BACKGROUND: Physical, chemical, and biological factors in the environment constantly influence in vivo and in vitro biological processes, including diverse histone modifications involved in cancer and metabolism. However, the intricate mechanisms of acetylation regulation remain poorly elucidated. In mammalian spermatogenesis, acetylation plays a crucial role in repairing double-strand DNA breaks, regulating gene transcription, and modulating various signaling pathways.
RESULTS: This review summarizes the histone acetylation sites in the mouse testis and provides a comprehensive overview of how histone acetylation is involved in different stages of spermatogenesis under the regulation by histone deacetylases. The regulatory functions of various class histone deacetylases during spermatogenesis and the crossroad between histone acetylation and other histone modifications are highlighted. It is imperative to understand the mechanisms of histone acetylation regulated by histone deacetylases in spermatogenesis, which facilitates to prevent and treat infertility-related diseases.

Lysine methylation is a crucial post-translational modification (PTM) that significantly impacts gene expression regulation. This modification not only influences cancer development directly but also has significant implications for the immune system. Lysine methylation modulates immune cell functions and shapes the anti-tumor immune response, highlighting its dual role in both tumor progression and immune regulation. In this review, we provide a comprehensive overview of the intrinsic role of lysine methylation in the activation and function of immune cells, detailing how these modifications affect cellular processes and signaling pathways. We delve into the mechanisms by which lysine methylation contributes to tumor immune evasion, allowing cancer cells to escape immune surveillance and thrive. Furthermore, we discuss the therapeutic potential of targeting lysine methylation in cancer immunotherapy. Emerging strategies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy, are being explored for their efficacy in modulating lysine methylation to enhance anti-tumor immune responses. By targeting these modifications, we can potentially improve the effectiveness of existing treatments and develop novel therapeutic approaches to combat cancer more effectively.

Cancer immunotherapy has emerged as a promising approach for the treatment of various cancers. However, the immunosuppressive tumor microenvironment (TME) limits the efficacy of current immunotherapies. In this study, we designed a dual-responsive DNA methyltransferase inhibitor nanoprodrug ACNPs for combination therapy with oncolytic herpes simplex virus (oHSV). We found that the epigenetic inhibitor 5-Azacytidine (5-Aza) upregulated gasdermin E (GSDME) expression at the gene level, whereas the oHSV decreased the ubiquitination and degradation of GSDME to elevate its levels. Based on these observations, we further discovered that ACNPs and oHSV synergistically enhanced GSDME-mediated pyroptosis. Additionally, the combination therapy of ACNPs and oHSV effectively inhibited tumor growth, remodeled the immunosuppressive TME, and improved the efficacy of immune checkpoint blockade (ICB) therapy. These results demonstrate the potential to overcome immunosuppression through synergistic combinations, offering a promising approach for cancer immunotherapy.

OBJECTIVE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 (H3K4) and has not been implicated in human disease.
METHODS: We identify five unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models.
RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles.
CONCLUSIONS: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.

Endothelial-to-mesenchymal transition (EndMT) is a key driver of atherosclerosis. Aerobic glycolysis is increased in the endothelium of atheroprone areas, accompanied by elevated lactate levels. Histone lactylation, mediated by lactate, can regulate gene expression and participate in disease regulation. However, whether histone lactylation is involved in atherosclerosis remains unknown. Here, we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactate-dependent histone H3 lysine 18 lactylation (H3K18la) in vitro and in vivo, as well as in atherosclerotic patients\' arteries. Mechanistically, the histone chaperone ASF1A was first identified as a cofactor of P300, which precisely regulated the enrichment of H3K18la at the promoter of SNAI1, thereby activating SNAI1 transcription and promoting EndMT. We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction. Functional analysis based on Apoe KO Asf1a ECKO mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endothelium-specific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development. Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la, SNAI1 transcription, and EndMT-induced atherosclerosis. This study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis, which provides emerging therapies for atherosclerosis.

Liver fibrosis is a pathological process caused by a variety of chronic liver diseases. Currently, therapeutic options for liver fibrosis are very limited, highlighting the urgent need to explore new treatment approaches. Epigenetic modifications and epitranscriptomic modifications, as reversible regulatory mechanisms, are involved in the development of liver fibrosis. In recent years, researches in epitranscriptomics and epigenetics have opened new perspectives for understanding the pathogenesis of liver fibrosis. Exploring the epigenetic mechanisms of liver fibrosis may provide valuable insights into the development of new therapies for chronic liver diseases. This review primarily focus on the regulatory mechanisms of N6-methyladenosine (m6A) modification, non-coding RNA, and DNA methylation in organ fibrosis. It discusses the interactions between m6A modification and DNA methylation, as well as between m6A modification and non-coding RNA, providing a reference for understanding the interplay between epitranscriptomics and epigenetics.

Long non-coding RNAs (LncRNAs) are a class of RNA molecules with nucleic acid lengths ranging from 200 bp to 100 kb that cannot code for proteins, which are diverse and widely expressed in both animals and plants. Scholars have found that lncRNAs can regulate human physiological processes at the gene and protein levels, mainly through the regulation of epigenetic, transcriptional and post-transcriptional levels of genes and proteins, as well as in the immune response by regulating the expression of immune cells and inflammatory factors, and thus participate in the occurrence and development of a variety of diseases. From the downstream targets of lncRNAs, we summarize the new research progress of lncRNA mechanisms other than miRNA sponges in recent years, aiming to provide new ideas and directions for the study of lncRNA mechanisms.

Bisphenol A (BPA) is a commonly used organic compound. Over the past decades, many studies have examined the mechanisms of BPA toxicity, with BPA-induced alterations in epigenetic modifications receiving considerable attention. Particularly in the male reproductive system, abnormal alterations in epigenetic markers can adversely affect reproductive function. Furthermore, these changes in epigenetic markers can be transmitted to offspring through the father. Here, we review the effects of BPA exposure on various epigenetic markers in the male reproductive system, including DNA methylation, histone modifications, and noncoding RNA, as well as associated changes in the male reproductive function. We also reviewed the effects of father\'s exposure to BPA on offspring epigenetic modification patterns.

Phenanthrene (Phe) is a commonly occurring polycyclic aromatic hydrocarbon (PAH) found in various food sources and drinking water. Previous studies have shown that long-term exposure to Phe in male mice leads to insulin resistance in a dose-dependent manner. However, the effect of Phe on glucose homeostasis in female mice remains unknown. To address this knowledge gap, female Kunming mice were exposed to Phe through their drinking water at concentrations of 0.05, 0.5, and 5 ng/mL. After 270 d of exposure, we surprisingly discovered a low-dose effect of Phe on insulin resistance in female mice, which differed from the effect observed in male mice and showed sexual dimorphism. Specifically, insulin resistance was only observed in the 0.05 ng/mL treatment, and this low-dose effect was also reflected in the concentration of Phe in white adipose tissue (WAT). Differences in metabolic enzyme activities in the liver may potentially explain this effect. The observed sexual dimorphism in Phe exposure could be attributed to variations in estrogen (E2) level and estrogen receptor beta (ERβ) expression in WAT. These findings highlight the association between environmental factors and the development of insulin resistance, emphasizing the pathogenic effect of even low doses of Phe. Moreover, sex dependent-effect should be given more attention when studying the toxic effects of environmental pollutants.

Ewing\'s sarcoma (EWS) is a highly aggressive malignant bone tumor primarily affecting adolescents and young adults. Despite the efficacy of chemoradiotherapy in some cases, the cure rate for patients with metastatic and recurrent disease remains low. Therefore, there is an urgent need for innovative therapeutic approaches to address the challenges associated with EWS treatment. Epigenetic regulation, a crucial factor in physiological processes, plays a significant role in controlling cell proliferation, maintaining gene integrity, and regulating transcription. Recent studies highlight the importance of abnormal epigenetic regulation in the initiation and progression of EWS. A comprehensive understanding of the intricate interactions between EWS and aberrant epigenetic regulation is essential for advancing clinical drug development. This review aims to provide a comprehensive overview of both epigenetic targets implicated in EWS, integrating various therapeutic modalities to offer innovative perspectives for the clinical diagnosis and treatment of EWS.