Spliceosome dysfunction and aberrant RNA splicing underline unresolved inflammation and immunopathogenesis. Here, we revealed the misregulation of mRNA splicing via the spliceosome in the pathogenesis of rheumatoid arthritis (RA). Among them, decreased expression of RNA binding motif protein 25 (RBM25) was identified as a major pathogenic factor in RA patients and experimental arthritis mice through increased proinflammatory mediator production and increased hyperinflammation in macrophages. Multiomics analyses of macrophages from RBM25-deficient mice revealed that the transcriptional enhancement of proinflammatory genes (including Il1b, Il6, and Cxcl10) was coupled with histone 3 lysine 9 acetylation (H3K9ac) and H3K27ac modifications as well as hypoxia inducible factor-1α (HIF-1α) activity. Furthermore, RBM25 directly bound to and mediated the 14th exon skipping of ATP citrate lyase (Acly) pre-mRNA, resulting in two distinct Acly isoforms, Acly Long (Acly L) and Acly Short (Acly S). In proinflammatory macrophages, Acly L was subjected to protein lactylation on lysine 918/995, whereas Acly S did not, which influenced its affinity for metabolic substrates and subsequent metabolic activity. RBM25 deficiency overwhelmingly increased the expression of the Acly S isoform, enhancing glycolysis and acetyl-CoA production for epigenetic remodeling, macrophage overactivation and tissue inflammatory injury. Finally, macrophage-specific deletion of RBM25 led to inflammaging, including spontaneous arthritis in various joints of mice and inflammation in multiple organs, which could be relieved by pharmacological inhibition of Acly. Overall, targeting the RBM25-Acly splicing axis represents a potential strategy for modulating macrophage responses in autoimmune arthritis and aging-associated inflammation.

The phytohormone abscisic acid (ABA) is an important regulator of plant growth, but its potential participation in the process of in vitro shoot regeneration has not to date been reported. Here, we found that ABA appeared to inhibit in vitro shoot regeneration. ABA represses the formation of stem cell niches, thereby reducing the shoot regeneration by localizing the expression of WUSCHEL (WUS). During in vitro shoot regeneration, enrichment of H3K9ac in the specific region of WUS is a necessary event for its activation which could be inhibited by exogenous ABA. These findings reveal the potential function, as well as the possible way of ABA in regulating de novo shoot regeneration in Arabidopsis.

Impaired wound healing is one of the main clinical complications of type 2 diabetes (T2D) and a major cause of lower limb amputation. Diabetic wounds exhibit a sustained inflammatory state, and reducing inflammation is crucial to diabetic wounds management. Macrophages are key regulators in wound healing, and their dysfunction would cause exacerbated inflammation and poor healing in diabetic wounds. Gene regulation caused by histone modifications can affect macrophage phenotype and function during diabetic wound healing. Recent studies have revealed that targeting histone-modifying enzymes in a local, macrophage-specific manner can reduce inflammatory responses and improve diabetic wound healing. This article will review the significance of macrophage phenotype and function in wound healing, as well as illustrate how histone modifications affect macrophage polarization in diabetic wounds. Targeting macrophage phenotype with histone-modifying enzymes may provide novel therapeutic strategies for the treatment of diabetic wound healing.

Histone acetylation is a crucial epigenetic modification, one that holds the key to regulating gene expression by meticulously modulating the conformation of chromatin. Most histone acetylation enzymes (HATs) and deacetylation enzymes (HDACs) in fungi were originally discovered in yeast. The functions and mechanisms of HATs and HDACs in yeast that have been documented offer us an excellent entry point for gaining insights into these two types of enzymes. In the interaction between plants and pathogenic fungi, histone acetylation assumes a critical role, governing fungal pathogenicity and plant immunity. This review paper delves deep into the recent advancements in understanding how histone acetylation shapes the interaction between plants and fungi. It explores how this epigenetic modification influences the intricate balance of power between these two kingdoms of life, highlighting the intricate network of interactions and the subtle shifts in these interactions that can lead to either mutual coexistence or hostile confrontation.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown origin and the most common interstitial lung disease. However, therapeutic options for IPF are limited, and novel therapies are urgently needed. Histone deacetylases (HDACs) are enzymes that participate in balancing histone acetylation activity for chromatin remodeling and gene transcription regulation. Increasing evidence suggests that the HDAC family is linked to the development and progression of chronic fibrotic diseases, including IPF. This review aims to summarize available information on HDACs and related inhibitors and their potential applications in treating IPF. In the future, HDACs may serve as novel targets, which can aid in understanding the etiology of PF, and selective inhibition of single HDACs or disruption of HDAC genes may serve as a strategy for treating PF.

BACKGROUND: Human hexokinase 2 (HK2) plays an important role in regulating Warburg effect, which metabolizes glucose to lactate acid even in the presence of ample oxygen and provides intermediate metabolites to support cancer cell proliferation and tumor growth. HK2 overexpression has been observed in various types of cancers and targeting HK2-driven Warburg effect has been suggested as a potential cancer therapeutic strategy. Given that epigenetic enzymes utilize metabolic intermediates as substrates or co-factors to carry out post-translational modification of histones and nucleic acids modifications in cells, we hypothesized that altering HK2 expression could impact the epigenome and, consequently, chromatin stability in yeast. To test this hypothesis, we established genetic models with different yeast hexokinase 2 (HXK2) expression in Saccharomyces cerevisiae yeast cells and investigated the effect of HXK2-dependent metabolism on parental nucleosome transfer, a key DNA replication-coupled epigenetic inheritance process, and chromatin stability.
RESULTS: By comparing the growth of mutant yeast cells carrying single deletion of hxk1Δ, hxk2Δ, or double-loss of hxk1Δ hxk2Δ to wild-type cells, we firstly confirmed that HXK2 is the dominant HXK in yeast cell growth. Surprisingly, manipulating HXK2 expression in yeast, whether through overexpression or deletion, had only a marginal impact on parental nucleosome assembly, but a noticeable trend with decrease chromatin instability. However, targeting yeast cells with 2-deoxy-D-glucose (2-DG), a clinical glycolysis inhibitor that has been proposed as an anti-cancer treatment, significantly increased chromatin instability.
CONCLUSIONS: Our findings suggest that in yeast cells lacking HXK2, alternative HXKs such as HXK1 or glucokinase 1 (GLK1) play a role in supporting glycolysis at a level that adequately maintains epigenomic stability. While our study demonstrated an increase in epigenetic instability with 2-DG treatment, the observed effect seemed to occur dependent on non-glycolytic function of Hxk2. Thus, additional research is needed to identify the molecular mechanism through which 2-DG influences chromatin stability.

Hypoxic-ischemic encephalopathy (HIE) is a brain injury induced by many causes of cerebral tissue ischemia and hypoxia. Although HIE may occur at many ages, its impact on the neonatal brain is greater because it occurs during the formative stage. Recent research suggests that histone modifications may occur in the human brain in response to acute stress events, resulting in transcriptional changes and HIE development. Because there are no safe and effective therapies for HIE, researchers have focused on HIE treatments that target histone modifications. In this review, four main histone modifications are explored, histone methylation, acetylation, phosphorylation, and crotonylation, as well as their relevance to HIE. The efficacy of histone deacetylase inhibitors in the treatment of HIE is also explored. In conclusion, targeting histone modifications may be a novel strategy for elucidating the mechanism of HIE, as well as a novel approach to HIE treatment.

Although therapeutic targets for colorectal cancer (CRC) treatment have been developed, the treatment outcomes are not ideal and survival rates for CRC patients remain low. It is critical to identify a specific target and develop an effective CRC treatment system. The ZNF334 gene is a newly identified member of Zinc-finger proteins (ZNFs), which is essential for key biological processes associated with tumorigenesis. Abnormal epigenetic reprogramming of the ZNF334 gene promoter region decreases its expression in CRC and further induces the occurrence of CRC. Here, we clarified that P300 in CRC can regulate the H3K9/27 ac in the ZNF334 promoter. Furthermore, histone acetylation of the ZNF334 promoter region was increased by dCas9-P300 to normalize the deficiency of ZNF334 expression, thereby inhibiting the growth of CRC. Collectively, our findings enable a facile way to affect gene expression using CRISPR/Cas9-based epigenome editing and further determine the causal link between histone acetylation and gene activation, providing a promising gene therapy strategy for the CRC treatment.

Nicotine is developmentally toxic. Prenatal nicotine exposure (PNE) affects the development of multiple fetal organs and causes susceptibility to a variety of diseases in offspring. In this study, we aimed to investigate the effect of PNE on cartilage development and osteoarthritis susceptibility in female offspring rats. Wistar rats were orally gavaged with nicotine on days 9-20 of pregnancy. The articular cartilage was obtained at gestational day (GD) 20 and postnatal week (PW) 24, respectively. Further, the effect of nicotine on chondrogenic differentiation was explored by the chondrogenic differentiation model in human Wharton\'s jelly-derived mesenchymal stem cells (WJ-MSCs). The PNE group showed significantly shallower Safranin O staining and lower Collagen 2a1 content of articular cartilage in female offspring rats. Further, we found that PNE activated pyroptosis in the articular cartilage at GD20 and PW24. In vitro experiments revealed that nicotine inhibited chondrogenic differentiation and activated pyroptosis. After interfering with nod-like receptors3 (NLRP3) expression by SiRNA, it was found that pyroptosis mediated the chondrogenic differentiation inhibition of WJ-MSCs induced by nicotine. In addition, we found that α7-nAChR antagonist α-BTX reversed nicotine-induced NLRP3 and P300 high expression. And, P300 SiRNA reversed the increase of NLRP3 mRNA expression and histone acetylation level in its promoter region induced by nicotine. In conclusion, PNE caused chondrodysplasia and poor articular cartilage quality in female offspring rats. PNE increased the histone acetylation level of NLRP3 promoter region by α7-nAChR/P300, which resulting in the high expression of NLRP3. Further, NLRP3 mediated the inhibition of chondrogenic differentiation by activating pyroptosis.

Living cells navigate a complex landscape of mechanical cues that influence their behavior and fate, originating from both internal and external sources. At the molecular level, the translation of these physical stimuli into cellular responses relies on the intricate coordination of mechanosensors and transducers, ultimately impacting chromatin compaction and gene expression. Notably, epigenetic modifications on histone tails govern the accessibility of gene-regulatory sites, thereby regulating gene expression. Among these modifications, histone acetylation emerges as particularly responsive to the mechanical microenvironment, exerting significant control over cellular activities. However, the precise role of histone acetylation in mechanosensing and transduction remains elusive due to the complexity of the acetylation network. To address this gap, our aim is to systematically explore the key regulators of histone acetylation and their multifaceted roles in response to biomechanical stimuli. In this review, we initially introduce the ubiquitous force experienced by cells and then explore the dynamic alterations in histone acetylation and its associated co-factors, including HDACs, HATs, and acetyl-CoA, in response to these biomechanical cues. Furthermore, we delve into the intricate interactions between histone acetylation and mechanosensors/mechanotransducers, offering a comprehensive analysis. Ultimately, this review aims to provide a holistic understanding of the nuanced interplay between histone acetylation and mechanical forces within an academic framework.