Technology Bombay , Powai, Mumbai 400076 , India
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32
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Kurnaeva MA, Sheval EV, Musinova YR, Vassetzky YS. Tat basic domain: A "Swiss army knife" of HIV-1 Tat? Rev Med Virol 2019; 29:e2031. [PMID: 30609200 DOI: 10.1002/rmv.2031] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/05/2018] [Accepted: 12/06/2018] [Indexed: 01/16/2023]
Abstract
Tat (transactivator of transcription) regulates transcription from the HIV provirus. It plays a crucial role in disease progression, supporting efficient replication of the viral genome. Tat also modulates many functions in the host genome via its interaction with chromatin and proteins. Many of the functions of Tat are associated with its basic domain rich in arginine and lysine residues. It is still unknown why the basic domain exhibits so many diverse functions. However, the highly charged basic domain, coupled with the overall structural flexibility of Tat protein itself, makes the basic domain a key player in binding to or associating with cellular and viral components. In addition, the basic domain undergoes diverse posttranslational modifications, which further expand and modulate its functions. Here, we review the current knowledge of Tat basic domain and its versatile role in the interaction between the virus and the host cell.
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Affiliation(s)
- Margarita A Kurnaeva
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia
| | - Eugene V Sheval
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.,Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.,LIA 1066 LFR2O French-Russian Joint Cancer Research Laboratory, CNRS, Villejuif, France
| | - Yana R Musinova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.,LIA 1066 LFR2O French-Russian Joint Cancer Research Laboratory, CNRS, Villejuif, France.,Koltzov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia
| | - Yegor S Vassetzky
- LIA 1066 LFR2O French-Russian Joint Cancer Research Laboratory, CNRS, Villejuif, France.,Koltzov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia.,Nuclear Organization and Pathologies, CNRS, UMR8126, Université Paris-Sud, Institut Gustave Roussy, Villejuif, France
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33
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Tang B, Li B, Li B, Qin J, Zhao J, Xu J, Qiu Y, Wu Z, Fang M. Insights into the stereoselectivity of human SETD7 methyltransferase. RSC Adv 2019; 9:9218-9227. [PMID: 35517649 PMCID: PMC9062083 DOI: 10.1039/c9ra00190e] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 03/04/2019] [Indexed: 12/31/2022] Open
Abstract
Human SETD7 methyltransferase (hSETD7) is involved in a wide range of physiological processes, and has been considered as a significant target to develop new drugs. (R)-PFI-2, one hSETD7 inhibitor, could bind to the pocket of substrates with potent (low nanomolar) activity and high selectivity, while its enantiomer (S)-PFI-2 showed 500-fold less activity in IC50 determination. Why do this pair of enantiomers, with nearly identical structures, exert tremendously different inhibitory activity? We performed a total of 900 ns long-timescale molecular dynamics (MD) simulations and 80 ps hybrid quantum mechanics/molecular mechanics (QM/MM) MD simulations to understand the molecular mechanism of the stereoselectivity of hSETD7. For each SAM/hSETD7/PFI-2 system, we characterized and compared the residual fluctuation of hSETD7, and generated molecular interaction fingerprints (IFP) to exemplify the propensities of SAM/hSETD7-inhibitor interactions. Based on the QM/MM MD, we accurately captured the difference of hydrogen bonds between the SAM/hSETD7/(R)-PFI-2 and SAM/hSETD7/(S)-PFI-2 systems. Especially the strength of the hydrogen bond between G336 and two inhibitors, which determines the stability of the post-SET loop. The energy barrier for (S)-PFI-2 was much bigger than (R)-PFI-2 from global minimum to bioactive conformation as the potential energy surface scanning (PES) showed. Moreover, by estimating the binding affinity and phylogenetic tree analysis, we discovered 16 hotspots were essential for binding both enantiomers but the specific mode of interaction between these hotspots and enantiomorphs is different. Our findings reveal the effect of chirality on the inhibition activity of hSETD7 in detail, and provide valuable information for hSETD7 structure-based drug development. This work clearly reveals the interaction of SAM/hSET7/(R/S)-PFI-2 systems, and confirms that the different bioactive energy barriers of (R)-PFI-2 and (S)-PFI-2 lead to the tremendously different inhibitory activities between these two antipodes.![]()
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Affiliation(s)
- Bowen Tang
- School of Pharmaceutical Sciences
- Fujian Provincial Key Laboratory of Innovative Drug Target Research
- Xiamen University
- Xiamen 361000
- China
| | - Baicun Li
- School of Pharmaceutical Sciences
- Fujian Provincial Key Laboratory of Innovative Drug Target Research
- Xiamen University
- Xiamen 361000
- China
| | - Boqun Li
- School of Pharmaceutical Sciences
- Fujian Provincial Key Laboratory of Innovative Drug Target Research
- Xiamen University
- Xiamen 361000
- China
| | - Jingbo Qin
- School of Pharmaceutical Sciences
- Fujian Provincial Key Laboratory of Innovative Drug Target Research
- Xiamen University
- Xiamen 361000
- China
| | - Junming Zhao
- School of Pharmaceutical Sciences
- Fujian Provincial Key Laboratory of Innovative Drug Target Research
- Xiamen University
- Xiamen 361000
- China
| | - Jianwenn Xu
- School of Pharmaceutical Sciences
- Fujian Provincial Key Laboratory of Innovative Drug Target Research
- Xiamen University
- Xiamen 361000
- China
| | - Yingkun Qiu
- School of Pharmaceutical Sciences
- Fujian Provincial Key Laboratory of Innovative Drug Target Research
- Xiamen University
- Xiamen 361000
- China
| | - Zhen Wu
- School of Pharmaceutical Sciences
- Fujian Provincial Key Laboratory of Innovative Drug Target Research
- Xiamen University
- Xiamen 361000
- China
| | - Meijuan Fang
- School of Pharmaceutical Sciences
- Fujian Provincial Key Laboratory of Innovative Drug Target Research
- Xiamen University
- Xiamen 361000
- China
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34
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Costantino S, Libby P, Kishore R, Tardif JC, El-Osta A, Paneni F. Epigenetics and precision medicine in cardiovascular patients: from basic concepts to the clinical arena. Eur Heart J 2018; 39:4150-4158. [PMID: 29069341 PMCID: PMC6293269 DOI: 10.1093/eurheartj/ehx568] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 09/04/2017] [Accepted: 09/22/2017] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide and also inflict major burdens on morbidity, quality of life, and societal costs. Considering that CVD preventive medications improve vascular outcomes in less than half of patients (often relative risk reductions range from 12% to 20% compared with placebo), precision medicine offers an attractive approach to refine the targeting of CVD medications to responsive individuals in a population and thus allocate resources more wisely and effectively. New tools furnished by advances in basic science and translational medicine could help achieve this goal. This approach could reach beyond the practitioners 'eyeball' assessment or venerable markers derived from the physical examination and standard laboratory evaluation. Advances in genetics have identified novel pathways and targets that operate in numerous diseases, paving the way for 'precision medicine'. Yet the inherited genome determines only part of an individual's risk profile. Indeed, standard genomic approaches do not take into account the world of regulation of gene expression by modifications of the 'epi'genome. Epigenetic modifications defined as 'heritable changes to the genome that do not involve changes in DNA sequence' have emerged as a new layer of biological regulation in CVD and could advance individualized risk assessment as well as devising and deploying tailored therapies. This review, therefore, aims to acquaint the cardiovascular community with the rapidly advancing and evolving field of epigenetics and its implications in cardiovascular precision medicine.
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Affiliation(s)
- Sarah Costantino
- Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, Schlieren, Zurich, Switzerland
| | - Peter Libby
- Brigham and Women’s Hospital, Division of Cardiovascular Medicine, Boston, MA, USA
| | - Raj Kishore
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, MERB-953, 3500 N Broad Street, Philadelphia, PA, USA
- Department of Pharmacology, Temple University, Philadelphia, PA, USA
| | - Jean-Claude Tardif
- Montreal Health Innovations Coordinating Center (MHICC), Montreal, Canada
- Montreal Heart Institute, Université de Montréal, Montreal, Canada
| | - Assam El-Osta
- Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia
- Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
- Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR
| | - Francesco Paneni
- Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, Schlieren, Zurich, Switzerland
- University Heart Center, Cardiology, University Hospital Zürich, Zürich, Switzerland
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35
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Duan B, Bai J, Qiu J, Wang J, Tong C, Wang X, Miao J, Li Z, Li W, Yang J, Huang C. Histone-lysine N-methyltransferase SETD7 is a potential serum biomarker for colorectal cancer patients. EBioMedicine 2018; 37:134-143. [PMID: 30361067 PMCID: PMC6284455 DOI: 10.1016/j.ebiom.2018.10.036] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/04/2018] [Accepted: 10/11/2018] [Indexed: 01/14/2023] Open
Abstract
Background There is an urgent need for the identification of new, clinically useful biomarkers of CRC to enhance diagnostic and prognostic capabilities. Methods We performed proteomic profiling on serum samples from paired pre- and post-operative CRC patients, colorectal polyps patients and healthy controls using an approach combining magnetic bead-based weak cation exchange and matrix-assisted laser desorption ionization-time of flight mass spectrometry. We next performed liquid chromatography-electrospray ionization-tandem mass spectrometry to identify the proteins and selected potential biomarker based on bioinformatics analysis of the TCGA and GEO dataset. We examined SETD7 expression in serum and tissue samples by ELISA and immunohistochemistry respectively and explored the biological function of SETD7 in vitro. Findings 85 differentially expressed peptides were identified. Five peptides showing the most significant changes in abundance across paired pre- and post-operation CRC patients, colorectal polyps patients and healthy controls were identified as peptide regions of FGA, MUC5AC and SETD7. Bioinformatics analysis suggested that the up-regulation of SETD7 in CRC is relatively specific. Validation studies showed that SETD7 expression increased from healthy controls to those with colorectal polyps and finally CRC patients, and decreased after surgery. The sensitivity and specificity of SETD7 were 92.17% and 81.08%, with a high diagnostic value (AUC = 0.9477). In addition, SETD7 expression was significantly correlated with tumor stage and microsatellite instability. Knockdown of SETD7 inhibited cancer cell proliferation, induced G1/S cell cycle arrest and increased apoptosis. Interpretation Our data indicate that SETD7 could serve as a potential diagnostic and prognostic biomarker for CRC.
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Affiliation(s)
- Baojun Duan
- Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, Department of Cell Biology and Genetics, School of Basic Medical sciences, Xi'an Jiaotong University, Health Science Center, Shaanxi, Xi'an 710061, China; Department of Medical Oncology of Shaanxi Provincial People's Hospital, Shaanxi, Xi'an 710068, China
| | - Jun Bai
- Department of Medical Oncology of Shaanxi Provincial People's Hospital, Shaanxi, Xi'an 710068, China
| | - Jian Qiu
- Department of General Surgery of Shaanxi Provincial People's Hospital, Shaanxi, Xi'an 710068, China
| | - Jianhua Wang
- Department of General Surgery of Shaanxi Provincial People's Hospital, Shaanxi, Xi'an 710068, China
| | - Cong Tong
- Department of General Surgery of Shaanxi Provincial People's Hospital, Shaanxi, Xi'an 710068, China
| | - Xiaofei Wang
- Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, Department of Cell Biology and Genetics, School of Basic Medical sciences, Xi'an Jiaotong University, Health Science Center, Shaanxi, Xi'an 710061, China
| | - Jiyu Miao
- Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, Department of Cell Biology and Genetics, School of Basic Medical sciences, Xi'an Jiaotong University, Health Science Center, Shaanxi, Xi'an 710061, China
| | - Zongfang Li
- National & Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, Xi'an 710004, China
| | - Wensheng Li
- Department of Pathology of Shaanxi Provincial People's Hospital, Shaanxi, Xi'an 710068, China
| | - Juan Yang
- Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, Department of Cell Biology and Genetics, School of Basic Medical sciences, Xi'an Jiaotong University, Health Science Center, Shaanxi, Xi'an 710061, China.
| | - Chen Huang
- Key Laboratory of Environment and Disease-Related Gene, Ministry of Education, Department of Cell Biology and Genetics, School of Basic Medical sciences, Xi'an Jiaotong University, Health Science Center, Shaanxi, Xi'an 710061, China.
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van der Heijden CDCC, Noz MP, Joosten LAB, Netea MG, Riksen NP, Keating ST. Epigenetics and Trained Immunity. Antioxid Redox Signal 2018; 29:1023-1040. [PMID: 28978221 PMCID: PMC6121175 DOI: 10.1089/ars.2017.7310] [Citation(s) in RCA: 170] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
SIGNIFICANCE A growing body of clinical and experimental evidence has challenged the traditional understanding that only the adaptive immune system can mount immunological memory. Recent findings describe the adaptive characteristics of the innate immune system, underscored by its ability to remember antecedent foreign encounters and respond in a nonspecific sensitized manner to reinfection. This has been termed trained innate immunity. Although beneficial in the context of recurrent infections, this might actually contribute to chronic immune-mediated diseases, such as atherosclerosis. Recent Advances: In line with its proposed role in sustaining cellular memories, epigenetic reprogramming has emerged as a critical determinant of trained immunity. Recent technological and computational advances that improve unbiased acquisition of epigenomic profiles have significantly enhanced our appreciation for the complexities of chromatin architecture in the contexts of diverse immunological challenges. CRITICAL ISSUES Key to resolving the distinct chromatin signatures of innate immune memory is a comprehensive understanding of the precise physiological targets of regulatory proteins that recognize, deposit, and remove chemical modifications from chromatin as well as other gene-regulating factors. Drawing from a rapidly expanding compendium of experimental and clinical studies, this review details a current perspective of the epigenetic pathways that support the adapted phenotypes of monocytes and macrophages. FUTURE DIRECTIONS We explore future strategies that are aimed at exploiting the mechanism of trained immunity to improve the prevention and treatment of infections and immune-mediated chronic disorders.
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Affiliation(s)
| | - Marlies P Noz
- 1 Department of Internal Medicine, Radboud University Medical Center , Nijmegen, The Netherlands
| | - Leo A B Joosten
- 1 Department of Internal Medicine, Radboud University Medical Center , Nijmegen, The Netherlands
| | - Mihai G Netea
- 1 Department of Internal Medicine, Radboud University Medical Center , Nijmegen, The Netherlands .,2 Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn , Bonn, Germany
| | - Niels P Riksen
- 1 Department of Internal Medicine, Radboud University Medical Center , Nijmegen, The Netherlands
| | - Samuel T Keating
- 1 Department of Internal Medicine, Radboud University Medical Center , Nijmegen, The Netherlands
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Dang Y, Ma X, Li Y, Hao Q, Xie Y, Zhang Q, Zhang F, Qi X. Inhibition of SETD7 protects cardiomyocytes against hypoxia/reoxygenation-induced injury through regulating Keap1/Nrf2 signaling. Biomed Pharmacother 2018; 106:842-849. [DOI: 10.1016/j.biopha.2018.07.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 06/28/2018] [Accepted: 07/01/2018] [Indexed: 12/25/2022] Open
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Yerra VG, Advani A. Histones and heart failure in diabetes. Cell Mol Life Sci 2018; 75:3193-3213. [PMID: 29934664 PMCID: PMC6063320 DOI: 10.1007/s00018-018-2857-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 06/12/2018] [Accepted: 06/15/2018] [Indexed: 12/22/2022]
Abstract
Although heart failure is now accepted as being a major long-term complication of diabetes, many of the recent advances in our understanding of the pathobiology of diabetes complications have come about through the study of more traditional microvascular or macrovascular diseases. This has been the case, for example, in the evolving field of the epigenetics of diabetes complications and, in particular, the post-translational modification of histone proteins. However, histone modifications also occur in human heart failure and their perturbation also occurs in diabetic hearts. Here, we review the principal histone modifications and their enzymatic writers and erasers that have been studied to date; we discuss what is currently known about their roles in heart failure and in the diabetic heart; we draw on lessons learned from the studies of microvascular and macrovascular complications; and we speculate that therapeutically manipulating histone modifications may alter the natural history of heart failure in diabetes.
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Affiliation(s)
- Veera Ganesh Yerra
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, 6-151, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
| | - Andrew Advani
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, 6-151, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada.
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Biological processes and signal transduction pathways regulated by the protein methyltransferase SETD7 and their significance in cancer. Signal Transduct Target Ther 2018; 3:19. [PMID: 30013796 PMCID: PMC6043541 DOI: 10.1038/s41392-018-0017-6] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Revised: 02/05/2018] [Accepted: 03/21/2018] [Indexed: 02/07/2023] Open
Abstract
Protein methyltransferases have been shown to methylate histone and non-histone proteins, leading to regulation of several biological processes that control cell homeostasis. Over the past few years, the histone-lysine N-methyltransferase SETD7 (SETD7; also known as SET7/9, KIAA1717, KMT7, SET7, SET9) has emerged as an important regulator of at least 30 non-histone proteins and a potential target for the treatment of several human diseases. This review discusses current knowledge of the structure and subcellular localization of SETD7, as well as its function as a histone and non-histone methyltransferase. This work also underlines the putative contribution of SETD7 to the regulation of gene expression, control of cell proliferation, differentiation and endoplasmic reticulum stress, which indicate that SETD7 is a candidate for novel targeted therapies with the aim of either stimulating or inhibiting its activity, depending on the cell signaling context.
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Ding H, Lu WC, Hu JC, Liu YC, Zhang CH, Lian FL, Zhang NX, Meng FW, Luo C, Chen KX. Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search. Molecules 2018; 23:567. [PMID: 29498708 PMCID: PMC6017732 DOI: 10.3390/molecules23030567] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 02/23/2018] [Accepted: 02/28/2018] [Indexed: 12/17/2022] Open
Abstract
SET7, serving as the only histone methyltransferase that monomethylates 'Lys-4' of histone H3, has been proved to function as a key regulator in diverse biological processes, such as cell proliferation, transcriptional network regulation in embryonic stem cell, cell cycle control, protein stability, heart morphogenesis and development. What's more, SET7 is involved inthe pathogenesis of alopecia aerate, breast cancer, tumor and cancer progression, atherosclerosis in human carotid plaques, chronic renal diseases, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis. Therefore, there is urgent need to develop novel SET7 inhibitors. In this paper, based on DC-S239 which has been previously reported in our group, we employed scaffold hopping- and 2D fingerprint-based similarity searches and identified DC-S285 as the new hit compound targeting SET7 (IC50 = 9.3 μM). Both radioactive tracing and NMR experiments validated the interactions between DC-S285 and SET7 followed by the second-round similarity search leading to the identification ofDC-S303 with the IC50 value of 1.1 μM. In cellular level, DC-S285 retarded tumor cell proliferation and showed selectivity against MCF7 (IC50 = 21.4 μM), Jurkat (IC50 = 2.2 μM), THP1 (IC50 = 3.5 μM), U937 (IC50 = 3.9 μM) cell lines. Docking calculations suggested that DC-S303 share similar binding mode with the parent compoundDC-S239. What's more, it presented good selectivity against other epigenetic targets, including SETD1B, SETD8, G9a, SMYD2 and EZH2. DC-S303 can serve as a drug-like scaffold which may need further optimization for drug development, and can be used as chemical probe to help the community to better understand the SET7 biology.
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Affiliation(s)
- Hong Ding
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
- CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
| | - Wen Chao Lu
- CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
| | - Jun Chi Hu
- CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
| | - Yu-Chih Liu
- Shanghai ChemPartner Co., Ltd., #5 Building, 998 Halei Road, Shanghai 201203, China.
| | - Chen Hua Zhang
- Shanghai ChemPartner Co., Ltd., #5 Building, 998 Halei Road, Shanghai 201203, China.
| | - Fu Lin Lian
- CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
| | - Nai Xia Zhang
- CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
| | - Fan Wang Meng
- CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
- Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.
| | - Cheng Luo
- CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
| | - Kai Xian Chen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
- CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
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Keating ST, van Diepen JA, Riksen NP, El-Osta A. Epigenetics in diabetic nephropathy, immunity and metabolism. Diabetologia 2018; 61:6-20. [PMID: 29128937 PMCID: PMC6448927 DOI: 10.1007/s00125-017-4490-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 06/22/2017] [Indexed: 01/01/2023]
Abstract
When it comes to the epigenome, there is a fine line between clarity and confusion-walk that line and you will discover another fascinating level of transcription control. With the genetic code representing the cornerstone of rules for information that is encoded to proteins somewhere above the genome level there is a set of rules by which chemical information is also read. These epigenetic modifications show a different side of the genetic code that is diverse and regulated, hence modifying genetic transcription transiently, ranging from short- to long-term alterations. While this complexity brings exquisite control it also poses a formidable challenge to efforts to decode mechanisms underlying complex disease. Recent technological and computational advances have improved unbiased acquisition of epigenomic patterns to improve our understanding of the complex chromatin landscape. Key to resolving distinct chromatin signatures of diabetic complications is the identification of the true physiological targets of regulatory proteins, such as reader proteins that recognise, writer proteins that deposit and eraser proteins that remove specific chemical moieties. But how might a diverse group of proteins regulate the diabetic landscape from an epigenomic perspective? Drawing from an ever-expanding compendium of experimental and clinical studies, this review details the current state-of-play and provides a perspective of chromatin-dependent mechanisms implicated in diabetic complications, with a special focus on diabetic nephropathy. We hypothesise a codified signature of the diabetic epigenome and provide examples of prime candidates for chemical modification. As for the pharmacological control of epigenetic marks, we explore future strategies to expedite and refine the search for clinically relevant discoveries. We also consider the challenges associated with therapeutic strategies targeting epigenetic pathways.
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Affiliation(s)
- Samuel T Keating
- Department of Internal Medicine, Department of Internal Medicine (463), Radboud University Medical Center, Nijmegen, PO Box 9101, 6500 HB, Nijmegen, the Netherlands.
| | - Janna A van Diepen
- Department of Internal Medicine, Department of Internal Medicine (463), Radboud University Medical Center, Nijmegen, PO Box 9101, 6500 HB, Nijmegen, the Netherlands
| | - Niels P Riksen
- Department of Internal Medicine, Department of Internal Medicine (463), Radboud University Medical Center, Nijmegen, PO Box 9101, 6500 HB, Nijmegen, the Netherlands
| | - Assam El-Osta
- Central Clinical School, Monash University, 99 Commercial Road, Melbourne, VIC, 3004, Australia.
- Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
- Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, China.
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Wu XN, Shi TT, He YH, Wang FF, Sang R, Ding JC, Zhang WJ, Shu XY, Shen HF, Yi J, Gao X, Liu W. Methylation of transcription factor YY2 regulates its transcriptional activity and cell proliferation. Cell Discov 2017; 3:17035. [PMID: 29098080 PMCID: PMC5665210 DOI: 10.1038/celldisc.2017.35] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 08/08/2017] [Indexed: 01/05/2023] Open
Abstract
Yin Yang 1 (YY1) is a multifunctional DNA-binding transcription factor shown to be critical in a variety of biological processes, and its activity and function have been shown to be regulated by multitude of mechanisms, which include but are not limited to post-translational modifications (PTMs), its associated proteins and cellular localization. YY2, the paralog of YY1 in mouse and human, has been proposed to function redundantly or oppositely in a context-specific manner compared with YY1. Despite its functional importance, how YY2’s DNA-binding activity and function are regulated, particularly by PTMs, remains completely unknown. Here we report the first PTM with functional characterization on YY2, namely lysine 247 monomethylation (K247me1), which was found to be dynamically regulated by SET7/9 and LSD1 both in vitro and in cultured cells. Functional study revealed that SET7/9-mediated YY2 methylation regulated its DNA-binding activity in vitro and in association with chromatin examined by chromatin immunoprecipitation coupled with sequencing (ChIP-seq) in cultured cells. Knockout of YY2, SET7/9 or LSD1 by CRISPR (clustered, regularly interspaced, short palindromic repeats)/Cas9-mediated gene editing followed by RNA sequencing (RNA-seq) revealed that a subset of genes was positively regulated by YY2 and SET7/9, but negatively regulated by LSD1, which were enriched with genes involved in cell proliferation regulation. Importantly, YY2-regulated gene transcription, cell proliferation and tumor growth were dependent, at least partially, on YY2 K247 methylation. Finally, somatic mutations on YY2 found in cancer, which are in close proximity to K247, altered its methylation, DNA-binding activity and gene transcription it controls. Our findings revealed the first PTM with functional implications imposed on YY2 protein, and linked YY2 methylation with its biological functions.
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Affiliation(s)
- Xiao-Nan Wu
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, China
| | - Tao-Tao Shi
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, China
| | - Yao-Hui He
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, China
| | - Fei-Fei Wang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, China
| | - Rui Sang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, China
| | - Jian-Cheng Ding
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, China
| | - Wen-Juan Zhang
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, China
| | - Xing-Yi Shu
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, China
| | - Hai-Feng Shen
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, China
| | - Jia Yi
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, China
| | - Xiang Gao
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, China
| | - Wen Liu
- School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian, China
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Hang LH, Xu ZK, Wei SY, Shu WW, Luo H, Chen J. Spinal SET7/9 may contribute to the maintenance of cancer-induced bone pain in mice. Clin Exp Pharmacol Physiol 2017; 44:1001-1007. [PMID: 28557056 DOI: 10.1111/1440-1681.12789] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 05/14/2017] [Accepted: 05/17/2017] [Indexed: 11/29/2022]
Abstract
Cancer-induced bone pain (CIBP) profoundly influences patients' quality of life. Exploring the mechanisms by which CIBP occurs is essential for developing efficacious therapies. Various studies have shown that proinflammatory factors were involved in CIBP. SET domain containing lysine methyltransferase 7/9 (SET7/9) may modulate the expression of NF-κB-dependent proinflammatory genes in vitro. However, whether SET7/9 may participate in the maintenance of CIBP remains unknown. In this study, NCTC 2472 cells were inoculated into the intramedullary space of the femur to establish a mouse model of CIBP. Upregulation of spinal SET7/9 expression was related to pain behaviours in tumour-inoculated mice. Intrathecal cyproheptadine (10 or 20 nmol) attenuated response to painful stimuli in a dose-dependent manner. Moreover, there was a concomitant decrease in spinal SET7/9 and RANTES expression. The antinociceptive effects of cyproheptadine were abolished by pre-intrathecal administration of SET 7/9 (0.2 μg) for 30 minutes before intrathecal cyproheptadine (20 nmol) administration. These results indicated that spinal SET7/9 may contribute to the maintenance of CIBP in mice. Hence, targeting of spinal SET7/9 might be a useful alternative therapy for the treatment of CIBP.
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Affiliation(s)
- Li-Hua Hang
- Department of Anesthesiology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu, China
| | - Zhen-Kai Xu
- Department of Anesthesiology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu, China
| | - Shi-You Wei
- Department of Anesthesiology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu, China
| | - Wei-Wei Shu
- Department of Anesthesiology, the Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Hong Luo
- Department of Anesthesiology, the Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jian Chen
- Department of General Surgery, the First People's Hospital of Kunshan affiliated to Jiangsu University, Kunshan, Jiangsu, China
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Wang CM, Cheng BH, Xue QJ, Chen J, Bai B. MiR-1298 affects cell proliferation and apoptosis in C6 cells by targeting SET domain containing 7. Int J Immunopathol Pharmacol 2017; 30:264-271. [PMID: 28762861 PMCID: PMC5815257 DOI: 10.1177/0394632017720546] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Our previous high-throughput sequencing indicated that rno-miR-1298 was down-regulated in ischemia-reperfusion model of rat. However, little is known about the function and molecular mechanism of rno-miR-1298 in rat tumor cell. In this study, rno-miR-1298 was detected to be significantly down-regulated in rat tumor C6 cells. Moreover, overexpression of rno-miR-1298 obviously inhibited the proliferation and induced apoptosis in C6 cells. SET domain containing 7 (SETD 7) was identified to be a target of rno-miR-1298 using bioinformatics and luciferase reporter assays. Overexpression of rno-miR-1298 markedly reduced the expression of SETD 7 at protein level. Knockdown of SETD 7 also suppressed proliferation and promoted apoptosis in C6 cells. It was indicated that rno-miR-1298 affected cell proliferation and apoptosis of rat tumor cells by targeting SETD 7. Thus, the newly identified miR-1298/SETD 7 expands the elaboration of the mechanisms of the development and progression of tumors and may provide therapeutic target for tumors of nervous system.
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Affiliation(s)
- Chun-Mei Wang
- Neurobiology Institute, Jining Medical University, Jining, P.R. China
| | - Bao-Hua Cheng
- Neurobiology Institute, Jining Medical University, Jining, P.R. China
| | - Qing-Jie Xue
- Neurobiology Institute, Jining Medical University, Jining, P.R. China
| | - Jing Chen
- Neurobiology Institute, Jining Medical University, Jining, P.R. China
| | - Bo Bai
- Neurobiology Institute, Jining Medical University, Jining, P.R. China
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Kietzmann T, Petry A, Shvetsova A, Gerhold JM, Görlach A. The epigenetic landscape related to reactive oxygen species formation in the cardiovascular system. Br J Pharmacol 2017; 174:1533-1554. [PMID: 28332701 PMCID: PMC5446579 DOI: 10.1111/bph.13792] [Citation(s) in RCA: 177] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 03/06/2017] [Accepted: 03/08/2017] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases are among the leading causes of death worldwide. Reactive oxygen species (ROS) can act as damaging molecules but also represent central hubs in cellular signalling networks. Increasing evidence indicates that ROS play an important role in the pathogenesis of cardiovascular diseases, although the underlying mechanisms and consequences of pathophysiologically elevated ROS in the cardiovascular system are still not completely resolved. More recently, alterations of the epigenetic landscape, which can affect DNA methylation, post-translational histone modifications, ATP-dependent alterations to chromatin and non-coding RNA transcripts, have been considered to be of increasing importance in the pathogenesis of cardiovascular diseases. While it has long been accepted that epigenetic changes are imprinted during development or even inherited and are not changed after reaching the lineage-specific expression profile, it becomes more and more clear that epigenetic modifications are highly dynamic. Thus, they might provide an important link between the actions of ROS and cardiovascular diseases. This review will provide an overview of the role of ROS in modulating the epigenetic landscape in the context of the cardiovascular system. LINKED ARTICLES This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
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Affiliation(s)
- Thomas Kietzmann
- Faculty of Biochemistry and Molecular Medicine, Biocenter OuluUniversity of OuluOuluFinland
| | - Andreas Petry
- Experimental and Molecular Pediatric CardiologyGerman Heart Center Munich at the TU MunichMunichGermany
- DZHK (German Centre for Cardiovascular Research)Partner Site Munich Heart AllianceMunichGermany
| | - Antonina Shvetsova
- Faculty of Biochemistry and Molecular Medicine, Biocenter OuluUniversity of OuluOuluFinland
| | - Joachim M Gerhold
- Institute of Molecular and Cell BiologyUniversity of TartuTartuEstonia
| | - Agnes Görlach
- Experimental and Molecular Pediatric CardiologyGerman Heart Center Munich at the TU MunichMunichGermany
- DZHK (German Centre for Cardiovascular Research)Partner Site Munich Heart AllianceMunichGermany
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Keating ST, Plutzky J, El-Osta A. Epigenetic Changes in Diabetes and Cardiovascular Risk. Circ Res 2017; 118:1706-22. [PMID: 27230637 DOI: 10.1161/circresaha.116.306819] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 04/30/2016] [Indexed: 01/03/2023]
Abstract
Cardiovascular complications remain the leading causes of morbidity and premature mortality in patients with diabetes mellitus. Studies in humans and preclinical models demonstrate lasting gene expression changes in the vasculopathies initiated by previous exposure to high glucose concentrations and the associated overproduction of reactive oxygen species. The molecular signatures of chromatin architectures that sensitize the genome to these and other cardiometabolic risk factors of the diabetic milieu are increasingly implicated in the biological memory underlying cardiovascular complications and now widely considered as promising therapeutic targets. Atherosclerosis is a complex heterocellular disease where the contributing cell types possess distinct epigenomes shaping diverse gene expression. Although the extent that pathological chromatin changes can be manipulated in human cardiovascular disease remains to be established, the clinical applicability of epigenetic interventions will be greatly advanced by a deeper understanding of the cell type-specific roles played by writers, erasers, and readers of chromatin modifications in the diabetic vasculature. This review details a current perspective of epigenetic mechanisms of macrovascular disease in diabetes mellitus and highlights recent key descriptions of chromatinized changes associated with persistent gene expression in endothelial, smooth muscle, and circulating immune cells relevant to atherosclerosis. Furthermore, we discuss the challenges associated with pharmacological targeting of epigenetic networks to correct abnormal or deregulated gene expression as a strategy to alleviate the clinical burden of diabetic cardiovascular disease.
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Affiliation(s)
- Samuel T Keating
- From the Epigenetics in Human Health and Disease Laboratory (S.T.K., A.E.-O.) and Epigenomics Profiling Facility (A.E.-O.), Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.P.); Department of Pathology, The University of Melbourne, Victoria, Australia (A.E.-O.); and Central Clinical School, Department of Medicine, Monash University, Victoria, Australia (A.E.-O.)
| | - Jorge Plutzky
- From the Epigenetics in Human Health and Disease Laboratory (S.T.K., A.E.-O.) and Epigenomics Profiling Facility (A.E.-O.), Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.P.); Department of Pathology, The University of Melbourne, Victoria, Australia (A.E.-O.); and Central Clinical School, Department of Medicine, Monash University, Victoria, Australia (A.E.-O.)
| | - Assam El-Osta
- From the Epigenetics in Human Health and Disease Laboratory (S.T.K., A.E.-O.) and Epigenomics Profiling Facility (A.E.-O.), Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (J.P.); Department of Pathology, The University of Melbourne, Victoria, Australia (A.E.-O.); and Central Clinical School, Department of Medicine, Monash University, Victoria, Australia (A.E.-O.).
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Niu Y, Shi D, Li L, Guo J, Liu H, Yao X. Revealing inhibition difference between PFI-2 enantiomers against SETD7 by molecular dynamics simulations, binding free energy calculations and unbinding pathway analysis. Sci Rep 2017; 7:46547. [PMID: 28417976 PMCID: PMC5394549 DOI: 10.1038/srep46547] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 03/17/2017] [Indexed: 11/24/2022] Open
Abstract
SETD7 is associated with multiple diseases related signaling pathways. (R)-PFI-2 is the first SETD7 inhibitor with nanomolar inhibitory potency. The activity of (R)-PFI-2 is about 500 times over that of (S)-PFI-2. Understanding the mechanism behind this difference will be helpful to discovery and design of more potent SETD7 inhibitors. A computational study combining molecular dynamics simulation, binding free energy calculations, and residue interaction network (RIN) was performed on the (S)-PFI-2/SETD7 and (R)-PFI-2/SETD7 complexes to explore the molecular mechanism behind the different inhibition activity. The results from Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculation show (R)-PFI-2 has lower binding free energy. Residues H252, D256, L267, Y335, G336 and H339 are responsible for the binding of SETD7 to the (R)-PFI-2. RIN analysis indicates van der Waals interaction is critical for the binding of (R)-PFI-2. The results from adaptive basing force (ABF) simulation confirm that the free energy barrier of (R)-PFI-2 dissociating from the SETD7 is larger than that of (S)-PFI-2. (S)-PFI-2 and (R)-PFI-2 dissociate from the SETD7 binding site along different reaction coordinate and have potential mean of force (PMF) depth. Our simulations results will be useful to understand molecular mechanism of activity difference between PFI-2 enantiomers against SETD7.
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Affiliation(s)
- Yuzhen Niu
- State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China
| | - Danfeng Shi
- State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China
| | - Lanlan Li
- State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China
| | - Jingyun Guo
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Huanxiang Liu
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Xiaojun Yao
- State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.,Key Lab of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou 730000, China
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48
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Guitot K, Drujon T, Burlina F, Sagan S, Beaupierre S, Pamlard O, Dodd RH, Guillou C, Bolbach G, Sachon E, Guianvarc'h D. A direct label-free MALDI-TOF mass spectrometry based assay for the characterization of inhibitors of protein lysine methyltransferases. Anal Bioanal Chem 2017; 409:3767-3777. [PMID: 28389916 DOI: 10.1007/s00216-017-0319-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 03/06/2017] [Accepted: 03/14/2017] [Indexed: 12/27/2022]
Abstract
Histone lysine methylation is associated with essential biological functions like transcription activation or repression, depending on the position and the degree of methylation. This post-translational modification is introduced by protein lysine methyltransferases (KMTs) which catalyze the transfer of one to three methyl groups from the methyl donor S-adenosyl-L-methionine (AdoMet) to the amino group on the side chain of lysines. The regulation of protein lysine methylation plays a primary role not only in the basic functioning of normal cells but also in various pathologies and KMT deregulation is associated with diseases including cancer. These enzymes are therefore attractive targets for the development of new antitumor agents, and there is still a need for direct methodology to screen, identify, and characterize KMT inhibitors. We report here a simple and robust in vitro assay to quantify the enzymatic methylation of KMT by MALDI-TOF mass spectrometry. Following this protocol, we can monitor the methylation events over time on a peptide substrate. We detect in the same spectrum the modified and unmodified substrates, and the ratios of both signals are used to quantify the amount of methylated substrate. We first demonstrated the validity of the assay by determining inhibition parameters of two known inhibitors of the KMT SET7/9 ((R)-PFI-2 and sinefungin). Next, based on structural comparison with these inhibitors, we selected 42 compounds from a chemical library. We applied the MALDI-TOF assay to screen their activity as inhibitors of the KMT SET7/9. This study allowed us to determine inhibition constants as well as kinetic parameters of a series of SET7/9 inhibitors and to initiate a structure activity discussion with this family of compounds. This assay is versatile and can be easily adapted to other KMT substrates and enzymes as well as automatized.
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Affiliation(s)
- Karine Guitot
- Sorbonne Universités, UPMC Univ Paris 06, Ecole Normale Supérieure, CNRS, Laboratoire des Biomolécules (LBM), 4 place Jussieu, 75005, Paris, France.,Département de Chimie, Ecole Normale Supérieure, PSL Research University, UPMC Univ Paris 06, CNRS, Laboratoire des Biomolécules (LBM), 75005, Paris, France
| | - Thierry Drujon
- Sorbonne Universités, UPMC Univ Paris 06, Ecole Normale Supérieure, CNRS, Laboratoire des Biomolécules (LBM), 4 place Jussieu, 75005, Paris, France.,Département de Chimie, Ecole Normale Supérieure, PSL Research University, UPMC Univ Paris 06, CNRS, Laboratoire des Biomolécules (LBM), 75005, Paris, France
| | - Fabienne Burlina
- Sorbonne Universités, UPMC Univ Paris 06, Ecole Normale Supérieure, CNRS, Laboratoire des Biomolécules (LBM), 4 place Jussieu, 75005, Paris, France.,Département de Chimie, Ecole Normale Supérieure, PSL Research University, UPMC Univ Paris 06, CNRS, Laboratoire des Biomolécules (LBM), 75005, Paris, France
| | - Sandrine Sagan
- Sorbonne Universités, UPMC Univ Paris 06, Ecole Normale Supérieure, CNRS, Laboratoire des Biomolécules (LBM), 4 place Jussieu, 75005, Paris, France.,Département de Chimie, Ecole Normale Supérieure, PSL Research University, UPMC Univ Paris 06, CNRS, Laboratoire des Biomolécules (LBM), 75005, Paris, France
| | - Sandra Beaupierre
- Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS UPR 2301, 1 Avenue de la Terrasse, 91198, Gif-sur-Yvette, France
| | - Olivier Pamlard
- Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS UPR 2301, 1 Avenue de la Terrasse, 91198, Gif-sur-Yvette, France
| | - Robert H Dodd
- Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS UPR 2301, 1 Avenue de la Terrasse, 91198, Gif-sur-Yvette, France
| | - Catherine Guillou
- Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS UPR 2301, 1 Avenue de la Terrasse, 91198, Gif-sur-Yvette, France
| | - Gérard Bolbach
- Sorbonne Universités, UPMC Univ Paris 06, Ecole Normale Supérieure, CNRS, Laboratoire des Biomolécules (LBM), 4 place Jussieu, 75005, Paris, France.,Département de Chimie, Ecole Normale Supérieure, PSL Research University, UPMC Univ Paris 06, CNRS, Laboratoire des Biomolécules (LBM), 75005, Paris, France.,UPMC Univ Paris 06, IBPS/FR3631, Plateforme de Spectrométrie de Masse et Protéomique, 7-9 Quai Saint Bernard, 75005, Paris, France
| | - Emmanuelle Sachon
- Sorbonne Universités, UPMC Univ Paris 06, Ecole Normale Supérieure, CNRS, Laboratoire des Biomolécules (LBM), 4 place Jussieu, 75005, Paris, France.,Département de Chimie, Ecole Normale Supérieure, PSL Research University, UPMC Univ Paris 06, CNRS, Laboratoire des Biomolécules (LBM), 75005, Paris, France.,UPMC Univ Paris 06, IBPS/FR3631, Plateforme de Spectrométrie de Masse et Protéomique, 7-9 Quai Saint Bernard, 75005, Paris, France
| | - Dominique Guianvarc'h
- Sorbonne Universités, UPMC Univ Paris 06, Ecole Normale Supérieure, CNRS, Laboratoire des Biomolécules (LBM), 4 place Jussieu, 75005, Paris, France. .,Département de Chimie, Ecole Normale Supérieure, PSL Research University, UPMC Univ Paris 06, CNRS, Laboratoire des Biomolécules (LBM), 75005, Paris, France.
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49
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Metabolism and chromatin dynamics in health and disease. Mol Aspects Med 2017; 54:1-15. [DOI: 10.1016/j.mam.2016.09.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 09/22/2016] [Accepted: 09/27/2016] [Indexed: 01/04/2023]
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Esnault C, Gualdrini F, Horswell S, Kelly G, Stewart A, East P, Matthews N, Treisman R. ERK-Induced Activation of TCF Family of SRF Cofactors Initiates a Chromatin Modification Cascade Associated with Transcription. Mol Cell 2017; 65:1081-1095.e5. [PMID: 28286024 PMCID: PMC5364370 DOI: 10.1016/j.molcel.2017.02.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Revised: 12/19/2016] [Accepted: 02/06/2017] [Indexed: 12/20/2022]
Abstract
We investigated the relationship among ERK signaling, histone modifications, and transcription factor activity, focusing on the ERK-regulated ternary complex factor family of SRF partner proteins. In MEFs, activation of ERK by TPA stimulation induced a common pattern of H3K9acS10ph, H4K16ac, H3K27ac, H3K9acK14ac, and H3K4me3 at hundreds of transcription start site (TSS) regions and remote regulatory sites. The magnitude of the increase in histone modification correlated well with changes in transcription. H3K9acS10ph preceded the other modifications. Most induced changes were TCF dependent, but TCF-independent TSSs exhibited the same hierarchy, indicating that it reflects gene activation per se. Studies with TCF Elk-1 mutants showed that TCF-dependent ERK-induced histone modifications required Elk-1 to be phosphorylated and competent to activate transcription. Analysis of direct TCF-SRF target genes and chromatin modifiers confirmed this and showed that H3S10ph required only Elk-1 phosphorylation. Induction of histone modifications following ERK stimulation is thus directed by transcription factor activation and transcription.
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Affiliation(s)
- Cyril Esnault
- Signalling and Transcription Group, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Francesco Gualdrini
- Signalling and Transcription Group, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Stuart Horswell
- Bioinformatics and Biostatistics STP, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Gavin Kelly
- Bioinformatics and Biostatistics STP, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Aengus Stewart
- Bioinformatics and Biostatistics STP, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Phil East
- Bioinformatics and Biostatistics STP, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Nik Matthews
- Advanced Sequencing STP, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Richard Treisman
- Signalling and Transcription Group, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
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