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Tumor cells are known to enhance glycolysis, even under normoxic conditions, via the Warburg effect, producing excess lactic acid in the tumor microenvironment. Lactic acid enhances the IL-23/IL-17 pathway and induces chronic inflammation. The acidic microenvironment formed by lactic acid suppresses immune cell proliferation and activation. In the present study, we clarified that lactic acid had two novel activities for immune cells. First, lactic acid specifically enhanced acetylation at lysine 27 of histone H3 (H3K27ac) in splenic B cells and monocytes/macrophages, and this epigenetically up-regulates the expression of genes. Acetylation and methylation of other residues of histone H3 were rarely induced. Second, lactic acid induced a particularly-marked enhancement of Il10 gene expression in B cells, leading to an increase in IL-10-producing regulatory B (Breg) cells. Furthermore, two pathways should be involved in both the enhancement of H3K27ac and the induction of Breg cells by lactic acid: a direct pathway that enhances the CD40 signal in B cells, and an indirect pathway that affects B cells by activating the exchange protein directly activated by cAMP (EPAC) 1/2 in non-B cells. In tumor-bearing mice, the levels of H3K27ac of tumor-infiltrating B cells were significantly higher than splenic B cells and were suppressed by intraperitoneal injection of the EPAC1/2 inhibitor. In conclusion, tumor-derived lactic acid increases H3K27ac and IL-10-producing Breg cells, causing the suppression of anti-tumor immunity., (© 2024 UICC.)

Purpose: Although the B-cell receptor (BCR) signal plays a critical role in chronic lymphocytic leukemia (CLL) cell survival and a target of current therapies (ibrutinib targets Bruton's tyrosine kinase; idelalisib targets PI3Kδ), contribution of the cytokine-driven JAK2 pathway to the "CLL cell-survival signaling network" is largely undefined., Experimental Design: Patients with CLL were enrolled to investigate expression/activation of JAK2 and acylglycerol kinase (AGK), and their functional implication in primary CLL cell survival. A series of biochemical and molecular biology assays were employed to uncover the underlying mechanism., Results: We detected that compared with normal B cells, CLL cells aberrantly express constitutively active JAK2. Mechanistically, HSP90 forms a chaperoning complex with JAK2, resulting in its aberrant accumulation in CLL cells. We also discovered aberrant upregulation of a novel mitochondrial lipid kinase, AGK, which remains complexed with HSP90 in CLL cells activating JAK2. Although AGK is typically mitochondrial, we detected its nuclear localization in association with JAK2 in some CLL cells. Functionally, JAK2 phosphorylates its noncanonical substrate, histone H3(Y41), but not STAT3, activating transcription of diverse sets of genes in a patient-specific manner. Additionally, JAK2 activates the BCR signal in CLL cells via LYN/Bruton's tyrosine kinase axis. Targeted inhibition of JAK2 as monotherapy, or in combination with the BCR inhibitors or venetoclax (a BCL2 inhibitor), induced apoptosis synergistically in CLL cells., Conclusions: These findings suggest that aberrantly expressed AGK activates JAK2, independent of cytokine, leading to activation of diverse sets of gene transcription in CLL cells. Combined targeting of JAK2 and BCR signals or BCL2 may be effective in some patients with CLL., (©2024 American Association for Cancer Research.)

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Hepatitis B virus (HBV) is the main pathogen for HCC development. HBV covalently closed circular DNA (cccDNA) forms extra-host chromatin-like minichromosomes in the nucleus of hepatocytes with host histones, non-histones, HBV X protein (HBx) and HBV core protein (HBc). Epigenetic alterations are dynamic and reversible, which regulate gene expression without altering the DNA sequence and play a pivotal role in the regulation of HCC onset and progression. The aim of this review is to elucidate the deregulation of epigenetic mechanisms involved in the pathogenesis of HBV-related HCC (HBV-HCC), including post-translational histone and non-histone modifications, DNA hypermethylation and hypomethylation, non-coding RNA modification on HBV cccDNA minichromosomes and host factors, effecting the replication/transcription of HBV cccDNA and transcription/translation of host genes, and thus HBV-HCC progression. It is expected that the epigenetic regulation perspective provides new ways for more in-depth development of therapeutic control of HBV-HCC., (© 2025 John Wiley & Sons Ltd.)

Objective: Gliomas are the predominant form of malignant brain tumors. We investigated the mechanism of hypoxia-inducible factor-1α (HIF-1α) affecting glioma metabolic reprogramming, proliferation and invasion., Methods: Human glioma cell U87 was cultured under hypoxia and treated with small interfering (si)HIF-1α, si-B cell lymphoma-2/adenovirus E1B 19-kDa interacting protein 3 (siBNIP3), si-YT521-B homology domain 2 (siYTHDF2), 3-methyladenine and 2-deoxyglucose, with exogenous sodium lactate-treated normally-cultured cells as a lactate-positive control. Cellular hexokinase 2, lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 enzyme activities, glucose uptake, and levels of lactic acid and adenosine triphosphate (ATP), and HIF-1α, glycolysis-related proteins, mitophagy-related proteins, histone H3 lysine 18 lactylation (H3K18la) and YTHDF2 were determined by ELISA, 2-NBDG, kits, and Western blot. Extracellular acidification rate (ECAR), and cell proliferation, invasion, apoptosis and mitophagy were evaluated by extracellular flux analysis, CCK-8, Transwell, flow cytometry, and immunofluorescence staining. H3K18la-YTHDF2 relationship and YTHDF2-BNIP3 interaction were assessed by ChIP and Co-IP assays., Results: Hypoxia-induced highly-expressed HIF-1α in glioma cells increased glycolysis-related protein levels, glycolytic enzyme activities, glucose uptake, lactic acid production, ATP level and ECAR, thereby promoting metabolic reprogramming, invasion and proliferation. HIF-1α mediated metabolic reprogramming, proliferation and invasion through BNIP3-dependent mitophagy, which were partly negated by mitophagy inhibition. HIF-1α induced histone Kla modification to upregulate YTHDF2. YTHDF2 downregulation impeded YTHDF2-BNIP3 interaction and inhibited HIF-1α-induced BNIP3-dependent mitophagy, curbing glioma cell metabolic reprogramming, proliferation and invasion., Conclusions: Hypoxia-induced high HIF-1α expression upregulated YTHDF2 through hH3K18la modification, enhanced YTHDF2-BNIP3 interaction, and regulated BNIP3-dependent mitophagy-mediated metabolic reprogramming to affect glioma proliferation and invasion., (© 2025 Wiley Periodicals LLC.)

Triple-negative breast cancer (TNBC) is known for frequent copy number alterations (CNAs) and metabolic reprogramming. However, the mechanism by which CNAs of metabolic genes drive distinct metabolic reprogramming and affect disease progression remains unclear. Through an integrated analysis of our TNBC multiomic dataset (n = 465) and subsequent experimental validation, we identify copy number amplification of the metabolic gene flavin-adenine dinucleotide synthetase 1 (FLAD1) as a crucial genetic event that drives TNBC progression. Mechanistically, FLAD1, but not its enzymatically inactive mutant, upregulates the enzymatic activity of FAD-dependent lysine-specific demethylase 1 (LSD1). LSD1 subsequently promotes the expression of sterol regulatory element-binding protein 1 (SREBP1) by demethylating dimethyl histone H3 lysine 9 (H3K9me2). The upregulation of SREBP1 enhances the expression of lipid biosynthesis genes, ultimately facilitating the progression of TNBC. Clinically, pharmacological inhibition of the FLAD1/LSD1/SREBP1 axis effectively suppresses FLAD1-induced tumor progression. Moreover, LSD1 inhibitor enhances the therapeutic effect of doxorubicin and sacituzumab govitecan (SG). In conclusion, our findings reveal the CNA-derived oncogenic signalling axis of FLAD1/LSD1/SREBP1 and present a promising treatment strategy for TNBC., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Sepsis-induced neurodegeneration and cognitive dysfunction remain critical challenges worldwide. Vitamin D was reported to reduce neuronal injury and neurotoxicity and its deficiency was associated with neurocognitive disorders. This study investigates the mechanisms by which vitamin D exerts neuroprotective potential against damage-associated molecular patterns (DAMPs), specifically extracellular histones, in sepsis-related brain dysfunction., Methods: The cultured mouse hippocampal neuronal HT22 cells were exposed to 20 µg/ml exogenous histone for 24 h to induce pyroptosis and ferroptosis in the presence or absence of the active form of vitamin D, calcitriol (1 nM). A cecal ligation and puncture mouse sepsis model was used to evaluate histone release and pyroptosis/ferroptosis biomarkers in the brain together with neurobehavioral performance with or without calcitriol treatment (1 µg/kg, i.p. injection) at 24 h or 1 week after sepsis onset., Results: In vitro, histone exposure triggered both pyroptosis and ferroptosis in neuronal cells, which was significantly suppressed by calcitriol treatment with the reduced expression of caspase-1 by 38 %, GSDMD by 30 %, ACSL4 by 33 %, and the increased expression of GPX4 by 35 % (n = 6, P < 0.05). Similarly, in vivo, calcitriol treatment inhibited both neuronal pyroptosis and ferroptosis by reducing expression of pyroptosis marker, GSDMD/NeuN (11.6 ± 1.2 % vs. 19.4 ± 1.1 %) and increasing expression of ferroptosis marker, GPX4/NeuN (21.4 ± 1.7 % vs. 13.5 ± 1.1 %), in the brain of septic mice (n = 6, P < 0.01). In addition, calcitriol increased survival rate (72 % vs. 41 %) and ameliorated cognitive dysfunction of septic mice (n = 8-13, P < 0.05)., Conclusions: This study demonstrates that vitamin D exerts a neuroprotective effect against sepsis by attenuating histone-induced pyroptosis and ferroptosis. These findings highlight the potential therapeutic role of vitamin D supplementation in mitigating brain dysfunction associated with sepsis which needs for further investigation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nanoplastics (NPs) exposure could disrupt the synthesis of steroid hormones, thereby posing a potential threat to male reproductive health. However, the existing comprehension of the molecular mechanisms participating in this process remains limited, and the reversibility of NPs-triggered male reproductive toxicity is poorly understood. This investigation focused on the impact of histone modification on testosterone production in mice under long-term exposure to environmentally relevant doses of polystyrene nanoplastics (PS-NPs). The results showed 500 nm and 100 nm PS-NPs could accumulate in mouse testis, with a subsequent significant decrease following a period of self-recovery. The testosterone levels significantly increased after exposure to 500 nm and 100 nm PS-NPs, and the protein levels of CYP11A1, CYP17A1, and 17β-HSD were upregulated. Furthermore, PS-NPs exposure decreased the levels of multiple histone modifications (H3K9me1/2, H3K4me2/3, and H3K4/9ac) while increased H3K9me3 in mouse testis. Histone H3K9 methylation is linked with gene inhibition, whereas H3K4 methylation and H3K4/9 acetylation contribute to gene activation. ChIP analysis further confirmed that H3K9me2 was markedly decreased in the promoter regions of Cyp11a1 and Hsd17b. Additionally, H3K9me2 demethylase Jhdm2a was significantly increased. These findings suggested that low-level PS-NPs inhibited H3K9me2 through upregulating Jhdm2a, thereby activating key steroidogenic proteins CYP11A1 and 17β-HSD, ultimately promoting testosterone synthesis in mouse testis. Importantly, the changes in testosterone, steroidogenic proteins and histone modifications were effectively reversed upon the cessation of exposure to 500 nm and 100 nm PS-NPs. Collectively, these discoveries offer fresh perspectives on the epigenetic mechanisms underlying male reproductive endocrine disruption caused by PS-NPs, and contribute to assessing the human health hazards associated with exposure to environmental NPs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

An early step in triploblastic embryo differentiation is the formation of the three germ layers. Maternal pioneer transcription factors (TFs) bind to embryonic enhancers before zygotic genome activation, initiating germ layer specification. While maternal TFs' role in establishing epigenetic marks is known, how early pluripotent cells gain spatially restricted epigenetic identities remains unclear. We show that by the early gastrula stage, H3K4me1-marked regions become distinct in each germ layer, with certain chromatin regions forming high density H3K4me1 marked regions (HDRs). Genes associated with these HDRs are more robustly expressed compared to those associated with low density H3K4me1 marked regions (LDRs) in the genome. This process is driven by the sequential actions of maternal and zygotic factors. Knockdown of key maternal endodermal TFs (Otx1, Vegt and Foxh1) leads to a loss of endodermal H3K4me1 marks in endoderm, with a concurrent emergence of ectodermal and mesodermal marks, indicating a shift in chromatin state. This work highlights the importance of coordinated activities of maternal and zygotic TFs in defining the regionally-resolved and dynamic process of chromatin modification conferred by H3K4me1 in the early Xenopus embryo., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Lysine succinylation (Ksu) has recently emerged as a protein modification that regulates diverse functions in various biological processes. However, the systemic, precise role of lysine succinylation in erythropoiesis remains to be fully elucidated. In this study, we noted a prominent increase of succinyl-CoA and lysine succinylation during human erythroid differentiation. To explore the functional significance of succinylation, we inhibited succinylation by either knocking down key succinyltransferases or overexpressing desuccinylases. Succinylation inhibition led to suppressed cell proliferation, increased apoptosis, and disrupted erythroid differentiation. In vivo overexpression of the desuccinylase SIRT5 delayed erythroid differentiation. Furthermore, integrative proteome and succinylome analysis identified 939 succinylated proteins with 3,562 Ksu sites, distributed across various cellular compartments and involved in multiple cellular processes. Significantly, inconsistencies were observed between protein expression levels and succinylation levels, indicating that the succinylation of certain proteins may function independently of expression. Mechanistically, we implicated KAT2A-mediated succinylation of histone H3 K79, leading to chromatin remodeling and, subsequently, regulation of erythropoiesis. Specifically, we identified CYCS as a key regulator of erythropoiesis, a function that depends on its succinylation sites K28/K40. Taken together, our comprehensive investigation of the succinylation landscape during erythropoiesis provides valuable insights into its regulatory role and offers potential implications for erythroid-related diseases.

Histones are integral components of eukaryotic chromatin that have a pivotal role in the organization and function of the genome. The dynamic regulation of chromatin involves the incorporation of histone variants, which can dramatically alter its structural and functional properties. Contrary to an earlier view that limited individual histone variants to specific genomic functions, new insights have revealed that histone variants exert multifaceted roles involving all aspects of genome function, from governing patterns of gene expression at precise genomic loci to participating in genome replication, repair and maintenance. This conceptual change has led to a new understanding of the intricate interplay between chromatin and DNA-dependent processes and how this connection translates into normal and abnormal cellular functions., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. Springer Nature Limited.)

Pulmonary pleomorphic carcinoma (PC) is a rare non-small-cell lung carcinoma (NSCLC) with a poor prognosis, characterized by tumor necrosis (TN). NETosis is a form of neutrophil-specific cell death, which is morphologically characterized by prominent neutrophil infiltration and cell detritus in the necrotic foci. Seventy-six patients with pulmonary PC who underwent complete resection were enrolled. Tumor necrosis was evaluated using digitally scanned resected specimens. The regions of NETosis were quantified using citrullinated histone H3 (citH3)- and myeloperoxidase-positive regions. We examined the association between the NETosis area and the prognostic outcomes and assessed the correlation between the NETosis area and systemic inflammation. Tumor necrosis was observed in 70 patients (92%). In all the cases, the TN region was accompanied by a citH3-positive region. The patients with high NETosis area (n = 54) had significantly shorter overall survival than those with low NETosis area (n = 16) (p = 0.013). Furthermore, a high NETosis area was an independent poor prognostic factor in the multivariate analyses. Systemic inflammatory markers, including C-reactive protein (CRP), CRP-to-albumin ratio, and neutrophil-to-lymphocyte ratio, were significantly higher in patients with high NETosis area than in those with low NETosis area. Furthermore, the levels of these inflammatory markers were significantly decreased postsurgery. This study shows that in surgically resected pulmonary PC, patients with high NETosis areas have higher systemic inflammation and worse prognosis., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Biochemical crosstalk between two or more histone modifications is often observed in epigenetic enzyme regulation, but its functional significance in cells has been difficult to discern. Previous enzymatic studies revealed that Lys14 acetylation of histone H3 can inhibit Lys4 demethylation by lysine-specific demethylase 1 (LSD1). In the present study, we engineered a mutant form of LSD1, Y391K, which renders the nucleosome demethylase activity of LSD1 insensitive to Lys14 acetylation. K562 cells with the Y391K LSD1 CRISPR knockin show decreased expression of a set of genes associated with cellular adhesion and myeloid leukocyte activation. Chromatin profiling revealed that the cis-regulatory regions of these silenced genes display a higher level of H3 Lys14 acetylation, and edited K562 cells show diminished H3 mono-methyl Lys4 near these silenced genes, consistent with a role for enhanced LSD1 demethylase activity. These findings illuminate the functional consequences of disconnecting histone modification crosstalk for a key epigenetic enzyme., Competing Interests: Competing interests: P.A.C. is a co-founder of Acylin Therapeutics, which is involved in developing epigenetic agents, and has been a consultant for the pharmaceutical companies AbbVie and Constellation. He also is a co-inventor on US patent 11,565,994 B2 that concerns LSD1 and CoREST complex inhibitors. B.B.L. has received research funding from Eisai and AstraZeneca and is a shareholder and member of the scientific advisory board of Light Horse Therapeutics. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Cancer cells experience multiple reversible changes during their metastatic spread. Epigenetic reprogramming, being reversible, has emerged as a critical driver of cancer metastasis. Epigenetic modulator Enhancer of Zeste homolog 2 (EZH2) is an important candidate for such reprogramming events. Both EZH2 protein and its catalytic function (H3K27me3) have been shown to promote solid tumor metastasis, although EZH2 functional inhibition has limited impact on primary tumor growth in some cancers. The dichotomous gene regulatory roles of EZH2 and H3K27me3 are currently being investigated to understand how they collectively contribute to promote metastasis. Here, we examine the multifaceted role of EZH2 in modulating solid tumor metastasis and its therapeutic potential., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Recent advancements in Genetic Code Expansion (GCE) have significantly enhanced our understanding of post-translational modifications (PTMs), which are critical for protein regulation. GCE facilitates the precise incorporation of unnatural amino acids (UAAs) at specific sites within proteins of interest (POIs), making it a powerful tool for modulating PTMs in vivo. This review summarizes the various UAAs utilized to directly incorporate PTMs into proteins through GCE, with a focus on their applications in both histone and non-histone PTMs research. We also discuss the challenges associated with incorporating certain PTMs into target proteins via GCE and provide an overview of the latest strategies developed to overcome these hurdles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Condensin, a family of structural maintenance of chromosome complexes, has been shown to regulate chromosome compaction and segregation during mitosis. NCAPD3, a HEAT-repeat subunit of condensin II, plays a dominant role in condensin-mediated chromosome dynamics but remains unexplored in lymphoma., Objectives: The study aims to unravel the molecular function and mechanism of NCAPD3 in diffuse large B-cell lymphoma (DLBCL)., Methods: The expression and clinical significance of NCAPD3 were assessed in public database and clinical specimens. Chromosome spreads, co-immunoprecipitation (co-IP), mass spectrometry (MS), and chromatin immunoprecipitation (ChIP) assays were conducted to untangle the role and mechanism of NCAPD3 in DLBCL., Results: NCAPD3 was highly expressed in DLBCL, correlated with poor prognosis. NCAPD3 deficiency impeded cell proliferation, induced apoptosis and increased the chemosensitivity. Instead, NCAPD3 overexpression facilitated cell proliferation. In vivo experiments further indicated targeting NCAPD3 suppressed tumor growth. Noteworthily, NCAPD3 deficiency disturbed the mitosis, triggering the formation of aneuploids. To reveal the function of NCAPD3 in DLBCL, chromosome spreads were conducted, presenting that chromosomes became compact upon NCAPD3 overexpression, instead, loose, twisted and lacking axial rigidity upon NCAPD3 absence. Meanwhile, the classical transcription-activated marker, H3K4 trimethylation, was found globally upregulated after NCAPD3 knockout, suggesting that NCAPD3 might participate in chromatin remodeling and transcription regulation. MS revealed NCAPD3 could interact with transcription factor, TFII I. Further co-IP and ChIP assays verified NCAPD3 could be anchored at the promoter of SIRT1 by TFII I and then supported the transcription of SIRT1 via recognizing H3K9 monomethylation (H3K9me1) on SIRT1 promoter. Function reversion assay verified the oncogenic role of NCAPD3 in DLBCL was partially mediated by SIRT1., Conclusion: This study demonstrated that dysregulation of NCAPD3 could disturb chromosome compaction and segregation and regulate the transcription activity of SIRT1 in an H3K9me1-dependent manner, which provided novel insights into targeted strategy for DLBCL., (Copyright © 2023. Published by Elsevier B.V.)

Aim: The hypoxic tumor microenvironment (TME) in oral squamous cell carcinoma (OSCC) is primarily regulated by hypoxia-inducible factor-1 alpha (HIF-1α), impacting histone acetylation and methylation, which contribute to drug resistance. Vorinostat, a histone deacetylase inhibitor (HDACi), de-stabilizes HIF-1α, while PX-12, a thioredoxin-1 (Trx-1) inhibitor, prevents HIF-1α accumulation. Combining HDACi with a Trx-1 inhibitor may enhance efficacy and reduce resistance by increasing reactive oxygen species (ROS) in cancer cells. This study examines how PX-12 influences vorinostat-induced histone modifications under hypoxia in the OSCC cell line CAL 27 using mass spectrometry., Materials and Methods: The OSCC cell line CAL 27 was used to assess histone post-translational modifications induced by PX-12 and Vorinostat under hypoxic conditions through mass spectrometry., Results: The proteomic analysis (ProteomeXchange identifier PXD053244) revealed several crucial histone marks, such as H3K4me1, H3K9ac, H3K9me, H3K14ac, H3K27me, H3K36me, H4K12Ac, and H4K16ac. Along with site-specific histone modifications, exposure of cells to vorinostat and PX-12 alone or in combination affects the global acetylation and methylation levels under hypoxia., Conclusion: Mass spectrometry-based proteomics highlighted the impact of vorinostat and PX-12 on histone acetylation and methylation, offering valuable insights into the epigenetic mechanisms in OSCC and paving a way for epigenetic-based oral cancer therapeutics.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive lymphohematopoietic malignancy associated with poor prognosis. We aimed to improve the understanding of BPDCN, explore its prognostic significance, and identify potential therapeutic targets. Data from 14 BPDCN patients were retrospectively collected and analyzed, focusing on their clinicopathological characteristics, diagnostic features, immunophenotype, treatment regimens, and prognostic factors. Additionally, immunohistochemistry was used to detect the expression of multiple oncogenes in BPDCN. The cohort comprised 14 patients (10 males, 4 females) with a median age of 63.5 years at the time of diagnosis. Of these specimens, H3K27me3, ASXL1, BAP1, RAC1, TCF4 and AURKA were highly expressed in BPDCN, with expression rates of 71.4 % (10/14), 92.9 % (13/14), 85.7 % (12/14), 100 % (13/13), 12/14 (85.7 %) and 46.2 % (6/13), respectively. The survival of patients in this cohort ranged from 1 to 84 months, with a median overall survival (OS) of 18.5 months. The survival rates for 1, 2, 3, 4 and 5 years were 71.43 %, 53.57 %, 44.64 %, 44.64 %, and 44.64 %, respectively. In the overall BPDCN cohort, patients with positive expression of H3K27me3 exhibited significantly better overall survival compared to those with negative expression H3K27me3 (P = 0.0056). Our analysis showed that the absence of H3K27me3 expression may indicate a poor prognosis in patients with BPDCN, and H3K27me3 may be a potential prognostic indicator for BPDCN., Competing Interests: Declaration of competing interest All authors have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In vivo, microspores in the anthers follow the gametophytic development pathway, culminating in the formation of pollen grains. Conversely, in vitro, under stress treatments, microspores can be reprogrammed into totipotent cells, initiating an embryogenic pathway that produces haploid and double-haploid embryos, which are important biotechnological tools in plant breeding. There is growing evidence that epigenetic reprogramming occurs during microspore embryogenesis through DNA methylation, but less is known about the role of histone modifications. This study investigates the dynamics of histone acetylation during the two microspore developmental pathways, microspore embryogenesis and pollen development, in Brassica napus. We analyzed histone H3 and H4 acetylation levels, histone acetyltransferase (HAT) activity and expression of HAC5 acetyltransferase using immunofluorescence, enzymatic activity assays, ELISA-like tests, and qPCR. Results showed a decrease in global histone acetylation levels during pollen maturation, correlated with reduced HAT activity and downregulation of the BnHAC5-like gene. In contrast, stress-induced microspore reprogramming led to increased histone acetylation levels, enhanced HAT activity, and upregulation of BnHAC5-like. Treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor widely used in animal research but barely applied to plants, enhanced microspore embryogenesis initiation and proembryo formation, while increased histone acetylation levels. SAHA-treated proembryos showed higher expression than control of key embryogenesis transcription factors BnFUS3, BnAGL15, and BnLEC2, suggesting that histone hyperacetylation facilitates transcriptional activation of essential genes for somatic embryogenesis initiation. These findings provided new insights into the epigenetic regulation of this process and revealed new opportunities with histone epigenetic regulator inhibitors, to improve microspore embryogenesis induction for crop improvement., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Neuropeptide cocaine- and amphetamine-regulated transcript peptide (CARTp) is known to play an important role in reward processing. The rats conditioned to intra-cranial self-stimulation (ICSS) showed massive upregulation of CART protein and mRNA in the vicinity of the electrode implanted to deliver the electric current directly at the lateral hypothalamus (LH)-medial forebrain bundle (MFB) area. However, the underlying mechanisms leading to the upregulation of CART in ICSS animals remain elusive. We tested the putative role of CREB-binding protein (CBP), an epigenetic enzyme with intrinsic histone acetyltransferase (HAT) activity, in regulating CART expression during ICSS. An electrode was implanted in LH-MFB and the rats were conditioned to self-stimulation in an operant chamber. CBP siRNA was delivered ipsilaterally in the LH-MFB to knock-down CBP and the effects on lever press activity were monitored. While ICSS-conditioned rats showed distinct increase in CART, CBP and pCREB levels, enhanced CBP binding and histone acetylation (H3K9ac) were noticed on the CART promoter in chromatin immunoprecipitation assay. Direct infusion of CBP siRNA in the LH-MFB lowered lever press activity, CBP levels, histone acetylation at the CART promoter, and CART mRNA and peptide expression. Co-infusion of CARTp in LH-MFB rescued the waning effects of CBP siRNA on self-stimulation. We suggest that CBP-mediated histone acetylation may play a causal role in CART expression in LH, which in turn may drive the positive reinforcement of lever press activity., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Consent for Publication: All authors consent to the publication of this manuscript., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The histone gene H2AX and its phosphorylated protein γ-H2AX play a crucial role in the DNA damage response. This study investigates the expression of H2AX mRNA and its phosphorylated γ-H2AX protein in oropharyngeal squamous cell carcinoma (OPSCC), its association with distinct biological pathway alterations and its potential as a biomarker., Materials and Methods: Expression of H2AX mRNA in 76 OPSCC from The Cancer Genome Atlas (TCGA) cohort was analyzed. Patients were stratified into H2AX high - and H2AX low OPSCC based on a survival-associated cutoff. Differentially expressed genes were identified using DESeq2, followed by pathway enrichment analyses. Immunohistochemical staining of γ-H2AX protein expression was performed on an independent cohort of 209 OPSCC, followed by survival and Cox regression analyses., Results: High H2AX mRNA expression was a significant prognostic factor associated with shorter OS in the TCGA OPSCC cohort (HR 4.77, p = 0.04). In H2AX high tumors, differential gene expression analysis revealed upregulation of genes regulating DNA repair and cell cycle (CDK1, CCNB1, ZWINT). High γ-H2AX protein expression was significantly associated with HPV-negative OPSCC (p = 0.005), and remained an independent predictor of poor survival in the total OPSCC cohort (HR 2.24, p = 0.03) and particularly in HPV-negative patients (HR 3.67, p = 0.007)., Conclusion: H2AX/γ-H2AX expression is a potential prognostic biomarker in OPSCC, with elevated levels indicating poor survival, especially in HPV-negative cases. These findings suggest distinct molecular behaviors in OPSCC based on H2AX expression and highlight the need for further investigation into its therapeutic implications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Lignin, a major wood component, is the key limiting factor for wood conversion efficiency. Its biosynthesis is controlled by transcriptional regulatory networks involving transcription factor (TF)-DNA interactions. However, the epigenetic mechanisms underlying these interactions in lignin biosynthesis remain largely unknown. Here, using yeast one-hybrid, chromatin immunoprecipitation, and electrophoretic mobility shift assays, we identified that PtrbZIP44-A1, a key wood-forming TF, directly interacts with the promoters of PtrCCoAOMT2 and PtrCCR2, genes involved in the monolignol biosynthetic pathway. We used yeast two-hybrid, bimolecular fluorescence complementation, biochemical analyses, transient and CRISPR-mediated transgenesis in Populus trichocarpa to demonstrate that PtrHDA15, a histone deacetylase, acts as an epigenetic inhibitor and is recruited by PtrbZIP44-A1 for chromatin histone modifications to repress PtrCCoAOMT2 and PtrCCR2, leading to reduced lignin deposition. In transgenic lines overexpressing PtrbZIP44-A1 or PtrHDA15, histone acetylation at the promoters of PtrCCoAOMT2 and PtrCCR2 decreased, reducing their expression and lignin content. Conversely, in loss-of-function ptrbzip44-a1 and ptrhda15 mutants, histone acetylation levels at PtrCCoAOMT2 and PtrCCR2 promoters increased, enhancing target gene expression and lignin content. Our study uncovered an epigenetic mechanism that suppresses lignin biosynthesis. This finding may help fill a knowledge gap between epigenetic regulation and lignin biosynthesis during wood formation in Populus., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Organisms are repeatedly exposed to fluctuating environmental and nutritional conditions. Transcriptional memory has been shown to be a mechanism to cope with these fluctuations because it increases the speed and the magnitude of the cellular response to a certain re-occurring condition and therefore optimizes adaptation and fitness in a given environment. We found that genes coding for sterigmatocystin (ST) production in Aspergillus nidulans are activated stronger when cells are repeatedly exposed to nutrient starvation, compared to cells that experience this condition for the first time. We studied possible underlying mechanisms and found that persistence of the transcription factor AflR, which can undergo activation-inactivation cycles, accounts for a large part of the memory. In addition, a chromatin-based mechanism through histone H3 lysine 4 dimethylation (H3K4me2) and extracellular metabolites produced during the first activation phase contribute to the memory process. Genome-wide transcriptome and chromatin analyses showed that only a few genes within the ST and other starvation-induced biosynthetic gene clusters gain the H3K4me2 mark during the 1st activation, but the majority of those which receive the mark also maintain it during the subsequent repression and re-activation phase. Combined with previous findings on chromatin-level regulation of biosynthetic gene clusters (BGCs) our recent data suggest that the H3K4me2 mark may contribute to the correct 3D organization of BGCs and that this is a prerequisite for activation and transcriptional memory., Competing Interests: Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier GmbH.)

To ensure that the embryo can package exponentially increasing amounts of DNA, replication-dependent histones are some of the earliest transcribed genes from the zygotic genome. However, how the histone genes are identified is not known. The Drosophila melanogaster pioneer factor CLAMP regulates the embryonic histone genes and helps establish the histone locus body, a suite of factors that controls histone mRNA biosynthesis, but CLAMP is not unique to the histone genes. Zelda collaborates with CLAMP across the genome to regulate zygotic genome activation and target early activated genes. We hypothesized that Zelda helps identify histone genes for early embryonic expression. We found that Zelda targets the histone gene locus early during embryogenesis, prior to histone gene expression. However, depletion of zelda in the early embryo does not affect histone mRNA levels or prevent the recruitment of other factors. These results suggest the earliest events responsible for specifying the zygotic histone genes remain undiscovered., Competing Interests: Conflicts of interest: The authors declare no financial conflicts of interest.

Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high mortality rate. Merkel cell polyomavirus causes 80% of MCCs, encoding the viral oncogenes small T and truncated large T (tLT) antigens. These proteins impair the RB1-dependent G1/S checkpoint blockade and subvert the host cell epigenome to promote cancer. Whole-proteome analysis and proximal interactomics identified a tLT-dependent deregulation of DNA damage response (DDR). Our investigation revealed, to our knowledge, a previously unreported interaction between tLT and the histone methyltransferase EHMT2. T antigen knockdown reduced DDR protein levels and increased the levels of the DNA damage marker γH2Ax. EHMT2 normally promotes H3K9 methylation and DDR signaling. Given that inhibition of EHMT2 did not significantly change the MCC cell proteome, tLT-EHMT2 interaction could affect the DDR. With tLT, we report that EHMT2 gained DNA damage repair proximal interactors. EHMT2 inhibition rescued proliferation in MCC cells depleted for their T antigens, suggesting impaired DDR and/or lack of checkpoint efficiency. Combined tLT and EHMT2 inhibition led to altered DDR, evidenced by multiple signaling alterations. In this study, we show that tLT hijacks multiple components of the DNA damage machinery to enhance tolerance to DNA damage in MCC cells, which could explain the genetic stability of these cancers., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Fusarium oxysporum f. sp. lycopersici (Fol) that causes a globally devastating wilt disease on tomato relies on the secretion of numerous effectors to mount an infection, but how the pathogenic fungus precisely regulates expression of effector genes during plant invasion remains elusive. Here, using molecular and cellular approaches, we show that the histone H4K8 acetyltransferase FolSas2 is a transcriptional regulator of early effector gene expression in Fol. Autoacetylation of FolSas2 on K269 represses K335 ubiquitination, preventing its degradation by the 26S proteasome. During the early infection process, Fol elevates FolSas2 acetylation by differentially changing transcription of itself and the FolSir1 deacetylase, leading to specific accumulation of the enzyme at this stage. FolSas2 subsequently activates the expression of an array of effectors genes, and as a consequence, Fol invades tomato successfully. These findings reveal a regulatory mechanism of effector gene expression via autoacetylation of a histone modifier during plant fungal invasion., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Lactate is a glycolytic end product that is further metabolized as an energy source. This end product has been associated with certain diseases, including sepsis and tumors, and it can regulate the transition of macrophages to an anti-inflammatory state. This study aimed to explore the effects of lactate on the inflammatory responses of mammary gland epithelial cells, which constitute the first line of defense against pathogens in mammary glands. Bovine mammary epithelial cells (BMECs) were challenged with lipopolysaccharide (LPS) in the presence or absence of D-sodium lactate (D-nala). LPS exposure increased the concentration of lactate both inside and outside the cells. Further, inhibiting glycolysis diminished the LPS-induced production of proinflammatory cytokines. Treatment with LPS, exogenous D-nala, and their combination upregulated the expression levels of MCT1, increased the intracellular levels of lactate and histone H3 lysine 18 lactylation (H3K18la), and activated the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathway. The lactylation of H3K18 was mediated by p300/CBP. The p300/CBP inhibitor C646 decreased the level of H3K18la, reversing the activation of the NF-κB signaling pathway and release of proinflammatory cytokines. Therefore, LPS increased the intracellular level of lactate by upregulating MCT1 and glycolysis. D-nala exacerbated the LPS-induced inflammatory responses in BMECs. Moreover, intracellular lactate enhanced the activation of the NF-κB signaling pathway through the p300/CBP-mediated lactylation of H3K18. Thus, the findings of this study expand our understanding of lactate function in immune regulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Histone lactylation is crucial in a variety of physiopathological processes; however, the function and mechanism of histone lactylation in endometriosis remain poorly understood. Therefore, the objective of this investigation was to illuminate the function and mechanism of histone lactylation in endometriosis. Immunohistochemistry was used to investigate the expression of histone lactylation. Cell Counting Kit-8 assay (CCK8), Transwell assay, and endometriosis mouse models were used to investigate the effects of histone lactylation in vitro and in vivo. Transcriptomics and immunoprecipitation-mass spectrometry (IP-MS), Western blot, co-immunoprecipitation (Co-IP), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and chromatin immunoprecipitation-qPCR (ChIP-qPCR) were used to explore the intrinsic mechanisms. In this study, we found that histone lactylation was upregulated in endometriosis and could promote endometriosis progression both in vivo and in vitro. Mechanistically, histone lactylation H3K18la promoted the transcription of Ras homolog enriched in striatum (RASD2), and RASD2, in turn, increased the stability of CTP synthase 1 (CTPS1) by promoting the SUMOylation and inhibiting the ubiquitination of CTPS1, thereby promoting endometriosis progression. Overall, our findings indicated that histone lactylation could promote the progression of endometriosis through the RASD2/CTPS1 axis. This investigation uncovered a novel mechanism and identified prospective targets for endometriosis diagnosis and therapy. NEW & NOTEWORTHY Our finding reveals a novel mechanism that promotes the progression of endometriosis, namely the histone lactylation/RASD2/CTPS1 axis. This finding suggests that inhibiting histone lactylation or inhibiting RASD2 and CTPS1 might be a potential therapeutic strategy to inhibit endometriosis lesion growth.

We wished to ascertain if there is an association between neutrophil extracellular traps and endometriosis (EMS). We collected the lesional tissues and normal endometrium of 30 patients suffering from endometriosis. Samples were also taken from healthy controls. Blood from the peripheral circulation was collected to isolate serum and neutrophils. A mouse model of endometriosis was also created. Expression of citrullinated histone and the myeloperoxidase level in tissue were measured by immunofluorescence staining and western blotting. The myeloperoxidase level in peripheral blood serum was measured by enzyme-linked immunosorbent assay. Staining (Trypan Blue) and flow cytometry were used to measure the apoptosis of neutrophils in peripheral blood. BALB/C mice were modeled by allotransplantation, and the experimental parameters noted above quantified. The myeloperoxidase content in the peripheral blood of patients with endometriosis was increased compared with that in healthy controls. Flow cytometry showed that the percent apoptosis of neutrophils in patients with endometriosis was lower than that in healthy controls. Expression of citrullinated histone was higher in the endometriosis group in humans and mice compared with respective controls according to immunofluorescence staining and western blotting. Our data suggest that a high concentration of neutrophil extracellular traps was observed in humans and mice suffering from endometriosis., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Myelomatous bone disease is a complication characterized by lytic bone lesions, reduced bone formation, bone pain, and increased fracture risk. Understanding these underlying mechanisms is crucial for developing effective therapeutic approaches. Here we show the role of enhancer of zeste homolog 2 (EZH2) in bone lesions induced by myeloma cells. Our research reveals that cytokines produced by myeloma-associated adipocytes activate the expression of EZH2 in myeloma cells. Furthermore, we find that EZH2 forms a transcriptional repression complex with transcription factor AP2α. This complex promotes trimethylation at lysine 27 of histone H3 (H3K27me3) in the promoter region of the tumor suppressor gene EMP1, resulting in transcriptional silencing. EMP1 silencing leads to increased myeloma cell proliferation and the concomitant secretion of osteolytic cytokines that contribute to bone destruction. Importantly, EZH2 inhibitors effectively treat myeloma-induced osteolytic lesions. Thus, targeting EZH2 represents a potential therapeutic strategy for preventing and managing myeloma bone disease., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

FOLFOX (5-fluorouracil, oxaliplatin, folinic acid) is a standard treatment for hepatocellular carcinoma, but its efficacy is often limited by drug resistance, the underlying mechanisms of which remain unclear. In this study, oxaliplatin (OXA)- and 5-fluorouracil (5-Fu)-resistant hepatocellular carcinoma cell lines were established, and enhanced glycolytic activity was identified in resistant cells. Inhibiting glycolysis effectively suppressed the malignant behavior of both OXA- and 5-Fu-resistant cells. Mechanistically, active glycolysis induced elevated levels of lactylation, predominantly histone lactylation, with H3K14la playing a key role in regulating gene expression. The ubiquitin E3 ligase NEDD4 was identified as a downstream target of H3K14la. Furthermore, NEDD4, regulated by histone lactylation, interacted with PTEN to mediate its ubiquitination and subsequent degradation. The downregulation of PTEN formed a positive feedback loop, further driving the malignant progression of OXA- and 5-Fu-resistant cells. This study elucidates a shared mechanism underlying OXA and 5-Fu resistance in hepatocellular carcinoma and highlights a promising therapeutic target for overcoming clinical chemotherapy resistance., Competing Interests: Competing interests: The authors declare no competing interests. Ethics: All animal experiments were approved by the Laboratory Animal Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University (WYYY-AEC-2022-029)., (© 2025. The Author(s).)

Nucleosomes, the building block of chromatin, are responsible for regulating access to the DNA sequence. This control is critical for essential cellular processes, including transcription and DNA replication and repair. Studying chromatin can be challenging both in vitro and in vivo, leading many to use a mono-nucleosome system to answer fundamental questions relating to chromatin regulators and binding partners. However, the mono-nucleosome fails to capture essential features of the chromatin structure, such as higher-order chromatin folding, local nucleosome-nucleosome interactions, and linker DNA trajectory and flexibility. We briefly review significant discoveries enabled by the mono-nucleosome and emphasize the need to go beyond this model system in vitro. Di-, tri-, and tetra-nucleosome arrays can answer important questions about chromatin folding, function, and dynamics. These multi-nucleosome arrays have highlighted the effects of varying linker DNA lengths, binding partners, and histone post-translational modifications in a more chromatin-like environment. We identify various chromatin regulatory mechanisms yet to be explored with multi-nucleosome arrays. Combined with in-solution biophysical techniques, studies of minimal multi-nucleosome chromatin models are feasible., (© 2025 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.)

During transcription, RNA polymerase II traverses through chromatin, and posttranslational modifications including histone methylations mark regions of active transcription. Histone protein H3 lysine 36 trimethylation (H3K36me3), which is established by the histone methyltransferase SET domain containing 2 (SETD2), suppresses cryptic transcription, regulates splicing, and serves as a binding site for transcription elongation factors. The mechanism by which the transcription machinery coordinates the deposition of H3K36me3 is not well understood. Here we provide cryo-electron microscopy structures of mammalian RNA polymerase II-DSIF-SPT6-PAF1c-TFIIS-IWS1-SETD2-nucleosome elongation complexes, revealing that the transcription machinery regulates H3K36me3 deposition by SETD2 on downstream and upstream nucleosomes. SPT6 binds the exposed H2A-H2B dimer during transcription, and the SPT6 death-like domain mediates an interaction with SETD2 bound to a nucleosome upstream of RNA polymerase II.

HIV-1 can integrate viral DNA into host cell chromosomes and establish a long-term stable latent viral reservoir, a major obstacle in curing HIV-1 infection. The reactivation of latent proviruses with latency-reversing agents (LRAs) is a prerequisite for the eradication of viral reservoirs. Previous reports have shown that tannic acid (TA) exerts several biological functions, including antioxidant and antitumor activities. Here, we identified a novel function of TA as a reactivator of HIV-1 latency. TA showed similar features to the HIV-1 transactivator of transcription (Tat) and was able to reactivate a larger number of proviruses from various integration sites. TA also showed a strong synergistic effect with other LRAs acting on different signaling pathways. Further studies revealed that the polycomb repressive complex 1 component, chromobox protein homolog 4 (CBX4), is specifically degraded by TA through ubiquitination. CBX4 is associated with the tri-methylation at lysine 27 of histone H3 (H3K27me3) which was enriched on HIV-1 long terminal repeat regions. The TA-induced CBX4 degradation decreased the H3K27me3 enrichment and subsequently enhanced the transcriptional activity of the integrated proviruses. These results suggest that TA is an efficient LRA aiming to a new target for HIV-1 latency, which could be developed to eradicate latent proviruses.IMPORTANCEHIV-1 remains a global health challenge, with its ability to integrate into the host genome and evade the effects of drugs. To overcome this obstacle, the "shock and kill" strategy was proposed, targeting the reactivation of latent HIV-1 for subsequent eradication through antiretroviral medication and immune system reinforcement. Here, we found a new reactivator for HIV-1 latency, tannic acid (TA), which can reactivate HIV-1 latency widely and deeply. Moreover, we demonstrated that TA could promote the interaction between the polycomb repressive complex 1 component CBX4 and the E3 ubiquitin ligase cullin 4A (CUL4A), resulting in CBX4 degradation through the ubiquitin-proteasome system. These events reduce H3K27me3 enrichment in the HIV-1 long terminal repeat region, thereby promoting HIV-1 transcription and ultimately reactivating HIV-1 latent infection. Our work may facilitate the identification of new latency-reversing agents and provide more theoretical evidence for the molecular mechanism of HIV-1 latency., Competing Interests: The authors declare no conflict of interest.

Difficult-to-heal wounds management accounts for about 4% of healthcare costs, highlighting the need for innovative solutions. Extracellular signals drive cell proliferation during tissue regeneration, while epigenetic mechanisms regulate stem cell homeostasis, differentiation, and skin repair. Exploring epigenetic regulation in adipose-derived stem cells (ADSCs) holds promise for improving skin injury treatments. We investigated the effects of histone deacetylase inhibitor (SAHA) on ADSCs to better understand its cellular and molecular impacts. ADSCs were treated with SAHA for 72 h, showing no change in cell viability at the studied concentrations. However, the expression of histone deacetylase decreased at 1000 nM, while the cell proliferation marker Ki-67 increased after SAHA treatment, as confirmed by immunofluorescence. CCND1 gene expression increased, whereas protein expression of the proliferating cell nuclear antigen (PCNA) decreased. Cell cycle analysis showed an increase in G2 phase in SAHA-treated cells. Microarray analysis revealed 74 upregulated and 40 downregulated differentially expressed genes, including upregulation of P53 targets, CDKN1A and MDM2. Proteomic analysis identified 631 upregulated and 823 downregulated proteins compared to the vehicle. Pathway enrichment analysis showed cell cycle, ATP-dependent chromatin remodeling and DNA processes were among the affected pathways. This study suggests SAHA modulates ADSCs' biological processes, highlighting its potential for skin regeneration., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Metabolic changes are an important characteristic of vascular complications in diabetes. The accumulation of lactate in the microenvironment can promote vascular smooth muscle cell (VSMC) calcification in diabetes, although the specific mechanism remains to be fully elucidated. In this study, we explored the characteristics of lactylation in diabetic arterial calcification and the underlying molecular mechanism. We found that in high-glucose calcified VSMC, the overall lactylation level was significantly increased. Mass spectrometry analysis revealed a significant up-regulation of H3 histone lactylation. After site-specific point-mutation at K18 to simulate the delactylation modification, VSMC calcification was significantly reduced. Through a combination of H3K18la ChIP-seq, RNA-seq, H3K18la ChIP-qPCR, and point-mutation experiments, we confirmed that H3K18la can up-regulate CHI3L1. CHI3L1 knockout significantly alleviated VSMC osteogenic phenotype transformation and mouse arterial calcification. RNA-seq analysis of the downstream molecular signaling showed that CHI3L1 activates the IL-13-IL-13Ra2-JAK1-STAT3 pathway. Targeted inhibition of IL-13Ra2 reduced VSMC calcification. We conclude that in a diabetic calcification environment, the H3 histone K18 site undergoes lactylation modification in VSMCs, upregulating CHI3L1, which, in turn, regulates the IL-13-IL-13Ra2-JAK1-STAT3 signaling pathway, ultimately exacerbating arterial calcification. Our study elucidates the epigenetic mechanism by which lactate promotes arterial calcification in diabetes., (© 2025 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.)

Chromatin regulatory proteins are expressed broadly and assumed to exert the same intrinsic function across cell types. Here, we report that 14 chromatin regulators undergo evolutionary-conserved neuron-specific splicing events involving microexons. Among them are two components of a histone demethylase complex: LSD1 H3K4 demethylase and the H3K4me0-reader PHF21A. We found that neuronal LSD1 splicing reduces the enzymes' affinity to the nucleosome. Meanwhile, neuronal PHF21A splicing significantly attenuates histone H3 binding and further ablates the DNA-binding function exerted by an AT-hook motif. Furthermore, in vitro reconstitution of the canonical and neuronal PHF21A-LSD1 complexes, combined with in vivo methylation mapping, identified the neuronal complex as a hypomorphic H3K4 demethylating machinery. The neuronal PHF21A, albeit with its weaker nucleosome binding, is necessary for normal gene expression and the H3K4 landscape in the developing brain. Thus, ubiquitously expressed chromatin regulatory complexes can exert neuron-specific functions via alternative splicing of their subunits., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Polycomb repressive complex 2 (PRC2), composed of the core subunits EED, SUZ12, and either EZH1 or EZH2, is critical for maintaining cellular identity in multicellular organisms. PRC2 deposits H3K27me3, which is thought to recruit the canonical form of PRC1 (cPRC1) to promote gene repression. Here, we show that EZH1-PRC2 and cPRC1 are the primary Polycomb complexes on target genes in non-dividing, quiescent cells. Furthermore, these cells are resistant to PRC2 inhibitors. While PROTAC-mediated degradation of EZH1-PRC2 in quiescent cells does not reduce H3K27me3, it partially displaces cPRC1. Our results reveal an evolutionarily conserved switch to less catalytically active Polycomb complexes in non-dividing cells and raise concerns about using PRC2 inhibitors in cancers with significant populations of non-dividing cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Menin is a scaffold protein encoded by the Men1 gene, and it interacts with a variety of chromatin regulators to activate or repress cellular processes. The potential importance of menin in immune regulation remains unclear. Here, we report that myeloid deletion of Men1 results in the development of spontaneous pulmonary alveolar proteinosis (PAP). This is strongly correlated with impaired development of alveolar macrophages (AM) through inactivation of the granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) pathway caused by Men1 deficiency. Mechanistically, menin directly interacts with the SET domain containing 2 (SETD2) through the N-terminal domain (NTD) and Palm domains to maintain protein stability and chromatin recruitment. SETD2 and menin collectively maintain CSF2 expression through H3K36me3, which orchestrates AM reprogramming and pulmonary immune homeostasis. Targeting H3K36me3 remodeling mitigated the aberrant activation of macrophages caused by lipopolysaccharide (LPS). Our results point to a nonredundant role of menin in the control of macrophage lineage maintenance via reinforcement of the H3K36me3 transcriptional program., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The H3K79 methyltransferase DOT1L is essential for multiple aspects of mammalian development where it has been shown to regulate gene expression. Here, by producing and integrating epigenomic and spike-in RNA-seq data, we decipher the molecular role of DOT1L during mouse spermatogenesis and show that it has opposite effects on gene expression depending on chromatin environment. On one hand, DOT1L represses autosomal genes that are devoid of H3K79me2 at their bodies and located in H3K27me3-rich/H3K27ac-poor environments. On the other hand, it activates the expression of genes enriched in H3K79me2 and located in H3K27me3-poor/H3K27ac-rich environments, predominantly X chromosome-linked genes, after meiosis I. This coincides with a significant increase in DOT1L expression at this stage and a genome-wide acquisition of H3K79me2, particularly on the sex chromosomes. Taken together, our results show that H3K79me2 positively correlates with male germ cell genetic program throughout spermatogenesis, with DOT1L predominantly inhibiting rather than activating gene expression. Interestingly, while DOT1L appears to directly regulate the (re)activation of X genes following meiotic sex chromosome inactivation, it also controls the timely expression of (autosomal) differentiation genes during spermatogenesis., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

A significant portion of human cancers utilize a recombination-based pathway, alternative lengthening of telomeres (ALT), to extend telomeres. To gain further insights into this pathway, we developed a high-throughput imaging-based screen named TAILS (telomeric ALT in situ localization screen) to identify genes that either promote or inhibit ALT activity. Screening over 1,000 genes implicated in DNA transactions, TAILS reveals both well-established and putative ALT modulators. Here, we present the validation of factors that promote ALT, such as the nucleosome-remodeling factor CHD4 and the chromatin reader SGF29, as well as factors that suppress ALT, including the RNA helicases DExD-box helicase 39A/B (DDX39A/B), the replication factor TIMELESS, and components of the chromatin assembly factor CAF1. Our data indicate that defects in histone deposition significantly contribute to ALT-associated phenotypes. Based on these findings, we demonstrate that pharmacological treatments can be employed to either exacerbate or suppress ALT-associated phenotypes., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Background: Histone H2B is highly expressed in many types of cancers and is involved in cancer development. H2B clustered histone 9 (H2BC9), a member of the H2B family, plays critical roles in gene expression regulation, chromosome structure, DNA repair stability, and cell cycle regulation. However, the diagnostic and prognostic value of H2BC9 in head and neck squamous cell carcinoma (HNSCC) remains unclear. This study aimed to evaluate the potential diagnostic and prognostic value of H2BC9 in HNSCC and investigate its biological role using bioinformatics., Methods: The expression pattern and diagnostic value of H2BC9 in HNSCC were explored using UCSC Xena and GEO database. H2BC9 expression was validated using the Human Protein Atlas database, qRT-PCR, and western blotting. Prognostic value was assessed using Kaplan-Meier curves, Cox regression analysis, and a nomogram. Drug sensitivity was predicted using the R package pRRophetic, and molecular interactions were analyzed using the DepMap database. The impact of H2BC9 on HNSCC cells was further investigated through in vitro experiments., Results: H2BC9 was markedly upregulated in HNSCC cell lines and tissues. High expression of H2BC9 was correlated with advanced-stage disease and poor prognosis. KEGG analysis linked H2BC9 to cell cycle regulation and DNA replication. H2BC9 expression influenced the drug sensitivity of paclitaxel, docetaxel, cisplatin, and 5-fluorouracil. Key molecules, such as TONSL, PITX2, NOTCH1, and H2BC10, were positively correlated with H2BC9 expression. Silencing H2BC9 suppressed cell proliferation, induced G2/M cell cycle arrest, and enhanced apoptosis and DNA damage in HNSCC cells., Conclusion: We demonstrated that H2BC9 expression may be associated with HNSCC development and prognosis. These findings may provide a potential therapeutic target for HNSCC., Competing Interests: Declarations. Ethical approval and consent to participate: The studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University and the approval number was 2024-E533-01. This study has been officially sanctioned by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University, thereby waiving the requirement for informed consent from participants. The study did not involve minors. All experiments were performed in accordance with relevant guidelines and regulations. The study was conducted according to the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

This study examined the effects of treadmill running (TR) regimens on craniofacial pain- and anxiety-like behaviors, as well as their effects on neural changes in specific brain regions of male mice subjected to repeated social defeat stress (SDS) for 10 days. Behavioral and immunohistochemical experiments were conducted to evaluate the impact of TR regimens on SDS-related those behaviors, as well as epigenetic and neural activity markers in the anterior cingulate cortex (ACC), insular cortex (IC), rostral ventromedial medulla (RVM), and cervical spinal dorsal horn (C2). Behavioral responses were quantified using multiple tests, while immunohistochemistry measured histone H3 acetylation, histone deacetylases (HDAC1, HDAC2), and neural activity markers (FosB and phosphorylated cAMP response element-binding protein (pCREB). The effects of both short-term TR (2 days, TR2) and long-term TR (10 days, TR10) regimens were conducted. TR10 significantly reduced anxiety- and formalin-evoked craniofacial pain-like behaviors in SDS mice. It normalized SDS-induced increases in histone H3 acetylation in both the anterior and posterior portions of the ACC, as well as the anterior portion of the IC. These inhibitory effects were also observed in SDS-related increases in HDAC1, FosB, and pCREB expression. Additionally, TR10 normalized increased histone H3 acetylation in the RVM and C2 regions, with specific effects on FosB and pCREB expression observed in the C2 region. In contrast, TR2 showed limited effects on craniofacial pain-like behaviors but reduced anxiety-like behaviors in SDS mice. Under sham conditions, TR2 had minimal impact on histone H3 acetylation. Paradoxically, TR2 increased formalin-evoked craniofacial pain-like behaviors during the early phase despite not altering acetylated histone H3 expression. In conclusion, the TR10 regimen is effective in attenuating SDS-induced craniofacial pain- and anxiety-like behaviors, likely by normalizing epigenetic modifications and neural activity in key brain regions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Piriyaprasath et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In recent years, epigenetic modifications have attracted significant attention due to their unique regulatory mechanisms and profound biological implications. Acting as a bridge between environmental stimuli and changes in gene activity, they reshape gene expression patterns, providing organisms with regulatory mechanisms to respond to environmental changes. A growing body of evidence indicates that epigenetic regulation plays a crucial role in the pathogenesis and progression of psoriasis. A deeper understanding of these epigenetic mechanisms not only helps unveil the molecular mechanisms underlying the initiation and progression of psoriasis but may also provide new insights into diagnostic and therapeutic strategies. Given the unique roles and significant contributions of various cell types involved in the process of psoriasis, a thorough analysis of specific epigenetic patterns in different cell types becomes a key entry point for elucidating the mechanisms of disease development. Although epigenetic modifications encompass multiple complex layers, this review will focus on histone modifications and DNA methylation, describing how they function in different cell types and subsequently impact the pathophysiological processes of psoriasis. Finally, we will summarize the current problems in research concerning histone modifications and DNA methylation in psoriasis and discuss the clinical application prospects and challenges of targeting epigenetic modifications as therapeutic strategies for psoriasis., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

An ideal chemotherapeutic agent damages DNA, specifically in cancer cells, without harming normal cells. Recently, we used Box A of HMGB1 plasmid as molecular scissors to produce DNA gaps in normal cells. The DNA gap relieves DNA tension and increases DNA strength, preventing DNA double-strand breaks (DSBs). Since the formation of HMGB1-produced DNA gaps in cancers may differ from normal cells, the outcome of introducing Box A into cancer cells may be different. We demonstrated that in lung cancer cells, γH2AX foci and histone modification associating DSBs were produced by Box A. We transfected Box A plasmid into lung cancer cell lines to overexpress Box A and evaluated the expression levels of γH2AX foci and other DNA damage response (DDR) signaling cascade markers, including ATM, ATR, and p53. Then, we demonstrated the downstream effects of DSBs on lung cancer, lowering cell proliferation, decreasing cell migration, and promoting apoptosis. Thus, Box A in lung cancer promoted the opposite outcome to normal cells by breaking cancer DNA., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Chromatin remodeling, which involves the histone-to-protamine exchange process during spermiogenesis, is crucial for sperm nuclear condensation and male fertility. However, the key regulators and underlying molecular mechanisms involved in this process remain largely unexplored. In this study, we discovered that deficiency in the family with sequence similarity 170 member A (Fam170a) led to abnormal sperm nuclear morphology and male infertility in mice, mirroring the observation of very low Fam170a transcription levels in sperm of infertile men with teratozoospermia. Further investigation revealed that Fam170a plays a significant role in the histone-to-protamine chromatin remodeling process. This was evidenced by the earlier core histone removal, accelerated translation and degradation of transition proteins, and reduced protamine incorporation during spermiogenesis in Fam170a-deleted mice. Mechanistically, we found that Fam170a interacts with chromatin remodeling-associated proteins and regulates the transcription of genes related to chromatin remodeling. Notably, Fam170a directly interacts with the deubiquitinating enzyme Usp7 and facilitates its nuclear translocation in elongating sperm, enhancing the deubiquitinating activity of Usp7 on testis-specific histone H2A and H2B variants. Collectively, our findings identify Fam170a as a previously unrecognized key regulator of sperm chromatin remodeling and suggest that histone deubiquitination may play an essential role in the histone-to-protamine exchange process., (© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Mammalian J-domain protein DNAJC9 interacts with histones H3-H4 and is important for cell proliferation. However, its exact function remains unclear. Here, we show that, in the fission yeast Schizosaccharomyces pombe, loss of Djc9, the ortholog of DNAJC9, renders the histone chaperone Asf1 no longer essential for growth. Utilizing AlphaFold-based structural prediction, we identified a histone-binding surface on Djc9 that binds to helix α3 of H3 in a manner that precludes simultaneous helix α3-binding by Asf1. Djc9 and Asf1 indeed compete for binding to the H3-H4 dimer in vitro, and an H3-α3 mutation impeding Djc9 binding also renders Asf1 non-essential, indicating that the role of Asf1 needed for growth in fission yeast is to prevent histone binding by Djc9. In the absence of Asf1, cell growth is hindered due to unrestrained Djc9-mediated downregulation of H3 and H4. In the presence of Asf1, Djc9 confers resistance to the DNA replication inhibitor hydroxyurea and dominant negative disease-related histone mutants by promoting the degradation of superfluous or dysfunctional histones. Our findings provide new insights into the function and mechanism of this conserved histone-binding protein., (© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Although lipid-derived acetyl-coenzyme A (CoA) is a major carbon source for histone acetylation, the contribution of fatty acid β-oxidation (FAO) to this process remains poorly characterized. To investigate this, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1, distal FAO enzyme) knockout macrophages. 13 C-carbon tracing confirmed reduced FA-derived carbon incorporation into histone H3, and RNA sequencing identified diminished interferon-stimulated gene expression in the absence of ACAT1. Chromatin accessibility at the Stat1 locus was diminished in ACAT1 -/- cells. Chromatin immunoprecipitation analysis demonstrated reduced acetyl-H3 binding to Stat1 promoter/enhancer regions, and increasing histone acetylation rescued Stat1 expression. Interferon-β release was blunted in ACAT1 -/- and recovered by ACAT1 reconstitution. Furthermore, ACAT1-dependent histone acetylation required an intact acetylcarnitine shuttle. Last, obese subjects' monocytes exhibited increased ACAT1 and histone acetylation levels. Thus, our study identifies an intriguing link between FAO-mediated epigenetic control of type I interferon signaling and uncovers a potential mechanistic nexus between obesity and type I interferon signaling.

The number and variety of identified histone post-translational modifications (PTMs) are continually increasing. However, the specific consequences of each histone PTM remain largely unclear, primarily due to the lack of methods for selectively and rapidly introducing a desired histone PTM in living cells without genetic engineering. Here, we report the development of a cell-permeable histone acetylation catalyst, BAHA-LANA-PEG-CPP44, which selectively enters leukemia cells, binds to chromatin, and acetylates H2BK120 of endogenous histones in a short reaction time. Time-course analyses of this in-cell catalytic reaction revealed that H2BK120 acetylation attenuates the chromatin binding of negative elongation factor E (NELFE), an onco-transcription factor. This H2BK120 acetylation-mediated removal of NELFE from chromatin reshapes transcription, slows leukemia cell viability, and reduces their tumorigenic potential in mice. Therefore, this histone acetylation catalyst provides a unique tool for elucidating the time-resolved consequences of histone PTMs and may offer a modality for cancer chemotherapy., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

We take a wide variety of antioxidants, including polyphenols, daily from our diet. They are generally considered to be beneficial for our health. However, the intrinsic function of antioxidants in biological systems remain unknown. On the other hand, antioxidants in general are sensitive to oxidation, generating their oxidized intermediates. Intriguingly, these intermediates are highly reactive to proteins. Although the specific cellular targets and response mechanism remain unclear, protein modification by oxidized antioxidants may represent the intrinsic "moonlight" function of antioxidants by taking on a secondary role beyond their traditional activity. This minireview summarizes recent findings on antioxidants, with a particular focus on the interactions of antioxidant-modified proteins with histones., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Centromeres are marked by the centromere-specific histone H3 variant CENP-A/CENH3. Throughout the cell cycle, the constitutive centromere-associated network is bound to CENP-A chromatin, but how this protein network modifies CENP-A nucleosome conformations in vivo is unknown. Here, we purify endogenous centromeric chromatin associated with the CENP-C complex across the cell cycle and analyze the structures by single-molecule imaging and biochemical assays. CENP-C complex-bound chromatin was refractory to MNase digestion. The CENP-C complex increased in height throughout the cell cycle culminating in mitosis, and the smaller CENP-C complex corresponds to the dimensions of in vitro reconstituted constitutive centromere-associated network. In addition, we found two distinct CENP-A nucleosomal configurations; the taller variant was associated with the CENP-C complex. Finally, CENP-A mutants partially corrected CENP-C overexpression-induced centromeric transcription and mitotic defects. In all, our data support a working model in which CENP-C is critical in regulating centromere homeostasis by supporting a unique higher order structure of centromeric chromatin and altering the accessibility of the centromeric chromatin fiber for transcriptional machinery., (© 2025 Melters et al.)