Search Results (585)

Maternal undernutrition (MUN) causes severe metabolic disruption in the offspring of mammals. Here we determined the role of histone modification in hepatic gene expression in late-gestation fetuses of nutritionally restricted cows, an established model using low-nutrition (LN) and high-nutrition (HN) conditions. The chromatin immunoprecipitation sequencing results show that genes with an altered trimethylation of histone 3 lysine 4 (H3K4me3) are associated with cortisol synthesis and secretion, the PPAR signaling pathway, and aldosterone synthesis and secretion. Genes with the H3K27me3 alteration were associated with glutamatergic synapse and gastric acid secretion. Compared to HN fetuses, promoter H3K4me3 levels in LN fetuses were higher in GDF15, IRF2BP2, PPP1R3B, and QRFPR but lower in ANGPTL4 and APOA5. Intriguingly, genes with the greatest expression changes (>1.5-fold) exhibited the anticipated up-/downregulation from elevated or reduced H3K4me3 levels; however, a significant relationship was not observed between promoter CpG methylation or H3K27me3 and the gene set with the greatest expression changes. Furthermore, the stress response genes EIF2A, ATF4, DDIT3, and TRIB3 were upregulated in the MUN fetal liver, suggesting activation by upregulated GDF15. Thus, H3K4me3 likely plays a crucial role in MUN-induced physiological adaptation, altering the hepatic gene expression responsible for the integrated stress response and systemic energy metabolism, especially circulating lipoprotein lipase regulation. Full article

The histone H2A variant H2AZ plays pivotal roles in shaping chromatin architecture and regulating gene expression. We recently identified H2AZ.2 in histone H2A lysine 119 ubiquitination (H2AK119ub)-enriched nucleosomes, but it is not known whether its highly related isoform H2AZ.1 also regulates this modification. In this study, we employed isoform-specific epitope-tagged knock-in mouse embryonic stem cell (ESC) lines to dissect the roles of each isoform in Polycomb Repressive Complex 1 (PRC1)-mediated H2AK119ub. Our results show that H2AZ.1 and H2AZ.2 share highly overlapping genomic binding profiles, both co-localizing extensively with H2AK119ub-enriched loci. The knockdown of either isoform led to reduced H2AK119ub levels; however, the two isoforms appear to function through distinct mechanisms. H2AZ.1 facilitates the recruitment of Ring1B, the catalytic subunit of PRC1, thereby promoting the deposition of H2AK119ub. In contrast, H2AZ.2 does not significantly affect Ring1B recruitment but instead functions as a structural component that stabilizes H2AK119ub-modified nucleosomes. In vitro ubiquitination assays indicate that H2AZ.1-containing nucleosomes serve as more efficient substrates for PRC1-mediated ubiquitination compared to those containing H2AZ.2. Thus, these findings define the distinct mechanisms of the two H2AZ variants in regulated PRC1-mediated H2AK119 ubiquitination and highlight a functional division of labor in epigenetic regulation. Full article

Class IIa histone deacetylases (HDACs) are pleiotropic regulators of various differentiation pathways and adaptive responses. They form complexes with other co-repressors and can bind to DNA by interacting with selected transcription factors, with members of the Myocyte Enhancer Factor-2 (MEF2) family being the best characterized. A notable feature of class IIa HDACs is the substitution of tyrosine for histidine in the catalytic site, which has occurred over the course of evolution and has a profound effect on the efficiency of catalysis against acetyl-lysine. Another distinctive feature of this family of “pseudoenzymes” is the regulated nucleus–cytoplasm shuttling associated with several non-histone proteins that have been identified as potential substrates, including proteins localized in the cytosol. Within the complexity of class IIa HDACs, several aspects deserve further investigation. In the following, I will discuss some of the recent advances in our knowledge of class IIa HDACs. Full article

Cardiovascular diseases (CVD), such as myocardial hypertrophy, heart failure, atherosclerosis, and myocardial ischemia/reperfusion (I/R) injury, are among the major threats to human health worldwide. Post-translational modifications alter the function of proteins through dynamic chemical modification after synthesis. This mechanism not only plays an important role in maintaining homeostasis and plays a crucial role in maintaining normal cardiovascular function, but is also closely related to the pathological state of various diseases. Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression, and play important roles in post-translational modification by catalyzing the deacetylation of key lysine residues in nucleosomal histones, which are closely associated with the occurrence and development of cardiovascular diseases. Recent studies indicate that HDAC inhibitors (HDACis) may represent a new class of drugs for the treatment of cardiovascular diseases by influencing post-translational modifications. In this review, we systematically summarize the mechanism of action of HDACs and HDACis in post-translational modifications related to common cardiovascular diseases, providing new ideas for the treatment of CVD, and explore possible future research directions on the relationship between HDAC and HDACi in post-translational modifications and cardiovascular diseases. Full article

Osteoclasts, which are derived from myeloid precursors, are essential for physiologic bone remodeling but also mediate pathological bone loss in inflammatory diseases such as periodontitis and rheumatoid arthritis. Lysine-specific demethylase (LSD1/KDM1A) is a histone demethylase that modulates the chromatin landscape via demethylation of H3K4me1/2 and H3K9me1/2, thereby regulating the expression of genes essential for deciding cell fate. We previously demonstrated that myeloid-specific deletion of LSD1 (LSD1LysM-Cre) disrupts osteoclast differentiation, leading to enhanced BV/TV under physiological conditions. In this study, we show that LSD1LysM-Cre female mice are similarly resistant to inflammatory bone loss in both ligature-induced periodontitis and K/BxN serum-transfer arthritis models. Bulk RNA-seq of mandibular-derived preosteoclasts from LSD1LysM-Cre mice with ligature-induced periodontitis revealed the upregulation of genes involved in inflammation, lipid metabolism, and immune response. Notably, LSD1 deletion blocked osteoclastogenesis even under TGF-β and TNF co-stimulation, which is an alternative RANKL-independent differentiation pathway. Upregulation of Nlrp3, Hif1α, and Acod1 in LSD1LysM-Cre preosteoclasts suggests that LSD1 is essential for repressing inflammatory and metabolic programs that otherwise hinder osteoclast commitment. These findings establish LSD1 as a critical epigenetic gatekeeper integrating inflammatory and metabolic signals to regulate osteoclast differentiation and bone resorption. Therapeutic inhibition of LSD1 may selectively mitigate inflammatory bone loss while preserving physiological bone remodeling. Full article

In this study, we investigated the mitochondrial defects resulting from the deletion of GCN5, a lysine-acetyltransferase, in the yeast Saccharomyces cerevisiae. Gcn5 serves as the catalytic subunit of the SAGA acetylation complex and functions as an epigenetic regulator, primarily acetylating N-terminal lysine residues on histones H2B and H3 to modulate gene expression. The loss of GCN5 leads to mitochondrial abnormalities, including defects in mitochondrial morphology, a reduced mitochondrial DNA copy number, and defective mitochondrial inheritance due to the depolarization of actin filaments. These defects collectively trigger the activation of the mitophagy pathway. Interestingly, deleting CSN5, which encodes to Csn5/Rri1 (Csn5), the catalytic subunit of the COP9 signalosome complex, rescues the mitochondrial phenotypes observed in the gcn5Δ strain. Furthermore, these defects are suppressed by exogenous ergosterol supplementation, suggesting a link between the rescue effect mediated by CSN5 deletion and the regulatory role of Csn5 in the ergosterol biosynthetic pathway. Full article

Aurora kinase B (AURKB), a serine/threonine protein kinase, is essential for accurate chromosome segregation and cytokinesis during mitosis. Dysregulation of AURKB, often characterized by its overexpression, has been implicated in various malignancies, including breast cancer. However, the mechanisms governing its dysregulation remain incompletely understood. Here, we identify a pivotal role for the MOF/MSL complex—which includes the histone acetyltransferase MOF (KAT8)—in modulating AURKB stability through acetylation at lysine 215 (K215). This post-translational modification inhibits AURKB ubiquitination, thereby stabilizing its protein levels. MOF/MSL-mediated AURKB stabilization promotes the proper assembly of the chromosomal passenger complex (CPC), ensuring mitotic fidelity. Notably, inhibition of MOF reduces AURKB K215 acetylation, leading to decreased AURKB expression and activity. Consequently, this downregulation suppresses expression of the downstream oncogene c-MYC, ultimately attenuating the malignant proliferation of breast cancer cells. Collectively, our findings reveal a novel mechanism by which lysine acetylation regulates AURKB stability, highlight the significance of the MOF-AURKB-c-MYC axis in breast cancer progression, and suggest potential therapeutic strategies targeting this pathway in clinical settings. Full article

In this study, we identify cortical molecular biomarkers potentially associated with learning in mice using artificial intelligence (AI), inclusive of established and novel feature selection combined with supervised learning technologies. We applied multiple machine learning (ML) algorithms, using public domain ML software, to a public domain dataset, in order to support reproducible findings. We developed technologies tasked with predicting whether a given mouse was shocked to learn, based on protein expression levels extracted from their cortices. Results indicate that it is possible to predict whether a mouse has been shocked to learn or not based only on the following cortical molecular biomarkers: brain-derived neurotrophic factor (BDNF), NR2A subunit of N-methyl-D-aspartate receptor, B-cell lymphoma 2 (BCL2), histone H3 acetylation at lysine 18 (H3AcK18), protein kinase R-like endoplasmic reticulum kinase (pERK), and superoxide dismutase 1 (SOD1). These results were obtained with a novel redundancy-aware feature selection method. Five out of six protein expression biomarkers (BDNF, NR2A, H3AcK18, pERK, SOD1) identified have previously been associated with aspects of learning in the literature. Three of the proteins (BDNF, NR2A, and BCL2) have previously been associated with pruning, and one has previously been associated with apoptosis (BCL2), implying a potential connection between learning and both cortical pruning and apoptosis. The results imply that these six protein expression profiles (BDNF, NR2A, BCL2, H3AcK18, pERK, SOD1) are highly predictive of whether or not a mouse has been shocked to learn. Full article

Haploinsufficiency disorders are genetic diseases caused by reduced gene expression, leading to developmental, metabolic, and tumorigenic abnormalities. The dosage-sensitive Retinoic Acid Induced 1 (RAI1) gene, located within the 17p11.2 region, is central to the core features of Smith––Magenis syndrome (SMS) and Potocki––Lupski syndrome (PTLS), caused by the reciprocal microdeletions and microduplications of this region, respectively. SMS and PTLS present contrasting phenotypes. SMS is characterized by severe neurobehavioral manifestations, sleep disturbances, and metabolic abnormalities, and PTLS shows milder features. Here, we detail the molecular functions of RAI1 in its wild-type and haploinsufficiency conditions (RAI1+/−), as studied in animal and cellular models. RAI1 acts as a transcription factor critical for neurodevelopment and synaptic plasticity, a chromatin remodeler within the Histone 3 Lysine 4 (H3K4) writer complex, and a regulator of faulty 5′-capped pre-mRNA degradation. Alterations of RAI1 functions lead to synaptic scaling and transcriptional dysregulation in neural networks. This review highlights key molecular mechanisms of RAI1, elucidating its role in the interplay between genetics and phenotypic features and summarizes innovative therapeutic approaches for SMS. These data provide a foundation for potential therapeutic strategies targeting RAI1, its mRNA products, or downstream pathways. Full article

Neuroinflammation, a complex nervous system response to brain injury and other pathological stimuli, exhibits a common denominator role in the pathogenesis of neurological disorders and their progression. Among several regulators of neuroinflammation, epigenetic mechanisms with particular emphasis on histone methylation have a prominent role by altering the expression of specific genes involved in the onset and progression of neuroinflammation. The Enhancer of Zeste 2 (EZH2) histone lysine methyltransferase is a multi-faceted and context-dependent regulator of immune response and neural cell function, significantly involved in the underlying mechanisms of neuroinflammation, such as inflammatory gene expression, astrocyte function, microglial activation, BBB integrity, and interactions with non-coding RNAs. Herein, we explore the intricate implication of EZH2 activity in the onset of neuroinflammation and associated pathological conditions, and discuss its potential as a therapeutic target. Currently available EZH2 inhibitors with neuroprotective effects are also addressed in an effort to reveal novel strategies for managing neuroinflammatory conditions, and potentially improving neurological health. Full article

Lactylation, referring to the covalent coupling of the lactyl group with lysine residues, is a recently defined post-translational modification. It has been demonstrated that lactylation can alter protein transcription, thereby affecting the transmission of genetic information and ultimately exerting diverse effects on health and diseases. Here, we review the existing literature and summarize the characteristics and mechanisms of lactylation on both histone and non-histone proteins. We hope to explore lactylation targets for different diseases, thus providing potential clues for new therapeutic strategies. Full article

The diverse methylation modifications of DNA, histones and RNA have emerged as pivotal regulatory mechanisms of gene expression in multiple biological processes at the epigenetic level. They function by coordinating gene expression through impacting gene transcription, mRNA processing and maturation, protein translation and metabolism. Changes in methylation profiles of nucleic acids and histones have been observed in many different types neural injuries in both the central nervous system and the peripheral nervous system, such as 5-methylcytosine in DNA, N6-methyladenosine in RNA and methylation of lysine residues in various histones. Importantly, altering these modifications plays key roles in regulation of neural injury and repair. In this review, we highlight recent research advances of the methylation-related epigenetic modifications in multiple aspects of neural injury and regeneration, including neural protection, axon regeneration, microenvironment modulation and neural functional recovery. We also discuss the current unsolved problems in the field and propose potential future research directions. Full article

Fusarium verticillioides is a globally prevalent phytopathogenic fungus responsible for multiple diseases in maize and a major producer of the mycotoxin fumonisin B1 (FB1), a highly toxic fungal secondary metabolite (FSM). The histone code, which includes reversible modifications such as acetylation and methylation, plays a critical role in regulating chromatin structure and gene expression. In fungi, di- and tri-methylation of histone H3 at lysine 9 (H3K9me2/3) serves as a key epigenetic mark associated with heterochromatin formation and transcriptional repression. In this study, we identified and characterized a putative heterochromatin protein 1 (HP1) family member in F. verticillioides, designated FvHP1, based on conserved domain architecture and phylogenetic analyses. FvHP1 retains essential residues required for H3K9me2/3 recognition, supporting its functional conservation within the HP1 protein family. Phenotypic analysis of the ΔFvHP1 mutant revealed impaired vegetative growth, reduced conidiation and virulence, and altered FB1 mycotoxin production. Additionally, the accumulation of red pigment in the mutant was linked to the deregulation of secondary metabolism, specifically the overproduction of fusarubin-type naphthoquinones, such as 8-O-methylnectriafurone. These results support the role of FvHP1 in facultative heterochromatin-mediated repression of sub-telomeric biosynthetic gene clusters, including the pigment-associated PGL1 cluster. Our findings provide new insights into the epigenetic regulation of fungal pathogenicity and metabolite production, as well as the first evidence of a functional HP1 homolog in F. verticillioides. Full article

Lysine acetyltransferase 8 (KAT8) is a member of the MYST family of histone acetyltransferases. It catalyzes the acetylation of histone H4 at lysine 16 (H4K16ac) and non-histone proteins. Abnormal upregulation or downregulation of KAT8 and its associated H4K16ac have been observed in malignant tumors, suggesting its close association with tumorigenesis and progression. Characterized by structural diversity and multi-target mechanisms, natural agents have been increasingly shown to possess significant antitumor activity. This review focuses on KAT8, summarizing its molecular mechanisms in regulating tumor development by catalyzing substrate protein acetylation, which impacts tumor cell proliferation, cell cycle regulation, apoptosis, DNA damage repair, and autophagy. It also systematically discusses the pharmacological activities and molecular mechanisms of small-molecule agents that target KAT8 to inhibit tumor proliferation, including natural compounds, synthetic drugs, and non-coding RNAs. Full article

Histone 3 lysine 4 methylation (H3K4me) is an evolutionarily conserved epigenetic marker associated with transcriptional activation, playing a crucial role in growth and development. In yeast, all forms of H3K4 methylation are catalyzed by the COMPASS complex. However, purifying endogenous COMPASS remains challenging due to its low abundance, compositional complexity, and structural instability, resulting in low yield, poor purity, and heterogeneity in isolated complexes. These technical limitations have impeded the structural elucidation of the intact COMPASS complex and contributed to inconsistencies in reported in vitro enzymatic activity, thereby limiting a comprehensive understanding of its functions. Here, we present an optimized tandem affinity purification strategy that enables the high-yield isolation of native COMPASS from Saccharomyces cerevisiae with >99% purity and intact subunit composition, as validated by biochemical analyses. Using recombinant nucleosomes as substrates, we systematically characterized its catalytic properties and found that endogenously purified COMPASS exhibited strict dependence on H2B ubiquitination for catalyzing H3K4 methylation. This work establishes an efficient purification strategy for future structural and functional studies of COMPASS and provides critical insights into its catalytic properties. Full article