Thyroid cancer (TC) is the most common endocrine cancer and is a serious health concern due to its aggressiveness and high incidence. Histone modifications affect DNA accessibility and gene transcriptional activity by altering the structure of chromatin. Abnormal histone modifications may affect genome stability and disrupt gene expression patterns, leading to many diseases, including cancer. A growing body of research suggests that histone modifications and TC progression are inextricably linked. This article discusses the impact of aberrant histone modification patterns on TC. By targeting specific histone-modifying enzymes, it may be possible to regulate gene expression and inhibit the growth of TC. Finally, we summarize the relevant histone modification inhibitors to better understand the development stage of the use of these drugs to inhibit histone-modifying enzymes in cancer treatment.

The target of rapamycin (TOR) kinase is a critical regulator of plant growth and development, integrating environmental and internal signals to modulate cellular processes. This review explores the emerging role of TOR in chromatin regulation, focusing on its nuclear activities and interactions with chromatin remodeling factors. We highlight the mechanisms by which TOR influences chromatin structure and gene expression, including its involvement in histone modifications and DNA methylation. Additionally, we discuss the interplay between TOR signaling, the cytoskeleton, and nuclear functions, emphasizing the potential of TOR to act as a bridge between cytoskeletal dynamics and chromatin regulation. Finally, besides TOR-mediated cyto-nuclear shuttling and metabolic regulation, we address the translational control of chromatin components by TOR as additional layers impacting the chromatin landscape. We also propose future research directions to further elucidate the complex regulatory network governed by TOR in plant cells.

Animal germ cells deploy a specialized small RNA-based silencing system, called the PIWI-interacting RNA (piRNA) pathway, to prevent unwanted expression of transposable elements (TEs) and maintain genome integrity. In Drosophila melanogaster germ cells, the majority of piRNA populations originate from dual-strand piRNA clusters, genomic regions highly enriched in TE fragments, via an elaborate machinery centered on the Heterochromatin Protein 1 homolog, Rhino. Although Rhino binds to peptides carrying tri-methylated H3K9 in vitro, it is not fully understood why in vivo only a fraction of H3K9me3-decorated heterochromatin is occupied by Rhino. Recent work revealed that Rhino is recruited to a subset of piRNA clusters by Kipferl. Here we identify a Kipferl-independent mode of Rhino recruitment that, in addition to the previously established role of H3K9me3, also depends on the histone H3 lysine 27 methyltransferase Enhancer of Zeste. At Kipferl-independent sites, we find that Rhino specifically binds to loci marked by both H3K9me3 and H3K27me3 via its chromodomain. Although the exact mechanism of how Rhino binding is influenced by dual histone modifications remains unclear from a structural and biochemical perspective, our work suggests that combinatorial modifications may regulate the specificity of chromatin-binding protein interactions. These findings provide an enhanced understanding of how Rhino targets piRNA source loci, highlighting the sophisticated epigenetic landscape governing TE silencing in Drosophila germ cells.

The present study aimed to investigate the clinicopathological features and diagnostic criteria for differentiating between chordoma and chordoid meningioma. A case of chordoma was retrospectively analyzed using clinical, radiographic, histological and immunohistochemical data, alongside a literature review. A 59-year-old male patient was admitted with headaches and dizziness persisting for 2 months without any obvious precipitating factors. The patient underwent two intracranial tumor resections between March 2022 and December 2023. The pathology report from the first surgery indicated that the tumor was composed of cords of epithelioid cells with vacuolated cytoplasm embedded in a basophilic stroma. Immunohistochemical analysis showed positivity for cytokeratin, vimentin, epithelial membrane antigen, synaptophysin, cytokeratin 8/18 and E-cadherin, with a Ki-67 proliferation index of 3%. Progesterone receptor, D2-40, glial fibrillary acidic protein, S100 and SOX10 staining were negative. Based on the pathology and immunohistochemical findings, the diagnosis was determined to be a chordoma-like meningioma (World Health Organization Grade 2). The pathology report from the second surgery revealed a tumor composed of cords and isolated epithelioid cells with intracytoplasmic vacuoles within a myxoid matrix. However, immunohistochemical analysis indicated positivity for Brachyury, leading to a diagnosis of chordoma. In conclusion, the histological morphology of chordoma is similar to that of chordoid meningioma and lacks clinical specificity. Immunohistochemical staining of tumor markers assists in both the diagnosis and differential diagnosis. Currently, treatment for chordoma and choroid mengioma primarily focuses on surgical resection, which is associated with high rates of relapse. The differential diagnosis predominantly influences the postoperative treatment strategy.

Globally, the incidence and death rates associated with cancer persist in rising, despite considerable advancements in cancer therapy. Although some malignancies are manageable by a mix of chemotherapy, surgery, radiation, and targeted therapy, most malignant tumors either exhibit poor responsiveness to early identification or endure post-treatment survival. The prognosis for prostate cancer (PCa) is unfavorable since it is a perilous and lethal malignancy. The capacity of phytochemical and nutraceutical chemicals to repress oncogenic lncRNAs and activate tumor suppressor lncRNAs has garnered significant attention as a possible strategy to diminish the development, proliferation, metastasis, and invasion of cancer cells. A potential technique to treat cancer and enhance the sensitivity of cancer cells to existing conventional therapies is the use of phytochemicals with anticancer characteristics. Functional studies indicate that lncRNAs modulate drug resistance, stemness, invasion, metastasis, angiogenesis, and proliferation via interactions with tumor suppressors and oncoproteins. Among them, numerous lncRNAs, such as HOTAIR, PlncRNA1, GAS5, MEG3, LincRNA-21, and POTEF-AS1, support the development of PCa through many molecular mechanisms, including modulation of tumor suppressors and regulation of various signal pathways like PI3K/Akt, Bax/Caspase 3, P53, MAPK cascade, and TGF-β1. Other lncRNAs, in particular, MALAT-1, CCAT2, DANCR, LncRNA-ATB, PlncRNA1, LincRNA-21, POTEF-AS1, ZEB1-AS1, SChLAP1, and H19, are key players in regulating the aforementioned processes. Natural substances have shown promising anticancer benefits against PCa by altering essential signaling pathways. The overexpression of some lncRNAs is associated with advanced TNM stage, metastasis, chemoresistance, and reduced survival. LncRNAs possess crucial clinical and transitional implications in PCa, as diagnostic and prognostic biomarkers, as well as medicinal targets. To impede the progression of PCa, it is beneficial to target aberrant long non-coding RNAs using antisense oligonucleotides or small interfering RNAs (siRNAs). This prevents them from transmitting harmful messages. In summary, several precision medicine approaches may be used to rectify dysfunctional lncRNA regulatory circuits, so improving early PCa detection and eventually facilitating the conquest of this lethal disease. Due to their presence in biological fluids and tissues, they may serve as novel biomarkers. Enhancing PCa treatments mitigates resistance to chemotherapy and radiation.

Epigenetic mechanisms are integral to plant growth, development, and adaptation to environmental stimuli. Over the past two decades, our comprehension of these complex regulatory processes has expanded remarkably, producing a substantial body of knowledge on both locus-specific mechanisms and genome-wide regulatory patterns. Studies initially grounded in the model plant Arabidopsis have been broadened to encompass a diverse array of crop species, revealing the multifaceted roles of epigenetics in physiological and agronomic traits. With recent technological advancements, epigenetic regulations at the single-cell level and at the large-scale population level are emerging as new focuses. This review offers an in-depth synthesis of the diverse epigenetic regulations, detailing the catalytic machinery and regulatory functions. It delves into the intricate interplay among various epigenetic elements and their collective influence on the modulation of crop traits. Furthermore, it examines recent breakthroughs in technologies for epigenetic modifications and their integration into strategies for crop improvement. The review underscores the transformative potential of epigenetic strategies in bolstering crop performance, advocating for the development of efficient tools to fully exploit the agricultural benefits of epigenetic insights.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with ~7% 5-year overall survival reflecting early metastasis and rapid acquired chemoresistance. Immunotherapy briefly extends overall survival in ~15% cases, yet predictive biomarkers are lacking. Targeted therapies are beginning to show promise, with a recently approved delta-like ligand 3 (DLL3)-targeted therapy impacting the treatment landscape. The increased availability of patient-faithful models, accumulating human tumour biobanks and numerous comprehensive molecular profiling studies have collectively facilitated the mapping and understanding of substantial intertumoural and intratumoural heterogeneity. Beyond the almost ubiquitous loss of wild-type p53 and RB1, SCLC is characterized by heterogeneously mis-regulated expression of MYC family members, yes-associated protein 1 (YAP1), NOTCH pathway signalling, anti-apoptotic BCL2 and epigenetic regulators. Molecular subtypes are based on the neurogenic transcription factors achaete-scute homologue 1 (ASCL1) and neurogenic differentiation factor 1 (NEUROD1), the rarer non-neuroendocrine transcription factor POU class 2 homeobox 3 (POU2F3), and immune- and inflammation-related signatures. Furthermore, SCLC shows phenotypic plasticity, including neuroendocrine-to-non-neuroendocrine transition driven by NOTCH signalling, which is associated with disease progression, chemoresistance and immune modulation and, in mouse models, with metastasis. Although these features pose substantial challenges, understanding the molecular vulnerabilities of transcription factor subtypes, the functional relevance of plasticity and cell cooperation offer opportunities for personalized therapies informed by liquid and tissue biomarkers.

Targeted covalent inhibition is a promising strategy to address the high dose and acquired drug resistance issues of the first-generation EZH2 noncovalent inhibitors. Recently we have reported a new generation of highly potent EZH2 covalent inhibitors, but further optimization to enhance aqueous solubility is required. Here, we described the systematic optimization of EPZ-6438 by preserving the aqueous groups, resulting in the identification of a highly potent and selective EZH2 covalent inhibitor 13, which displayed nanomolar potency in biochemical and cellular assays. Moreover, SAM competition experiments preliminarily confirmed that 13 was noncompetitive with SAM, leading to the remarkable reduction of the H3K27Me3 marker. In addition, 13 exhibited superior cell growth inhibition in the EZH2 mutant cancer cell lines. The discovery of 13 holds promise for the development of highly potent EZH2 covalent inhibitors.

The LCORL-NCAPG locus is a major quantitative trait locus (QTL) on bovine chromosome 6 (BTA6) that influences growth and carcass composition in cattle. To further understand the molecular mechanism responsible for the phenotypic changes associated with this locus, twenty-four Charolais-sired calves were selected for muscle transcriptome analysis based on alternative homozygous LCORL-NCAPG haplotypes (i.e., 12 "QQ" and 12 "qq", where "Q" is a haplotype harboring variation associated with increased growth). At 300 days of age, a biopsy of the longissimus dorsi muscle was collected from each animal for RNA sequencing.

Gene expression analysis identified 733 genes as differentially expressed between QQ and qq animals (q-value < 0.05). Notably, LCORL and genes known to be important regulators of growth such as IGF2 were upregulated in QQ individuals, while genes associated with adiposity such as FASN and LEP were downregulated, reflecting the increase in lean growth associated with this locus. Gene set enrichment analysis demonstrated QQ individuals had downregulation of pathways associated with adipogenesis, alongside upregulation of transcripts for cellular machinery essential for protein synthesis and energy metabolism, particularly ribosomal and mitochondrial components.

The differences in the muscle transcriptome between QQ and qq animals imply that muscle hypertrophy may be metabolically favored over accumulation of fat in animals with the QQ haplotype. Our findings also suggest this haplotype could be linked to a difference in LCORL expression that potentially influences the downstream transcriptional effects observed, though further research will be needed to confirm the molecular mechanisms underlying the associated changes in phenotype.

Quiescence cancer stem-like cells may play key roles in promoting tumor cell heterogeneity and recurrence for many tumors, including glioblastoma (GBM). Here we show that the protein acetyltransferase KAT5 is a key regulator of transcriptional, epigenetic, and proliferative heterogeneity impacting transitions into G0-like states in GBM. KAT5 activity suppresses the emergence of quiescent subpopulations with neurodevelopmental progenitor characteristics, while promoting GBM stem-like cell (GSC) self-renewal through coordinately regulating E2F- and MYC- transcriptional networks with protein translation. KAT5 inactivation significantly decreases tumor progression and invasive behavior while increasing survival after standard of care. Further, increasing MYC expression in human neural stem cells stimulates KAT5 activity and protein translation, as well as confers sensitivity to homoharringtonine, to similar levels to those found in GSCs and high-grade gliomas. These results suggest that the dynamic behavior of KAT5 plays key roles in G0 ingress/egress, adoption of quasi-neurodevelopmental states, and aggressive tumor growth in gliomas.

The mechanisms that regulate HIV-1 latency are not fully elucidated. Our previous studies showed that an HIV-1 antisense transcript (AST) promotes the deposition of histone modifications at the HIV-1 5' long terminal repeat, causing a closed chromatin state that suppresses viral transcription. Here, we report that ectopic expression of AST in CD4+ T cells from people living with HIV-1 undergoing antiretroviral therapy hinders the reactivation of viral transcription in response to ex vivo stimulation with pharmacologic and T cell receptor agonists, thus preventing the reversal of latency. We defined the structural domains and sequence motifs of AST that contribute to its latency-promoting functions. Last, we carried out an unbiased proteomic screen of AST interactors that revealed an array of host factors both previously known and not known to suppress HIV-1 expression. Our studies identify AST as a first-in-class biological molecule that is capable of enforcing HIV-1 latency and with actionable curative potential.

Tissue-based biomarkers that identify women with increased breast cancer risk are needed for cancer prevention. Enhancer of zeste 2 (EZH2) and fatty acid synthase (FASN) are associated with breast cancer aggressiveness, but their expression in normal breast tissues and association with breast cancer risk factors are unclear. Further, there is a need to characterize healthy breast tissue cohorts for unbiased biomarker evaluation. In this study, we employed the Susan G. Komen healthy volunteer tissue bank to evaluate EZH2 and FASN expression and their relationship to breast cancer risk factors. Normal breast core biopsies from 40 healthy donors with low or high Gail scores (<11 or >20, respectively) and normal or obese body mass index (BMI, <25 kg/m 2 or >30 kg/m 2 , respectively) were stained for H&E, EZH2, and FASN and scored independently and blindly using the Allred method. We analyzed the associations between EZH2 and FASN with Gail score, BMI, menopausal status, hormone replacement therapy (HRT), and family history of breast cancer. None of the donors had BRCA1/2 mutations or developed breast cancer after 5 to 9 years. We found that premenopausal women had significantly higher expression of FASN and that EZH2 was higher with increasing Gail risk scores, compared with postmenopausal women. In postmenopausal women, increased EZH2 expression was associated with >5 years of HRT compared with <1 year or no HRT. No associations were found with BMI. This study provides validation of a healthy breast tissue cohort and initial characterization of EZH2 and FASN and their associations with breast cancer risk factors.

While progressive striatal gene expression changes and epigenetic alterations are a prominent feature of Huntington's disease (HD), the mechanistic basis remains poorly understood. Using chromatin immunoprecipitation and sequencing (ChIP-seq), we show that the huntingtin protein (HTT) reproducibly occupies specific locations in the mouse genome. Striatal HTT ChIP-seq peaks were enriched in coding regions of spiny projection neuron identity genes that were found to have reduced expression in HD patients and mouse models, and had reduced occupancy in expanded polyglutamine HTT knock-in mice (HttQ111/Q111). By contrast, HTT occupancy was depleted near genes that are upregulated in HD. ChIP-seq of striatal histone modifications revealed genotype-specific colocalization of HTT with active chromatin marks and enhancer of zeste homolog 2 (EZH2), a key enzymatic component of the PRC2 complex. In the vicinity of genes that are differentially regulated in HD, greater HTT occupancy in HttQ111/Q111 vs wild-type mice was associated with increased EZH2 occupancy, increased H3K4me3 levels and decreased H3K27me3 levels. Our study suggests that HTT-chromatin interactions may play a role in organizing chromatin and promoting cell type-specific gene expression, with HTT occupancy predicting transcriptional dysregulation in HD.

Heterochromatin is a highly condensed chromatin structure observed in the nuclei of eukaryotic cells. It plays a pivotal role in repressing undesired gene expression and establishing functional chromosomal domains, including centromeres and telomeres. Heterochromatin is characterized by specific histone modifications and the formation of higher-order chromatin structures mediated by proteins, such as HP1 and Polycomb repressive complexes (PRCs), which recognize the specific histone modifications. Recent studies have identified the involvement of non-coding RNAs (ncRNAs) and intrinsically disordered proteins (IDPs) in heterochromatin, leading to the proposal of a new model in which liquid-liquid phase separation (LLPS) contributes to heterochromatin formation and function. This emerging model not only broadens our understanding of heterochromatin's molecular mechanisms but also provides insights into its dynamic regulation depending on cellular context. Such advancements pave the way for exploring heterochromatin's role in genome organization and stability, as well as its implications in development and disease.

This study aims to explore the role of enhancer of zeste homolog 2 (EZH2)-mediated histone methylation in basic fibroblast growth factor (bFGF)-induced angiogenesis of human umbilical vein endothelial cells (HUVECs). EZH2, vascular endothelial growth factor A (VEGFA), miR-340-5p, and nuclear factor-erythroid 2-related factor 2 (NRF2) expressions in bFGF-induced HUVECs were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. After transfection of EZH2 siRNA, NRF2 siRNA, or miR-340-5p inhibitor, cell migration and angiopoiesis were assessed by Transwell and tube formation assays. Chromatin immunoprecipitation (ChIP) was performed to analyze the enrichment of EZH2 or trimethylated H3 lysine 27 (H3K27me3) on NRF2 promoter. The binding between NRF2 and miR-340-5p was verified by ChIP and dual-luciferase assay. EZH2 was highly expressed while miR-340-5p and NRF2 were poorly expressed in bFGF-induced HUVECs. Silence of EZH2 restrained HUVEC migration, and reduced the number of branches and tube length. Mechanically, EZH2 enhances the enrichment of H3K27me3 on the NRF2 promoter, thereby repressing NRF2 expression and further leading to transcriptional repression of miR-340-5p. In conclusion, EZH2 inhibits the NRF2/miR-340-5p axis and promotes bFGF-induced angiogenesis of HUVECs by increasing the H3K27me3 modification on the NRF2 promoter.

Recognition of methylarginine marks by effector proteins ("readers") is a critical link between arginine methylation and various cellular processes. Recently, we identified methylation of AKT1 at arginine-391 (R391), but the reader for this methylation has yet to be characterized. Here, we show that bromodomain-containing protein 9 (BRD9), a reader of acetylated lysine, unexpectedly recognizes methylated R391 of AKT1 through an aromatic cage in its bromodomain. Disrupting the methylarginine reader function of BRD9 suppresses AKT activation and tumorigenesis. RNA sequencing data show that BRD9 and AKT coregulate a hallmark transcriptional program in part through enhancer of zeste homolog 2 (EZH2)-mediated methylation of histone-3 lysine-27. We also find that inhibitors of BRD9 and EZH2 display synergistic effects on suppression of cell proliferation and tumor growth. Collectively, our study reveals a previously unknown function of BRD9 and a potential therapeutic strategy for cancer treatment by combining BRD9 and EZH2 inhibitors.

Differentiation of antigen-activated B cells into proproliferative germinal center (GC) B cells depends on the activity of the transcription factors myelocytoma (MYC) and B-cell lymphoma 6 (BCL6), and the epigenetic writers disruptor of telomeric silencing 1-like (DOT1L) and enhancer of zeste homolog 2 (EZH2). GCB-like diffuse large B-cell lymphomas (GCB-DLBCLs) arise from GCB cells and closely resemble their cell of origin. Given the dependency of GCB cells on DOT1L and EZH2, we investigated the role of these epigenetic regulators in GCB-DLBCLs and observed that GCB-DLBCLs synergistically depend on the combined activity of DOT1L and EZH2. Mechanistically, inhibiting both enzymes led to enhanced derepression of polycomb repressive complex 2 target genes compared with EZH2 single treatment, along with the upregulation of BCL6 target genes and suppression of MYC target genes. The sum of all these alterations results in a "cell identity crisis," wherein GCB-DLBCLs lose their proproliferative GC identity and partially undergo plasma cell differentiation, a state associated with poor survival. In support of this model, combined epidrugging of DOT1L and EZH2 prohibited the outgrowth of human GCB-DLBCL xenografts in vivo. We conclude that the malignant behavior of GCB-DLBCLs strongly depends on DOT1L and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL.

We demonstrate that carcinogenesis and multi-therapy resistance in multiple myeloma (MM)-a treatable yet incurable plasma cell malignancy-are driven by epigenetic dysregulation. In this new paradigm, genomic and cytogenetic events unlock epigenetic plasticity, reshaping MM cell biology to evade tumor microenvironment constraints and therapeutic pressure. These conclusions are derived from a newly assembled cohort of nearly 1,000 patients, spanning premalignant to late-stage refractory MM, comprehensively characterized at molecular and clinical levels. Our findings provide a unifying framework to explain inter-patient genomic heterogeneity and the emergence of therapy resistance in sequential samples without new genomic alterations. In conclusion, we propose targeting epigenetic plasticity-mediated plasma cell evasion as a promising therapeutic strategy in MM.

Targeted protein degradation through autophagosome-tethering compounds (ATTECs) that bypasses the ubiquitination process has garnered increasing attention. LC3B, a key protein in autophagosome formation, recruits substrates into the autophagy-lysosome system for degradation. In this study, we systematically optimized 2,4-quinazolinedione derivatives as LC3B-recruiting fragments, utilizing the CDK9 indicator. By attaching the designed LC3B-recruiting fragment to CDK9 inhibitor SNS-032 through a linker, the resulting bifunctional ATTEC molecule simultaneously degraded CDK9 and its associated Cyclin T1. Two-dimensional NMR experiments confirmed the direct interaction between the novel LC3B-recruiting fragments and LC3B. Mechanistic studies elucidated that degradation occurred via an LC3B-dependent autophagy-lysosomal pathway. Additionally, the general applicability of leveraging LC3B-recruiting fragments linked to inhibitors for the targeted degradation of protein complexes was validated with PRC2 and CDK2/4/6 along with their respective Cyclins. This work provides a series of novel LC3B-recruiting fragments that enrich the ATTEC toolbox and can be applied to the degradation of diverse intracellular disease-causing proteins.

Background: The blood-brain barrier (BBB) plays an important role in regulating homeostasis of the central nervous system (CNS), and it is an obstacle for molecules with a molecular weight higher than 500 Da seeking to reach it, making many drugs ineffective simply because they cannot be delivered to where they are needed. As a result, crossing the BBB remains the rate-limiting factor in brain drug delivery during the treatment of brain diseases, specifically tumors such as diffuse intrinsic pontine glioma (DIPG), a highly aggressive pediatric tumor with onset in the pons Varolii, the middle portion of the three contiguous parts of the brainstem, located above the medulla and below the midbrain. Methods: Currently, radiotherapy (RT) relieves DIPG symptoms but chemotherapy drugs do not lead to significant results as they do not easily cross the BBB. Focused ultrasound (FUS) and microbubbles (MBs) can temporarily open the BBB, facilitating radiotherapy and the entry of drugs into the CNS. A patient-derived xenograft DIPG model exposed to high-intensity focalized ultrasound (HIFU) or low-intensity focalized ultrasound (LIFU) combined with MBs was treated with doxorubicin, panobinostat, olaparib, ONC201 (Dordaviprone®) and anti-PD1. Panobinostat has also been used in children with diffuse midline glioma, a broad class of brain tumors to which DIPG belongs. Results: Preliminary studies were performed using FUS to temporarily open the BBB and allow a milder use of radiotherapy and facilitate the passage of drugs through the BBB. The data collected show that after opening the BBB with FUS and MBs, drug delivery to the CNS significantly improved. Conclusions: FUS associated with MBs appears safe and feasible and represents a new strategy to increase the uptake of drugs in the CNS and therefore enhance their effectiveness. This review reports pre-clinical and clinical studies performed to demonstrate the usefulness of FUS in patients with DIPG treated with some chemotherapy. The papers reviewed were published in PubMed until the end of 2024 and were found using a combination of the following keywords: diffuse intrinsic pontine glioma (DIPG), DIPG H3K27-altered, blood-brain barrier and BBB, focused ultrasound (FUS) and radiotherapy (RT).

Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3), which promotes heterochromatin formation and gene silencing. Expression of EZH2 is frequently elevated in various malignancies, including hepatocellular carcinoma (HCC). Silencing of EZH2 has been pursued as a promising strategy to halt cancer progression. Here, we identified antisense oligonucleotides (ASOs) that efficiently silence EZH2 through promoting skipping of its exon 14, an exon encoding part of the essential CXC domain, increasing production of an internally shortened isoform that exerts dominant negative effect on the full-length EZH2. A lead ASO, hybridizing to an exonic splicing enhancer element bound by SRSF3, robustly promoted exon 14 skipping not only in cultured human HCC cell lines but also in mouse peripheral tissues after systemic administration, leading to dramatic reduction of EZH2 and H3K27me3 levels. The lead ASO potently inhibited HCC cell proliferation through multiple mechanisms including enhanced apoptosis, cell-cycle arrest, and reversed epithelial-mesenchymal transition, which is likely attributable to the suppression of diverse cancer-related pathways. In an orthotopic xenograft HCC mouse model, ASO treatment repressed tumor growth, improved tissue phenotype, and extended the median survival. Our data highlight therapeutic potential of the lead exon-skipping ASO in treating HCC.

Almost all patients of Neurofibromatosis Type I (NF1) develop benign peripheral nerve tumors called neurofibromas, which are derived from neural crest Schwann cell lineage progenitors with biallelic NF1 gene mutations. More than 90% of NF1 patients develop dermal neurofibromas (DN), and 25-50% develop plexiform neurofibromas (PN). In 8-13% of individuals with NF1, PN can transform into malignant peripheral nerve sheath tumors (MPNSTs), a type of nerve soft tissue sarcoma that is the main cause of mortality of NF1 patients. In addition to arising from benign neurofibromas (50%), MPNSTs can also occur spontaneously (~40%) or following radiation therapy (~10%). Treatment for MPNST is limited to complete resection with negative margins. Still, the high recurrence of MPNST is a major concern. However, full resection of the pre-malignant lesions can largely reduce the recurrence and mortality of patients. So, early diagnosis and distinguishing malignancy from benign and premalignant lesions are particularly important. During the progression from benign neurofibromas to malignancy, a variety of changes including tumor morphology, genetic mutations, expression of multiple signaling pathways-related proteins and genome instability gradually occur. In this review, we detail these changes with the goals of identifying the histological and/or molecular signs of malignancy initiation, and an optimal therapeutic intervention window, to inhibit tumor progression and reduce the rate of mortality.

Prostate cancer exhibits significant racial disparities, with African American (AA) individuals showing ∼64% higher incidence and 2.3 times greater mortality rates compared to their Caucasian (CA) counterparts. Understanding the complex interplay of genetic, environmental, lifestyle, socioeconomic, and healthcare access factors is crucial for developing effective interventions to reduce this disproportionate burden. This study aims to uncover the genetic and transcriptomic differences driving these disparities through a comprehensive analysis using RNA sequencing (RNA-seq) and exome sequencing of prostate cancer tissues from both Black and White patients. Our transcriptomics analysis revealed enhanced activity in pathways linked to immune response and cellular interactions in AA prostate cancer samples, with notable regulation by histone-associated transcription factors (HIST1H1A, HIST1H1D, and HIST1H1B) suggests potential involvement of histone modification mechanisms. Additionally, pseudogenes and long non-coding RNAs (lncRNAs) among the regulated genes indicate non-coding elements' role in these disparities. Exome sequencing identified unique variants in AA patient samples within key genes, including TP73 (tumor suppression), XYLB (metabolism), ALDH4A1 (oxidative stress), PTPRB (cellular signaling), and HLA-DRB5 (immune response). These genetic variations likely contribute to disease progression and therapy response disparities. This study highlights the importance of considering genetic and epigenetic variations in developing tailored therapeutic approaches to improve treatment efficacy and reduce mortality rates across diverse populations.

Tuberculosis (TB) persists as a significant health threat, affecting millions of people all over the world. Despite years of control measures, the elimination of TB has become a difficult task as morbidity and mortality rates remain unaffected for several years. Developing new diagnostics and therapeutics is paramount to keeping TB under control. However, it largely depends upon understanding the pathogenic mechanisms of Mycobacterium tuberculosis (Mtb), the causative agent of TB. Mtb is an intracellular pathogen capable of subverting the defensive functions of the immune cells, and it can survive and multiply within humans' mononuclear phagocytes. Emerging evidence indicates that long non-coding RNAs (lncRNAs), a class of RNA molecules with limited coding potential, are critical players in this intricate game as they regulate gene expression at transcriptional and post-transcriptional levels and also by chromatin modification. Moreover, they have been shown to regulate cellular processes by controlling the function of other molecules, such as DNA, RNA, and protein, through binding with them. Recent studies have shown that lncRNAs are differentially regulated in the tissues of TB patients and cells infected in vitro with Mtb. Some dysregulated lncRNAs are associated with essential roles in modulating immune response, apoptosis, and autophagy in the host cells, adding a new dimension to TB pathogenesis. In this article, we provide a comprehensive review of the recent literature in this field and the impact of lncRNAs in unraveling pathogenic mechanisms in TB. We also discuss how the studies involving lncRNAs provide insight into TB pathogenesis, especially Mtb-host interactions.

Neuronal maturation is guided by changes in the chromatin landscape that control developmental gene expression programs. Histone bivalency, the co-occurrence of activating and repressive histone modifications, has emerged as an epigenetic feature of developmentally regulated genes during neuronal maturation. Although initially associated with early embryonic development, recent studies have shown that histone bivalency also exists in differentiated and mature neurons. In this review, we discuss methods to study bivalency in specific populations of neurons and summarize emerging studies on the function of bivalency in central nervous system neuronal maturation and in adult neurons.

Flowering is an important developmental transition from the vegetative to the reproductive phase in plants. The role of histone modifications in the regulation of flowering time is well documented; however, their role in Chinese cabbage remains unclear. In the present study, we investigated a Chinese cabbage late-bolting mutant, M1407, which displayed a late-bolting time phenotype after vernalization. MutMap, kompetitive allele-specific PCR (KASP), and RNA interference (RNAi) analyses demonstrated that BrSWN, which encodes a catalytic subunit of the Polycomb repressive complex 2 (PRC2), mediates the flowering time in Chinese cabbage. BrSWN was functionally conserved and localized to the nucleus. Both BrSWN and Brswn interacted with BrVRN2 to form PRC2-like complexes. The BrSWN mutation decreased the global histone H3 lysine 27 trimethylation (H3K27me3) level and impaired the enrichment of H3K27me3 in the regions of flowering repressors, BrFLC2 and BrFLC3. This study demonstrates that BrSWN mediates the regulation of bolting time modulated by H3K27me3 deposition, providing insights into the epigenetic mechanisms regulating flowering time in Chinese cabbage.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide, posing significant challenges to healthcare systems. Despite advances in medical interventions, the molecular mechanisms underlying CVDs are not yet fully understood. For decades, protein-coding genes have been the focus of CVD research. However, recent advances in genomics have highlighted the importance of long non-coding RNAs (lncRNAs) in cardiovascular health and disease. Changes in lncRNA expression specific to tissues may result from various internal or external factors, leading to tissue damage, organ dysfunction, and disease. In this review, we provide a comprehensive discussion of the regulatory mechanisms underlying lncRNAs and their roles in the pathogenesis and progression of CVDs, such as coronary heart disease, atherosclerosis, heart failure, arrhythmias, cardiomyopathies, and diabetic cardiomyopathy, to explore their potential as therapeutic targets and diagnostic biomarkers.

Tropical theileriosis is a significant tick-borne disease affecting cattle. For decades an empirical live attenuated vaccine has been the primary method of controlling disease. The vaccine is produced through prolonged culture of Theileria annulata schizont-transformed macrophages, but how loss of virulence occurs remains unclear. Notably attenuated (vaccine) macrophages display dampened dissemination potential compared with their original, virulent counterparts. In addition, parasite schizonts in attenuated macrophages have significantly lost their ability to differentiate into merozoites. This review discusses the changes that occur during long-term passage of T. annulata-transformed bovine macrophages and how they contribute to loss of virulence, defined as heightened dissemination. Finally, we also suggest that a common parasite-dependent pathway is potentially involved in both macrophage dissemination and parasite merogony.

Aging of hematopoietic stem cells (HSCs) is implicated in various aging phenotypes, including immune dysfunction, anemia, and malignancies. The role of HSC proliferation in driving these aging phenotypes, particularly under stress conditions, remains unclear. Therefore, we induced forced replications of HSCs in vivo by a cyclical treatment with low-dose fluorouracil (5FU) and examined the impact on HSC aging. Our findings show that proliferative stress induces several aging phenotypes, including altered leukocyte counts, decreased lymphoid progenitors, accumulation of HSCs with high expression of Slamf1, and reduced reconstitution potential, without affecting stem cell self-renewal capacity. The divisional history of HSCs was imprinted in the DNA methylome, consistent with functional decline. Specifically, DNA methylation changes included global hypermethylation in non-coding regions and similar frequencies of hypo- and hyper-methylation at promoter regions, particularly affecting genes targeted by the PRC2 complex. Importantly, initial forced replication promoted DNA damage repair accumulated with age, but continuous proliferative stress led to the accumulation of double-strand breaks, independent of functional decline. Overall, our results suggest that HSC proliferation can drive some aging phenotypes primarily through epigenetic mechanisms, including DNA methylation changes.

Paternal lifestyle and environmental exposures can alter epigenetic changes in sperm and play a critical role in the offspring's future health, yet the underlying mechanisms remain elusive. The present study established a model of paternal obesity and found that the increased levels of H3K27me3 in sperm persist into the 8-cell embryo stage, resulting in a transgenerational decrease of Manf, which causes endoplasmic reticulum stress and activates the GRP78-PERK-EIF2α-ATF4-CHOP axis. This consequently leads to impaired glucose metabolism and apoptosis in the liver of female offspring. Based on these findings, the F0 mice are treated with 3-deazaneplanocin A, an EZH2 inhibitor, which successfully prevented metabolic dysfunction in F0 mice of the high-fat diet (HFD) group. Meanwhile, intravenous injection of recombinant human MANF in F1 female offspring can successfully rescue the metabolic dysfunction in the HFD-F1 group. These results demonstrate that paternal obesity triggers transgenerational metabolic dysfunction through sperm H3K27me3-dependent epigenetic regulation. The present study also identifies the H3K27me3-MANF pathway as a potentially preventive and therapeutic strategy for diabetes, although further studies are needed to validate its clinical applicability.

Atrial fibrillation (AF) is a prevalent and chronic cardiovascular disorder associated with various pathophysiological alterations, including atrial electrical and structural remodeling, disrupted calcium handling, autonomic nervous system dysfunction, aberrant energy metabolism, and immune dysregulation. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play a significant role in the pathogenesis of AF.

This discussion aims to elucidate the involvement of AF-related lncRNAs, with a specific focus on their role as miRNA sponges that modulate crucial signaling pathways, contributing to the progression of AF. We also address current limitations in AF-related lncRNA research and explore potential future directions in this field. Additionally, we summarize feasible strategies and promising delivery systems for targeting lncRNAs in AF therapy.

In conclusion, targeting AF-related lncRNAs holds substantial promise for future investigations and represents a potential therapeutic avenue for managing AF.

Aberrant upregulation or mutations of EZH2 frequently occur in human cancers. However, the clinical benefits of EZH2 inhibitors (EZH2i) remain unsatisfactory for majority of solid tumors. Therefore, there is an urgent need to develop new strategies to expand the therapeutic benefits of EZH2i. Nanocarriers have gained increased attention due to their advantages of prolonged blood circulation, enhanced cellular uptake, and active targeting capabilities. This study aims to address the challenges of EZH2i GSK126's limited efficacy and severe adverse effects against solid tumors.

A nano delivery system was developed by encapsulating GSK126 within albumin nanoparticles (GSK126 NPs).

The prepared GSK126 NPs exhibited a small spherical core with an average diameter of 30.09 nm ± 1.55 nm, high drug loading capacity (16.59% ± 2.86%) and good entrapment efficiency (99.53% ± 0.208%). GSK126 NPs decreased tumor weight and volume in the B16F10 xenograft mice, while such effects were not observed in the free GSK126 group. Subsequently, histological analysis demonstrated that GSK126 NPs significantly alleviated lipid-associated liver toxicity. Additionally, GSK126 NPs can partially counteract the effects of GSK126 on MDSCs, particularly by decreasing the infiltration of M-MDSCs into tumors.

Albumin-based EZH2i NPs have potent anti-cancer efficacy with tolerable adverse effects, providing promising opportunity for future clinical translation in treating solid tumors.

Circular RNAs (circRNAs) are a large family of non-coding RNAs characterized by a single-stranded, covalently closed structure, predominantly synthesized through a back-splicing mechanism. While thousands of circRNAs have been identified, only a few have been functionally characterized. Although circRNAs are less abundant than other RNA types, they exhibit exceptional stability due to their covalently closed structure and demonstrate high cell and tissue specificity. CircRNAs play a critical role in maintaining cellular homeostasis by influencing gene transcription, translation, and post-translation processes, modulating the immune system, and interacting with mRNA, miRNA, and proteins. Abnormal circRNA expression has been associated with a wide range of human diseases and various infections. Due to their remarkable stability in body fluids and tissues, emerging research suggests that circRNAs could serve as diagnostic and therapeutic biomarkers for these diseases. This review focuses on the emerging role of circRNAs in various human diseases, exploring their biogenesis, molecular functions, and potential clinical applications as diagnostic and therapeutic biomarkers with current evidence, challenges, and future perspectives. The key theme highlights the significance of circRNAs in regulating gene expression, their involvement in diseases like cancer, neurodegenerative disorders, cardiovascular diseases, and diabetes, and their potential use in translational medicine for developing novel therapeutic strategies. We also discuss recent clinical trials involving circRNAs. Thus, this review is important for both basic researchers and clinical scientists, as it provides updated insights into the role of circRNAs in human diseases, aiding further exploration and advancements in the field.