Role Of Histone Modifications Research Articles

Decreased histone H3K9 dimethylation in synergy with DNA demethylation of Spi-1 binding site contributes to ADAMTS-5 expression in articular cartilage of osteoarthritis mice.

Osteoarthritis (OA) is defined by articular cartilage degeneration, synovial membrane inflammation, and abnormal bone remodeling. Recent study has discovered that OA development is linked to an aberrant epigenetic modification of OA-related genes. Our previous research showed that DNA demethylation in ADAMTS-5 promoter region had a substantial impact on ADAMTS-5 expression in the mouse OA model. This process facilitated the binding of Spi-1 to ADAMTS-5 promoter. While alterations in histone methylation have been documented during embryonic development and cancer development, there is a paucity of data on the change in OA pathogenesis. Even no data have been reported on the role of histone modifications in ADAMTS-5 activation in OA. Following our previous study on the role of DNA methylation, we aimed to examine the contribution of histone H3K9 dimethylation in ADAMTS-5 activation in OA. Additionally, we aimed to elucidate the molecular mechanisms underlying the cooperative interaction between DNA methylation and histone H3K9 dimethylation. The potential for anti-OA intervention therapy which is based on modulating histone H3K9 dimethylation is also explored. We demonstrated that a reduction in histone H3K9 dimethylation, along with DNA demethylation of the Spi-1 binding site, had a role in ADAMTS-5 activation in the articular cartilage of OA mice. Significantly, the conditional deletion of histone demethylase to be identified as lysine-specific demethylase 1 (LSD1) in articular cartilage could alleviate the degenerative features of OA mice. Our study demonstrates the direct impact of histone H3K9 dimethylation on gene expression, which in turn contributes to OA development. This research enhances our understanding of the underlying causes of OA.

Research advances on the role of histone modification in cardiac aging and related vascular diseases

Research advances on the role of histone modification in cardiac aging and related vascular diseases

Actively Expressed Intergenic Genes Generated by Transposable Element Insertions in Gossypium hirsutum Cotton.

The genomes and annotated genes of allotetraploid cotton Gossypium hirsutum have been extensively studied in recent years. However, the expression, regulation, and evolution of intergenic genes (ITGs) have not been completely deciphered. In this study, we identified a novel set of actively expressed ITGs in G. hirsutum cotton, through transcriptome profiling based on deep sequencing data, as well as chromatin immunoprecipitation, followed by sequencing (ChIP-seq) of histone modifications and how the ITGs evolved. Totals of 17,567 and 8249 ITGs were identified in G. hirsutum and Gossypium arboreum, respectively. The expression of ITGs in G. hirsutum was significantly higher than that in G. arboreum. Moreover, longer exons were observed in G. hirsutum ITGs. Notably, 42.3% of the ITGs from G. hirsutum were generated by the long terminal repeat (LTR) insertions, while their proportion in genic genes was 19.9%. The H3K27ac and H3K4me3 modification proportions and intensities of ITGs were equivalent to genic genes. The H3K4me1 modifications were lower in ITGs. Additionally, evolution analyses revealed that the ITGs from G. hirsutum were mainly produced around 6.6 and 1.6 million years ago (Mya), later than the pegged time for genic genes, which is 7.0 Mya. The characterization of ITGs helps to elucidate the evolution of cotton genomes and shed more light on their biological functions in the transcriptional regulation of eukaryotic genes, along with the roles of histone modifications in speciation and diversification.

Initial Characterization of WDR5B Reveals a Role in the Proliferation of Retinal Pigment Epithelial Cells.

The chromatin-associated protein WDR5 has been widely studied due to its role in histone modification and its potential as a pharmacological target for the treatment of cancer. In humans, the protein with highest sequence homology to WDR5 is encoded by the retrogene WDR5B, which remains unexplored. Here, we used CRISPR-Cas9 genome editing to generate WDR5B knockout and WDR5B-FLAG knock-in cell lines for further characterization. In contrast to WDR5, WDR5B exhibits low expression in pluripotent cells and is upregulated upon neural differentiation. Loss or shRNA depletion of WDR5B impairs cell growth and increases the fraction of non-viable cells in proliferating retinal pigment epithelial (RPE) cultures. CUT&RUN chromatin profiling in RPE and neural progenitors indicates minimal WDR5B enrichment at established WDR5 binding sites. These results suggest that WDR5 and WDR5B exhibit several divergent biological properties despite sharing a high degree of sequence homology.

Basic Epigenetic Mechanisms of Aging

The process of aging is a complex biological phenomenon that is influenced by multiple factors, including genetics, environment, and lifestyle. Recent studies have shown that epigenetic modifications play an important role in the aging process, as they regulate gene expression and ultimately affect cellular function. Epigenetic modifications include DNA methylation, histone modification, and non-coding RNA expression, among others. The authors of the review discuss the role of DNA methylation in regulating gene expression and its relationship to age-related diseases such as cancer and neurodegeneration. Also, the role of histone modification and its impact on chromatin structure and gene expression is reviewed in the article. Additionally, review provides information on involvement of molecular hallmarks of aging in age-related diseases. Understanding the role of epigenetic mechanisms in aging is crucial for developing new interventions that could potentially slow down or even reverse the aging process.

The Epigenetic Regulation of Quiescent in Stem Cells.

This review article discusses the epigenetic regulation of quiescent stem cells. Quiescent stem cells are a rare population of stem cells that remain in a state of cell cycle arrest until activated to proliferate and differentiate. The molecular signature of quiescent stem cells is characterized by unique epigenetic modifications, including histone modifications and deoxyribonucleic acid (DNA) methylation. These modifications play critical roles in regulating stem cell behavior, including maintenance of quiescence, proliferation, and differentiation. The article specifically focuses on the role of histone modifications and DNA methylation in quiescent stem cells, and how these modifications can be dynamically regulated by environmental cues. The future perspectives of quiescent stem cell research are also discussed, including their potential for tissue repair and regeneration, their role in aging and age-related diseases, and their implications for cancer research. Overall, this review provides a comprehensive overview of the epigenetic regulation of quiescent stem cells and highlights the potential of this research for the development of new therapies in regenerative medicine, aging research, and cancer biology.

Role of Histone Modifications in Acute Kidney Injury Progressing to Chronic Kidney Disease

Acute kidney injury (AKI), a clinical syndrome caused by various factors, is characterized by a rapid decline in kidney function in a short period of time. AKI affects the short-term prognosis of patients and may also induce chronic kidney disease (CKD). However, the current treatment options for AKI mainly focus on symptom management. Specific therapeutic measures available for the prevention of transition from AKI to CKD are very limited in number. Histones are basic proteins that intricately bind the DNA in chromosomes. After translation, histones undergo various modifications on their amino-terminal tails, such as methylation, acetylation, phosphorylation, ubiquitination, and lactylation, collectively forming the "histone code", which affects the expression of genes mainly by regulating the elastic structure of chromatin or recruiting specific proteins. Extensive research conducted in recent years on histone post-translational modifications (PTMs) has also sparked continuous interest in their association with the AKI-to-CKD transition. Therefore, this paper highlights the significant role of PTMs in the process of AKI developing and progressing to CKD, with a view to finding new approaches to preventing the progression of AKI to CKD.

Echinococcus granulosus cyst fluid inhibits inflammatory responses through inducing histone demethylase KDM5B in macrophages

BackgroundEchinococcus granulosus cyst fluid (EgCF) weakens macrophage inflammatory responses, thereby enabling the parasite to evade the immune system. However, the role of histone modification in this process remains to be explored.MethodsThe levels of IL-6, TNF-α, IL-10, H3K4me3, and KDM5B were detected using quantitative real-time PCR, ELISA, and Western blotting. The enrichment of H3K4me3 and KDM5B at the promoter of inflammatory factors was detected by chromatin immunoprecipitation.ResultsBased on EgCF-stimulated macrophage models, we found that EgCF significantly inhibited mRNA expression and protein secretion of IL-6 and TNF-α and upregulated mRNA expression of IL-10 under the influence of TLR4. EgCF lowered the level of H3K4me3 and promoted the transcription and protein stability of histone demethylase KDM5B. Chromatin immunoprecipitation analysis revealed that EgCF suppressed the enrichment of H3K4me3 modification at the promoters of TNF-α and IL-6 and downregulated their expression in macrophages. Additionally, the inhibition of KDM5B activity by CPI-455 weakened the anti-inflammatory effect of EgCF.ConclusionsOur findings demonstrate a novel mechanism through which EgCF promotes KDM5B expression and inhibits the enrichment of H3K4me3 at the promoters of inflammatory cytokines to suppress the inflammatory response.Graphical

Research progress on the role of histone modification in sepsis

Sepsis is a life-threatening organ dysfunction caused by dysregulated body response to infection. It is also one of the major causes of death in critically ill patients. Over the past few years, despite the continuous improvement in the treatment of sepsis, there is no specific treatment, clinical morbidity and mortality are still rising. Therefore, finding effective methods to treat sepsis and reduce mortality is an urgent clinical problem. Histone modification is an epigenetic modification that produces heritable phenotypic changes without altering the DNA sequence. In recent years, many studies have shown that histone modification is closely related to sepsis. This review discusses the mechanism of histone modification in the pathogenesis of sepsis from the aspects of inflammatory factors, signaling pathways, and macrophage polarization, in aimed to provide reference for the clinical treatment of sepsis.

Advances in epigenetic research of adolescent idiopathic scoliosis and congenital scoliosis.

Scoliosis is a three-dimensional structural deformity of the spine; more than 80% of scoliosis has no specific pathogenesis but is understood to be closely related to genetic, hormonal, and environmental factors. In recent years, the epigenetic alterations observed in scoliosis have been analyzed in numerous studies to determine the pathogenesis and progression of this condition, however, there is currently no comprehensive review of the epigenetic factors to date. We searched PubMed, Embase, and Web of Science databases for relative studies without language and date restrictions in March 2023. Twenty-five studies were included in this review and analyzed from the four main aspects of epigenetic alteration: DNA methylation, non-coding RNAs, histone modifications, and chromatin remodeling. The relationship between DNA methylation, non-coding RNAs, and scoliosis was considerably reported in the literature, and the corresponding related signaling pathways and novel biomarkers observed in scoliosis provide insights into innovative prevention and treatment strategies. However, the role of histone modifications is rarely reported in scoliosis, and few studies have investigated the relationship between scoliosis and chromatin remodeling. Therefore, these related fields need to be further explored to elucidate the overall effects of epigenetics in scoliosis.

Maternal Kdm2a-mediated PI3K/Akt signaling and E-cadherin stimulate the morula-to-blastocyst transition revealing crucial roles in early embryonic development

Histone methylation plays an essential role in oocyte growth and preimplantation embryonic development. The modification relies on histone methyl-transferases and demethylases, and one of these, lysine-specific demethylase 2a (Kdm2a), is responsible for modulating histone methylation during oocyte and early embryonic development. The mechanism of how Kdm2a deficiency disrupts early embryonic development and fertility remains elusive. To determine if maternally deposited Kdm2a is required for preimplantation embryonic development, the expression profile of Kdm2a during early embryos was detected via immunofluorescence staining and RT-qPCR. The Kdm2a gene in oocytes was specifically deleted with the Zp3-Cre/LoxP system and the effects of maternal Kdm2a loss were studied through a comprehensive range of female reproductive parameters including fertilization, embryo development, and the number of births. RNA transcriptome sequencing was performed to determine differential mRNA expression, and the interaction between Kdm2a and the PI3K/Akt pathway was studied with a specific inhibitor and activator. Our results revealed that Kdm2a was continuously expressed in preimplantation embryos and loss of maternal Kdm2a suppressed the morula-to-blastocyst transition, which may have been responsible for female subfertility. After the deletion of Kdm2a, the global H3K36me2 methylation in mutant embryos was markedly increased, but the expression of E-cadherin decreased significantly in morula embryos compared to controls. Mechanistically, RNA-seq analysis revealed that deficiency of maternal Kdm2a altered the mRNA expression profile, especially in the PI3K/Akt signaling pathway. Interestingly, the addition of a PI3K/Akt inhibitor (LY294002) to the culture medium blocked embryo development at the stage of morula; however, the developmental block caused by maternal Kdm2a loss was partially rescued with a PI3K/Akt activator (SC79). In summary, our results indicate that loss of Kdm2a influences the transcriptome profile and disrupts the PI3K/Akt signaling pathway during the development of preimplantation embryo. This can result in embryo block at the morula stage and female subfertility, which suggests that maternal Kdm2a is a potential partial redundancy with other genes encoding enzymes in the dynamics of early embryonic development. Our results provide further insight into the role of histone modification, especially on Kdm2a, in preimplantation embryonic development in mice.

H3K9 methylation patterns during somatic embryogenic competence expression in tamarillo (Solanum betaceum Cav.)

The capacity to regenerate is intrinsic to plants and is the basis of natural asexual propagation and artificial cloning. Despite there are different ways of plant regeneration, they all require a change in cell fate and pluripotency reacquisition, in particular somatic embryogenesis. The mechanisms underlying somatic cell reprogramming for embryogenic competence acquisition, expression and maintenance remain not fully understood. These complex processes have been often associated with epigenetic markers, mainly DNA methylation, while little is known about the possible role of histone modifications. In the present study, the dynamics of global levels and distribution patterns of histone H3 methylation at lysine 9 (H3K9), a major repressive histone modification, were analyzed in somatic embryogenesis-induced cell lines with different embryogenic capacities and during somatic embryo initiation, in the woody species Solanum betaceum. Quantification of global H3K9 methylation showed similar levels in the three types of proliferating calli (embryogenic, long-term and non-embryogenic), kept in high sucrose and auxin-containing medium. Microscopic analyzes revealed heterogeneous cell organization and different cell types, particularly evident in embryogenic callus. The H3K9 dimethylation (H3K9me2) immunofluorescence signal was lower in nuclei of cells showing embryogenic-like and proliferating features, while labeling was higher in vacuolated, non-embryogenic cells with higher proliferation rates. By auxin removal, somatic embryo development was promoted in the embryogenic cell line. During the initiation of this process, increasing levels of global H3K9 methylation were found, together with increasing H3K9me2 immunofluorescence signals, especially in cells of the developing embryo. These results suggest that H3K9 methylation is involved in somatic embryo development, a developmental pathway in which this epigenetic mark could play a role in the gene transcription variation that is associated with embryogenic competence expression in S. betaceum. Altogether, these data provide new insights into the role of this epigenetic mark in somatic embryogenesis in trees, where scarce information is available.

Epigenetic regulation of SST2 expression in small intestinal neuroendocrine tumors.

Somatostatin receptor type 2 (SST2) expression is critical for the diagnosis and treatment of neuroendocrine tumors and is associated with improved patient survival. Recent data suggest that epigenetic changes such as DNA methylation and histone modifications play an important role in regulating SST2 expression and tumorigenesis of NETs. However, there are limited data on the association between epigenetic marks and SST2 expression in small intestinal neuroendocrine tumors (SI-NETs). Tissue samples from 16 patients diagnosed with SI-NETs and undergoing surgical resection of the primary tumor at Erasmus MC Rotterdam were analysed for SST2 expression levels and epigenetic marks surrounding the SST2 promoter region, i.e. DNA methylation and histone modifications H3K27me3 and H3K9ac. As a control, 13 normal SI-tissue samples were included. The SI-NET samples had high SST2 protein and mRNA expression levels; a median (IQR) of 80% (70-95) SST2-positive cells and 8.2 times elevated SST2 mRNA expression level compared to normal SI-tissue (p=0.0042). In comparison to normal SI-tissue, DNA methylation levels and H3K27me3 levels were significantly lower at five out of the eight targeted CpG positions and at two out of the three examined locations within the SST2 gene promoter region of the SI-NET samples, respectively. No differences in the level of activating histone mark H3K9ac were observed between matched samples. While no correlation was found between histone modification marks and SST2 expression, SST2 mRNA expression levels correlated negatively with DNA methylation within the SST2 promoter region in both normal SI-tissue and SI-NETs (p=0.006 and p=0.04, respectively). SI-NETs have lower SST2 promoter methylation levels and lower H3K27me3 methylation levels compared to normal SI-tissue. Moreover, in contrast to the absence of a correlation with SST2 protein expression levels, significant negative correlations were found between SST2 mRNA expression level and the mean level of DNA methylation within the SST2 promoter region in both normal SI-tissue and SI-NET tissue. These results indicate that DNA methylation might be involved in regulating SST2 expression. However, the role of histone modifications in SI-NETs remains elusive.

The Role of Histone Modifications in the Pathogenesis of Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. The pathogenesis of DKD is multifactorial, with several molecular pathways implicated. Recent data suggest that histone modification plays an important role in the development and progression of DKD. Histone modification appears to induce oxidative stress, inflammation and fibrosis in the diabetic kidney. In the present review, we summarize the current knowledge on the association between histone modification and DKD.

The Role of Histone Modifications in Heat Signal Transduction in Plants.

Global warming and the more frequent occurrence of extremly high temperatures seriously affect crop yields. Heat stress (HS) has become a major environmental factor threatening food security worldwide. Understanding how plants sense and respond to HS is of clear interest to plant scientists and crop breeders. However, it is not trivial to elucidate the underlying signaling cascade, as specific cellular responses (ranging from detrimental to systemic effects) must be disentangled. Plants respond and adapt to high temperatures in many ways. In this review, recent progress in understanding heat signal transduction and the role of histone modifications in regulating the expression of genes involved in HS responses are discussed. The outstanding issues that are crucial for understanding the interactions between plants and HS are also discussed. The study of heat signal transduction mechanisms in plants is essential to facilitate the cultivation of heat-resistant crop varieties.

Formaldehyde reacts with N-terminal proline residues to give bicyclic aminals

Formaldehyde (HCHO) is a potent electrophile that is toxic above threshold levels, but which is also produced in the nuclei of eukaryotic cells by demethylases. We report studies with the four canonical human histones revealing that histone H2B reacts with HCHO, including as generated by a histone demethylase, to give a stable product. NMR studies show that HCHO reacts with the N-terminal proline and associated amide of H2B to give a 5,5-bicyclic aminal that is relatively stable to competition with HCHO scavengers. While the roles of histone modification by this reaction require further investigation, we demonstrated the potential of N-terminal aminal formation to modulate protein function by conducting biochemical and cellular studies on the effects of HCHO on catalysis by 4-oxalocrotonate tautomerase, which employs a nucleophilic N-terminal proline. The results suggest that reactions of N-terminal residues with HCHO and other aldehydes have potential to alter protein function.

Epigenetics and Methylmercury-Induced Neurotoxicity, Evidence from Experimental Studies

MeHg is an environmental neurotoxin that can adversely affect the development of the nervous system. The molecular integrity of chromatin in the nucleus is an important target of MeHg. Low levels of MeHg trigger epigenetic mechanisms that may be involved in long-lasting and transgenerational neurotoxicity after exposure. Emerging evidence has shown that these mechanisms include histone modification, siRNA, and DNA methylation. The MeHg-induced inhibition of neurodifferentiation and neurogenesis are mechanistically associated with epigenetic alterations in critical genes, such as neurotrophin brain-derived neurotrophic factor (BDNF). Further, MeHg exposure has been shown to alter the activity and/or expression of the upstream regulators of chromatin structure, including histone deacetylases (HDACs) and DNA methyltransferase (DNMTs), which may trigger permanent alterations in histone modifications and DNA methylation. MeHg-exposure also alters several species of miRNA that are associated with neurodevelopment. Genetic studies in the C. elegans model of MeHg-induced toxicity proposes a potential interplay between exogenous RNAi and antioxidant defense. In this review, we discuss the molecular basis for MeHg exposure-induced alterations in chromatin structure and the roles of histone modifications, siRNA, and DNA methylation in MeHg-induced neurotoxic effects.

Comprehensive Survey of ChIP-Seq Datasets to Identify Candidate Iron Homeostasis Genes Regulated by Chromatin Modifications.

Vital biochemical reactions including photosynthesis to respiration require iron, which should be tightly regulated. Although increasing evidence reveals the importance of epigenetic regulation in gene expression and signaling, the role of histone modifications and chromatin remodeling in plant iron homeostasis is not well understood. In this study, we surveyed publicly available ChIP-seq datasets of Arabidopsis wild-type and mutants defective in key enzymes of histone modification and chromatin remodeling and compared the deposition of epigenetic marks on loci of genes involved in iron regulation. Based on the analysis, we compiled a comprehensive list of iron homeostasis genes with differential enrichment of various histone modifications. This report will provide a resource for future studies to investigate epigenetic regulatory mechanisms of iron homeostasis in plants.

Probiotic lactobacilli mediate their immunoregulatory functions in intestinal cells via modulation of H3 histone acetylation.

Probiotics maintain intestinal homeostasis through the regulation of the immune response of the host. Hence, the role of histone modifications as epigenetic agents on immune modulations by potential probiotic bacteria has been investigated. Human colonic epithelial cells (Caco-2) pre-treated with class I histone deacetylase (HDAC) specific inhibitor, MS-275, were incubated either with potential probiotic bacteria (Limosilactobacillus fermentum MTCC 5898 and Lacticaseibacillus rhamnosus MTCC 5897) or Escherichia coli (ATCC 14948) as an inflammatory agent. Initially, transcriptional expression of potential immune related genes (IL-6, IL-8 and hBD-2) was analyzed using RT-qPCR and later H3 histone acetylation (H3Ac) at the promoter region of these genes was confirmed with chromatin immunoprecipitation (ChIP) assay respectively. Potentially probiotic L. fermentum (MTCC 5898) significantly suppressed (P<0.05) the inhibitor-mediated elevated expression of immune related genes while another strain L. rhamnosus (MTCC 5897) did not influence these gene expression results. In contrast, as an inflammatory agent, E. coli (ATCC 14948) synergistically augmented the expression of immune related genes. Later, ChIP analysis confirmed the occurrence of H3 acetylation at these genes' promoter region, which was directly related to the transcriptional activity of host epithelial cells stimulated by L. fermentum and E. coli respectively. But in the case of L. rhamnosus, MTCC 5897, acetylation did not follow the transcription pattern and potentiated H3Ac on the promoter regions of these genes. Potential probiotics used in the study were found to regulate the immune response of host cells through histone acetylation in a strain-specific manner.

Histone methyltransferases SDG33 and SDG34 regulate organ-specific nitrogen responses in tomato.

Histone posttranslational modifications shape the chromatin landscape of the plant genome and affect gene expression in response to developmental and environmental cues. To date, the role of histone modifications in regulating plant responses to environmental nutrient availability, especially in agriculturally important species, remains largely unknown. We describe the functions of two histone lysine methyltransferases, SET Domain Group 33 (SDG33) and SDG34, in mediating nitrogen (N) responses of shoots and roots in tomato. By comparing the transcriptomes of CRISPR edited tomato lines sdg33 and sdg34 with wild-type plants under N-supplied and N-starved conditions, we uncovered that SDG33 and SDG34 regulate overlapping yet distinct downstream gene targets. In response to N level changes, both SDG33 and SDG34 mediate gene regulation in an organ-specific manner: in roots, SDG33 and SDG34 regulate a gene network including Nitrate Transporter 1.1 (NRT1.1) and Small Auxin Up-regulated RNA (SAUR) genes. In agreement with this, mutations in sdg33 or sdg34 abolish the root growth response triggered by an N-supply; In shoots, SDG33 and SDG34 affect the expression of photosynthesis genes and photosynthetic parameters in response to N. Our analysis thus revealed that SDG33 and SDG34 regulate N-responsive gene expression and physiological changes in an organ-specific manner, thus presenting previously unknown candidate genes as targets for selection and engineering to improve N uptake and usage in crop plants.