Xist RNA binds select autosomal genes and depends on Repeat B to regulate their expression.

Xist, a pivotal player in X chromosome inactivation (XCI), has long been perceived as a cis-acting long noncoding RNA that binds exclusively to the inactive X chromosome (Xi). However, Xist's ability to diffuse under select circumstances has also been documented, leading us to suspect that Xist RNA may have targets and functions beyond the Xi. Here, using female mouse embryonic stem cells (ES) and mouse embryonic fibroblasts (MEF) as models, we demonstrate that Xist RNA indeed can localize beyond the Xi. However, its binding is limited to ~100 genes in cells undergoing XCI (ES cells) and in post-XCI cells (MEFs). The target genes are diverse in function but are unified by their active chromatin status. Xist binds discretely to promoters of target genes in neighborhoods relatively depleted for Polycomb marks, contrasting with the broad, Polycomb-enriched domains reported for human XIST RNA. We find that Xist binding is associated with down-modulation of autosomal gene expression. However, unlike on the Xi, Xist binding does not lead to full silencing and also does not spread beyond the target gene. Over-expressing Xist in transgenic ES cells similarly lead to autosomal gene suppression, while deleting Xist's Repeat B motif reduces autosomal binding and perturbs autosomal down-regulation. Furthermore, treating female ES cells with the Xist inhibitor, X1, leads to loss of autosomal suppression. Altogether, our findings reveal Xist targets ~100 genes beyond the Xi, identify Repeat B as a crucial domain for its in-trans function in mice, and indicate that autosomal targeting can be disrupted by the X1 small molecule inhibitor.

Nanoplastic at environmentally relevant concentrations induces toxicity across multiple generations associated with inhibition in germline G protein-coupled receptor CED-1 in Caenorhabditis elegans.

Nanoplastics at environmentally relevant concentrations (ERCs) could cause transgenerational toxicity on organisms. Caenorhabditis elegans is an important model for the study of transgenerational toxicology of pollutants. Nevertheless, the underlying mechanisms for the control of transgenerational nanoplastic toxicity by germline signals remain largely unclear. In C. elegans, exposure to 1-100 µg/L polystyrene nanoparticle (PS-NP) decreased expression of germline ced-1 encoding a G protein-coupled receptor at parental generation (P0-G). After PS-NP exposure at P0-G, transgenerational decrease in germline ced-1 expression could be detected. Meanwhile, the susceptibility to transgenerational PS-NP toxicity was observed in ced-1(RNAi) animals. After PS-NP exposure at P0-G, germline RNAi of ced-1 increased expressions of met-2 and set-6 encoding histone methylation transferases. The susceptibility of ced-1(RNAi) to transgenerational PS-NP toxicity could be inhibited by RNAi of met-2 and set-6. Moreover, in PS-NP exposed met-2(RNAi) and set-6(RNAi) nematodes, expressions of ins-39, wrt-3, and/or efn-3 encoding secreted ligands were decreased. Therefore, our results demonstrated that inhibition in germline CED-1 mediated the toxicity induction of nanoplastics at ERCs across multiple generations in nematodes.

Macrophage plasticity: signaling pathways, tissue repair, and regeneration.

Macrophages are versatile immune cells with remarkable plasticity, enabling them to adapt to diverse tissue microenvironments and perform various functions. Traditionally categorized into classically activated (M1) and alternatively activated (M2) phenotypes, recent advances have revealed a spectrum of macrophage activation states that extend beyond this dichotomy. The complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications orchestrates macrophage polarization, allowing them to respond to various stimuli dynamically. Here, we provide a comprehensive overview of the signaling cascades governing macrophage plasticity, focusing on the roles of Toll-like receptors, signal transducer and activator of transcription proteins, nuclear receptors, and microRNAs. We also discuss the emerging concepts of macrophage metabolic reprogramming and trained immunity, contributing to their functional adaptability. Macrophage plasticity plays a pivotal role in tissue repair and regeneration, with macrophages coordinating inflammation, angiogenesis, and matrix remodeling to restore tissue homeostasis. By harnessing the potential of macrophage plasticity, novel therapeutic strategies targeting macrophage polarization could be developed for various diseases, including chronic wounds, fibrotic disorders, and inflammatory conditions. Ultimately, a deeper understanding of the molecular mechanisms underpinning macrophage plasticity will pave the way for innovative regenerative medicine and tissue engineering approaches.

Chidamide induces cell cycle arrest via NR4A3/P21 axis upregulation to suppress relapsed and refractory acute myeloid leukemia.

(1) Currently, the survival prognosis for patients with relapsed and refractory acute myeloid leukemia (R/R AML) is extremely poor. Therefore, the exploration of novel drugs is imperative to enhance the prognosis of patients with R/R AML. The therapeutic efficacy and mechanism of Chidamide, a novel epigenetic regulatory drug, in the treatment of R/R AML remain unclear. METHODS: The mechanism of action of Chidamide has been explored in various AML cell lines through various methods such as cell apoptosis, cell cycle analysis, high-throughput transcriptome sequencing, gene silencing, and xenograft models. RESULTS: Here, we have discovered that chidamide potently induces apoptosis, G0/G1 phase arrest, and mitochondrial membrane potential depolarization in R/R AML cells, encompassing both primary cells and cell lines. Through RNA-seq analysis, we further revealed that chidamide epigenetically regulates the upregulation of differentiation-related pathways while suppressing those associated with cell replication and cell cycle progression. Notably, our screening identified NR4A3 as a key suppressor gene whose upregulation by chidamide leads to P21-dependent cell cycle arrest in the G0/G1 phase. CONCLUSIONS: We have discovered a novel epigenetic regulatory mechanism of chidamide in the treatment of relapsed and refractory acute myeloid leukemia (R/R AML).

LOC730101 transmitted by exosomes facilitates laryngeal squamous cell carcinoma tumorigenesis via regulation of p38 MAPK gamma.

Laryngeal squamous cell carcinoma (LSCC) is a prevalent human cancer with a complex pathogenesis that remains incompletely understood. Here, we unveil a long non-coding RNA (lncRNA) associated with LSCC tumorigenesis and progression. LOC730101 exhibits significant overexpression in human LSCC tissues, and elevated LOC730101 levels correlate with malignant clinicopathological characteristics. Moreover, we demonstrate that LOC730101 is encapsulated into exosomes in an hnRNPA2B1-dependent manner, serving as a promising plasma biomarker for discriminating LSCC patients from healthy individuals (AUC = 0.92 with 89.36% sensitivity and 86.36% specificity). Exosomes derived from LSCC cells enhance the viability, DNA synthesis rate, and invasiveness of normal nasopharynx epithelial cells, with pronounced effects observed upon LOC730101 overexpression. Additionally, exosomal LOC730101 promotes tumor growth in vivo. Mechanistically, exosomal LOC730101 internalization by normal nasopharynx epithelial cells leads to increased H3K4me3 levels on the p38 MAPK gamma (p38γ) promoter via direct interaction with hnRNPA2B1. This interaction activates p38γ transcription, ultimately driving LSCC tumorigenesis. Collectively, our findings uncover a novel exosomal lncRNA that mediates communication between normal and LSCC cells during LSCC carcinogenesis, suggesting that targeting LOC730101 may represent a promising therapeutic strategy for LSCC treatment.

KLF4 is an epigenetically modulated, context-dependent tumor suppressor.

The epigenetic layer of regulation has become increasingly relevant in the research focused on tumor suppressors. KLF4 is a well-described zinc-finger transcription factor, mainly known for its role in the acquisition of cell pluripotency. Here we report and describe the most relevant epigenetic regulation mechanisms that affect KLF4 expression in tumors. CpG island methylation emerges as the most common mechanism in several tumors including lung adenocarcinoma, hepatocellular carcinoma, non-Hodgkin lymphomas, among others. Further layers of regulation represented by histone methylation and acetylation and by non-coding RNAs are described. Overall, KLF4 emerges as a crucial target in the fight against cancer.

Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells.

Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.

A systematic review of mechanisms of PTEN gene down-regulation mediated by miRNA in prostate cancer.

Background: The Phosphatase and Tensin Homolog gene (PTEN) is pivotal in regulating diverse cellular processes, including growth, differentiation, proliferation, and cell survival, mainly by modulating the PI3K/AKT/mTOR pathway. Alterations in the expression of the PTEN gene have been associated with epigenetic mechanisms, particularly the regulation by small non-coding RNAs, such as miRNAs. Modifications in the expression levels of miRNAs that control PTEN have been shown to lead to its underexpression. This underexpression, in turn, impacts the PI3K/AKT/mTOR pathway, thereby influencing crucial mechanisms like proliferation and apoptosis, playing an important role in the initiation and progression of prostate cancer (PCa). Thus, we aimed to systematically reviewed available information concerning the regulation of PTEN mediated by miRNA in PCa. Methods: Electronic databases were searched to identify studies assessing PTEN regulation via PCa miRNAs, the search included combination of the words microRNAs, PTEN and prostatic neoplasms. The quality assessment of the articles included was carried out using an adapted version of SYRCLE and CASP tool. Results: We included 39 articles that measured the relative gene expression of miRNAs in PCa and their relationship with PTEN regulation. A total of 42 miRNAs were reported involved in the development and progression of PCa via PTEN dysregulation (34 miRNAs up-regulated and eight miRNAs down-regulated). Sixteen miRNAs were shown as the principal regulators for genetic interactions leading to carcinogenesis, being the miR-21 the most reported in PCa associated with PTEN down-regulation. We showed the silencing of PTEN could be promoted by a loop between miR-200b and DNMT1 or by direct targeting of PTEN by microRNAs, leading to the constitutive activation of PI3K/AKT/mTOR and interactions with intermediary genes support apoptosis inhibition, proliferation, invasion, and metastasis in PCa. Conclusion: According to our review, dysregulation of PTEN mediated mainly by miR-21, -20a, -20b, -93, -106a, and -106b up-regulation has a central role in PCa development and could be potential biomarkers for diagnosis, prognostic, and therapeutic targets.

Modifications on histone tails in Parkinson's disease.

This study investigates the role of histone tail modifications in Parkinson's disease (PD), emphasizing the epigenetic regulation of genes associated with the disease. PD primarily manifests in individuals over 60, suggesting that PD-causal genes remain dormant until later in life, influenced by environmental factors and epigenetic modifications. Histone modifications such as methylation, acetylation, phosphorylation, and ubiquitylation play crucial roles in gene expression regulation by altering chromatin structure or interacting with gene regulatory regions. Specifically, modifications on histones H2A, H2AX, H3, and H4 have been linked to PD. For instance, α-synuclein (α-SYN) aggregation, a hallmark of PD, is regulated by histone modifications like H3K27ac and H3K4me3, which enhance α-SYN expression and contribute to PD progression. Conversely, repressive marks like H3K9ac and H3K27me3 can mitigate PD risk by reducing α-SYN levels. Therapeutic strategies targeting these histone modifications, such as the use of GSK-J4 or vitamin C-treated neural stem cells, show potential in alleviating PD symptoms by modulating histone marks and gene expression. Understanding these epigenetic mechanisms offers promising avenues for developing novel treatments for PD.

m6A-mediated HDAC9 upregulation promotes particulate matter-induced airway inflammation via epigenetic control of DUSP9-MAPK axis and acts as an inhaled nanotherapeutic target.

Exposure to particulate matter (PM) can cause airway inflammation and worsen various airway diseases. However, the underlying molecular mechanism by which PM triggers airway inflammation has not been completely elucidated, and effective interventions are lacking. Our study revealed that PM exposure increased the expression of histone deacetylase 9 (HDAC9) in human bronchial epithelial cells and mouse airway epithelium through the METTL3/m6A methylation/IGF2BP3 pathway. Functional assays showed that HDAC9 upregulation promoted PM-induced airway inflammation and activation of MAPK signaling pathway in vitro and in vivo. Mechanistically, HDAC9 modulated the deacetylation of histone 4 acetylation at K12 (H4K12) in the promoter region of dual specificity phosphatase 9 (DUSP9) to repress the expression of DUSP9 and resulting in the activation of MAPK signaling pathway, thereby promoting PM-induced airway inflammation. Additionally, HDAC9 bound to MEF2A to weaken its anti-inflammatory effect on PM-induced airway inflammation. Then, we developed a novel inhaled lipid nanoparticle system for delivering HDAC9 siRNA to the airway, offering an effective treatment for PM-induced airway inflammation. Collectively, we elucidated the crucial regulatory mechanism of HDAC9 in PM-induced airway inflammation and introduced an inhaled therapeutic approach targeting HDAC9. These findings contribute to alleviating the burden of various airway diseases caused by PM exposure.

[H3K27me3 Expression Level and Its Epigenetic Regulation Mechanisms in Th17 Cell Differentiation in Patients With Ankylosing Spondylitis]. / å¼ºç›´æ€§è„ŠæŸ±ç‚Žæ‚£è€ H3K27me3è¡¨è¾¾æ°´å¹³åŠå ¶è°ƒæŽ§Th17ç»†èƒžåˆ†åŒ–çš„è¡¨è§‚é—ä¼ æœºåˆ¶.

Objective: To investigate the roles of histone H3K27me3 methylation and its regulatory enzymes JMJD3 and EZH2 in the differentiation of Th17 cells in ankylosing spondylitis (AS), to unveil their potential involvement in the pathogenesis of AS, and to provide new strategies and targets for the clinical treatment of AS by analyzing the methylation state of H3K27me3 and its interactions with Th17-related factors. Methods: A total of 84 AS patients (42 active AS patiens and 42 patients in the stable phase of AS) were enrolled for the study, while 84 healthy volunteers were enrolled as the controls. Blood samples were collected. Peripheral blood mononuclear cells were isolated. ELISA assay was performed to examine Th17 cells and the relevant cytokines IL-21, IL-22, and IL-17. The mRNA expressions of RORc, JAK2, and STAT3 were analyzed by RT-PCR, the protein expressions of RORc, JAK2/STAT3 pathway protein, H3K27me3 and the relevant protease (EZH2 and JMJD3) were determined by Western blot. Correlation between H3K27me3, EZH2 and JMJD3 and the key signaling pathway molecules of Th cell differentiation was analyzed by Pearson correlation analysis. Results: The mRNA expressions of RORc, JAK2, and STAT3 were significantly higher in the active phase group than those in the stable phase group ( P<0.05). The relative grayscale values of H3K27me3 and EZH2 in the active phase group were lower than those of the stable phase group, which were lower than those of the control group, with the differences being statistically significant ( P<0.05). The relative grayscale values of JMJD3, RORc, JAK2, pJAK2, STAT3, and pSTAT3 proteins were significantly higher in the active phase group than those in the stable phase group, which were higher than those in the control group (all P<0.05). The proportion of Th17 and the expression level of inflammatory factors in the active period group were higher than those in the other two groups (P<0.05). H3K27me3 was negatively correlated with RORc, JAK2, STAT3, and IL-17, JMJD3 was positvely correlated with JAK2, STAT3, and IL-17, and EZH2 was negatively correlated with JAK2, STAT3, and IL-17 (all P<0.05). Conclusion: The low expression of H3K27me3 in AS is influenced by the gene loci JMJD3 and EZH2, which can regulate the differentiation of Th17 cells and thus play a role in the pathogenesis and progression of AS.

The role of lactate-induced protein lactylation in gliomas: implications for preclinical research and the development of new treatments.

The most prevalent primary brain tumors in adults are gliomas. In addition to insufficient therapeutic alternatives, gliomas are fatal mostly due to the rapid proliferation and continuous infiltration of tumor cells into the surrounding healthy brain tissue. According to a growing body of research, aerobic glycolysis, or the Warburg effect, promotes glioma development because gliomas are heterogeneous cancers that undergo metabolic reprogramming. Therefore, addressing the Warburg effect might be a useful therapeutic strategy for treating cancer. Lactate plays a critical role in reprogramming energy metabolism, allowing cells to rapidly access large amounts of energy. Lactate, a byproduct of glycolysis, is therefore present in rapidly proliferating cells and tumors. In addition to the protumorigenesis pathways of lactate synthesis, circulation, and consumption, lactate-induced lactylation has been identified in recent investigations. Lactate plays crucial roles in modulating immune processes, maintaining homeostasis, and promoting metabolic reprogramming in tumors, which are processes regulated by the lactate-induced lactylation of the lysine residues of histones. In this paper, we discuss the discovery and effects of lactylation, review the published studies on how protein lactylation influences cancer growth and further explore novel treatment approaches to achieve improved antitumor effects by targeting lactylation. These findings could lead to a new approach and guidance for improving the prognosis of patients with gliomas.

DNA methylation profile of inflammatory breast cancer and its impact on prognosis and outcome.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare disease characterized by rapid progression, early metastasis, and a high mortality rate. METHODS: Genome-wide DNA methylation analysis (EPIC BeadChip platform, Illumina) and somatic gene variants (105 cancer-related genes) were performed in 24 IBCs selected from a cohort of 140 cases. RESULTS: We identified 46,908 DMPs (differentially methylated positions) (66% hypomethylated); CpG islands were predominantly hypermethylated (39.9%). Unsupervised clustering analysis revealed three clusters of DMPs characterized by an enrichment of specific gene mutations and hormone receptor status. The comparison among DNA methylation findings and external datasets (TCGA-BRCA stages III-IV) resulted in 385 shared DMPs mapped in 333 genes (264 hypermethylated). 151 DMPs were associated with 110 genes previously detected as differentially expressed in IBC (GSE45581), and 68 DMPs were negatively correlated with gene expression. We also identified 4369 DMRs (differentially methylated regions) mapped on known genes (2392 hypomethylated). BCAT1, CXCL12, and TBX15 loci were selected and evaluated by bisulfite pyrosequencing in 31 IBC samples. BCAT1 and TBX15 had higher methylation levels in triple-negative compared to non-triple-negative, while CXCL12 had lower methylation levels in triple-negative than non-triple-negative IBC cases. TBX15 methylation level was associated with obesity. CONCLUSIONS: Our findings revealed a heterogeneous DNA methylation profile with potentially functional DMPs and DMRs. The DNA methylation data provided valuable insights for prognostic stratification and therapy selection to improve patient outcomes.

The landscape of epigenetic regulation and therapeutic application of N6-methyladenosine modifications in non-coding RNAs.

RNA N6-methyladenosine (m6A) methylation is the most abundant and conserved RNA modification in eukaryotes. It participates in the regulation of RNA metabolism and various pathophysiological processes. Non-coding RNAs (ncRNAs) are defined as small or long transcripts which do not encode proteins and display numerous biological regulatory functions. Similar to mRNAs, m6A deposition is observed in ncRNAs. Studying RNA m6A modifications on ncRNAs is of great importance specifically to deepen our understanding of their biological roles and clinical implications. In this review, we summarized the recent research findings regarding the mutual regulation between RNA m6A modification and ncRNAs (with a specific focus on microRNAs, long non-coding RNAs, and circular RNAs) and their functions. We also discussed the challenges of m6A-containing ncRNAs and RNA m6A as therapeutic targets in human diseases and their future perspective in translational roles.

Epigenetic diversity of genes with copy number variations among natural populations of the three-spined stickleback.

Duplicated genes provide the opportunity for evolutionary novelty and adaptive divergence. In many cases, having more gene copies increases gene expression, which might facilitate adaptation to stressful or novel environments. Conversely, overexpression or misexpression of duplicated genes can be detrimental and subject to negative selection. In this scenario, newly duplicate genes may evade purifying selection if they are epigenetically silenced, at least temporarily, leading them to persist in populations as copy number variations (CNVs). In animals and plants, younger gene duplicates tend to have higher levels of DNA methylation and lower levels of gene expression, suggesting epigenetic regulation could promote the retention of gene duplications via expression repression or silencing. Here, we test the hypothesis that DNA methylation variation coincides with young duplicate genes that are segregating as CNVs in six populations of the three-spined stickleback that span a salinity gradient from 4 to 30 PSU. Using reduced-representation bisulfite sequencing, we found DNA methylation and CNV differentiation outliers rarely overlapped. Whereas lineage-specific genes and young duplicates were found to be highly methylated, just two gene CNVs showed a significant association between promoter methylation level and copy number, suggesting that DNA methylation might not interact with CNVs in our dataset. If most new duplications are regulated for dosage by epigenetic mechanisms, our results do not support a strong contribution from DNA methylation soon after duplication. Instead, our results are consistent with a preference to duplicate genes that are already highly methylated.

Epigenetic insights into an epimutant colorless non-ripening: from fruit ripening to stress responses.

The epigenetic machinery has received extensive attention due to its involvement in plant growth, development, and adaptation to environmental changes. Recent studies often highlight the epigenetic regulatory network by discussing various epigenetic mutants across various plant species. However, a systemic understanding of essential epigenetic regulatory mechanisms remains limited due to a lack of representative mutants involved in multiple biological processes. Colorless Non-ripening (Cnr), a spontaneous epimutant isolated from a commercial population, was initially characterized for its role in fruit ripening regulation. Cnr fruits exhibit an immature phenotype with yellow skin, attributed to hypermethylation of the SQUAMOSA PROMOTER BINDING PROTEIN-LIKE-CNR (SlSPL-CNR) promoter, resulting in the repression of gene expression. In addition to DNA methylation, this process also involves histone modification and microRNA, integrating multiple epigenetic regulatory factors. Interestingly, knockout mutants of SlSPL-CNR display phenotypical distinctions from Cnr in fruit ripening, indicating complex genetic and epigenetic control over the non-ripening phenotype in Cnr fruits. Accumulating evidence suggests that Cnr epimutation is pleiotropic, participating in various biological processes such as Cd stress, Fe deficiency, vivipary, and cell death. Therefore, the Cnr epimutant serve as an excellent model for unveiling how epigenetic mechanisms are involved in diverse biological processes. This review paper focuses on recent research advances regarding the Cnr epimutant, delving into its complex genetic and epigenetic regulatory mechanisms, with the aim of enhancing our understanding and facilitating the development of high-quality, high-yield crops through epigenetic modification.

Development of a genome atlas for discriminating benign, preinvasive, and invasive lung nodules.

To tackle misdiagnosis in lung cancer screening with low-dose computed tomography (LDCT), we aimed to compile a genome atlas for differentiating benign, preinvasive, and invasive lung nodules and characterize their molecular pathogenesis. We collected 432 lung nodule tissue samples from Chinese patients, spanning benign, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA). We performed comprehensive sequencing, examining somatic variants, gene expressions, and methylation levels. Our findings uncovered EGFR and TP53 mutations as key drivers in - early lung cancer development, with EGFR mutation frequency increasing with disease progression. Both EGFR mutations and EGF/EGFR hypo-methylation activated the EGFR pathway, fueling cancer growth. Transcriptome analysis identified four lung nodule subtypes (G1-4) with distinct molecular features and immune cell infiltrations: EGFR-driven G1, EGFR/TP53 co-mutation G2, inflamed G3, stem-like G4. Estrogen/androgen response was associated with the EGFR pathway, proposing a new therapy combining tyrosine kinase inhibitors with antiestrogens. Preinvasive nodules exhibited stem cell pathway enrichment, potentially hindering invasion. Epigenetic regulation of various genes was essential for lung cancer initiation and development. This study provides insights into the molecular mechanism of neoplastic progression and identifies potential diagnostic biomarkers and therapeutic targets for lung cancer.

The significant role of amino acid metabolic reprogramming in cancer.

Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming of amino acids in tumor cells is intricately linked to protein synthesis, nucleotide synthesis, modulation of signaling pathways, regulation of tumor cell metabolism, maintenance of oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation of amino acid metabolism also impacts tumor microenvironment and tumor immunity. Amino acids can act as signaling molecules that modulate immune cell function and immune tolerance within the tumor microenvironment, reshaping the anti-tumor immune response and promoting immune evasion by cancer cells. Moreover, amino acid metabolism can influence the behavior of stromal cells, such as cancer-associated fibroblasts, regulate ECM remodeling and promote angiogenesis, thereby facilitating tumor growth and metastasis. Understanding the intricate interplay between amino acid metabolism and the tumor microenvironment is of crucial significance. Expanding our knowledge of the multifaceted roles of amino acid metabolism in tumor microenvironment holds significant promise for the development of more effective cancer therapies aimed at disrupting the metabolic dependencies of cancer cells and modulating the tumor microenvironment to enhance anti-tumor immune responses and inhibit tumor progression.

Plant responses to abiotic stress regulated by histone acetylation.

In eukaryotes, histone acetylation and deacetylation play an important role in the regulation of gene expression. Histone acetylation levels are reversibly regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Increasing evidence highlights histone acetylation plays essential roles in the regulation of gene expression in plant response to environmental stress. In this review, we discussed the recent advance of histone acetylation in the regulation of abiotic stress responses including temperature, light, salt and drought stress. This information will contribute to our understanding of how plants adapt to environmental changes. As the mechanisms of epigenetic regulation are conserved in many plants, research in this field has potential applications in improvement of agricultural productivity.

Epigenetic dysregulation in cancers by isocitrate dehydrogenase 2 (IDH2).

Recent advances in genome-wide studies have revealed numerous epigenetic regulations brought about by genes involved in cellular metabolism. Isocitrate dehydrogenase (IDH), an essential enzyme, that converts isocitrate into -ketoglutarate (KG) predominantly in the tricarboxylic acid (TCA) cycle, has gained particular importance due to its cardinal role in the metabolic pathway in cells. IDH1, IDH2, and IDH3 are the three isomeric IDH enzymes that have been shown to regulate cellular metabolism. Of particular importance, IDH2 genes are associated with several cancers, including gliomas, oligodendroglioma, and astrocytomas. These mutations lead to the production of oncometabolite D-2-hydroxyglutarate (D-2-HG), which accumulates in cells promoting tumor growth. The enhanced levels of D-2-HG competitively inhibit α-KG dependent enzymes, inhibiting cell TCA cycle, upregulating the cell growth and survival relevant HIF-1α pathway, promoting DNA hypermethylation related epigenetic activity, all of which synergistically contribute to carcinogenesis. The present review discusses epigenetic mechanisms inIDH2 regulation in cells and further its clinical implications.