Epigenetic Histone Modifications Research Articles

Oxidative-Stress-Mediated Epigenetic Dysregulation in Spermatogenesis: Implications for Male Infertility and Offspring Health.

Male reproductive health is governed by an intricate interplay of genetic, epigenetic, and environmental factors. Epigenetic mechanisms-encompassing DNA methylation, histone modifications, and non-coding RNA activity-are crucial both for spermatogenesis and sperm maturation. However, oxidative stress, driven by excessive reactive oxygen species, disrupts these processes, leading to impaired sperm function and male infertility. This disruption extends to epigenetic modifications, resulting in abnormal gene expression and chromatin remodeling that compromise genomic integrity and fertilization potential. Importantly, oxidative-stress-induced epigenetic alterations can be inherited, affecting the health and fertility of offspring and future generations. This review investigates how oxidative stress influences epigenetic regulation in male reproduction by modifying DNA methylation, histone modifications, and non-coding RNAs, ultimately compromising spermatogenesis. Additionally, it discusses the transgenerational implications of these epigenetic disruptions and their potential role in hereditary infertility and disease predisposition. Understanding these mechanisms is vital for developing therapeutic strategies that mitigate oxidative damage and restore epigenetic homeostasis in the male germline. By integrating insights from molecular, clinical, and transgenerational research, this work emphasizes the need for targeted interventions to enhance male reproductive health and prevent adverse outcomes in progeny. Furthermore, elucidating the dose-response relationships between oxidative stress and epigenetic changes remains a critical research priority, informing personalized diagnostics and therapeutic interventions. In this context, future studies should adopt standardized markers of oxidative damage, robust clinical trials, and multi-omic approaches to capture the complexity of epigenetic regulation in spermatogenesis. Such rigorous investigations will ultimately reduce the risk of transgenerational disorders and optimize reproductive health outcomes.

Genetic Mutation and Regulation in Pancreatic Ductal Adenocarcinoma Cancer: Developing Relevant Molecular Biomarkers

Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive and highly lethal malignant tumor. Due to the difficulty in early diagnosis and limited treatment options, the 5-year survival rate is less than 10%. Traditional treatments such as surgery, chemotherapy, and radiotherapy have limited effects on PDAC, which is mainly attributed to its unique tumor microenvironment (TME), common gene mutations (such as KRAS, and TP53), and immunosuppressive properties. In recent years, with the advancement of molecular biology and genomics technologies, the molecular mechanisms of PDAC have been studied more deeply, revealing the gene mutations and regulatory networks associated with its pathogenesis. In particular, KRAS mutations have become an important research direction for targeted therapy. However, the effect of immunotherapy in PDAC is limited by the immune escape characteristics of TME. This article systematically summarizes the key gene mutations in PDAC and their regulatory mechanisms, including epigenetic regulation, microRNA, histone modification and other influencing factors. CRISPR-Cas9 shows great potential in correcting gene mutations and reshaping TME. In addition, combining immunotherapy with targeted drug delivery (such as nanotechnology) can improve the precision of treatment and reduce side effects. These advances provide a comprehensive reference for future personalized and effective treatment options for PDAC

Epigenetic mechanisms mediate cytochrome P450 1A1 expression and lung endothelial injury caused by MRSA invitro and invivo.

Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of severe pneumonia and acute respiratory distress syndrome (ARDS). To advance our mechanistic understanding of this important pathogen, we characterized the effects of MRSA-induced epigenetic modification of histone 3 lysine 9 acetylation (H3K9ac), an activator of gene transcription, on lung endothelial cells (EC), a critical site of ARDS pathophysiology. Chromatin immunoprecipitation and sequencing (ChIP-seq) analysis revealed that MRSA induces H3K9ac in the promoter regions of multiple genes, with the highest ranked peak annotated to the CYP1A1 gene. Subsequent experiments confirm that MRSA increases CYP1A1 protein and mRNA expression, and its enzymatic activity in EC. Epigenetic inhibitors (C646, RVX-208) reduce MRSA-induced CYP1A1 expression and inflammatory responses, including cytokine release and adhesion molecule expression. Inhibition of the Aryl hydrocarbon receptor (Ahr), a known mediator of CYP1A1 expression, blocks MRSA-induced upregulation of CYP1A1 mRNA and protein expression, enzyme activity, and cytokine release. Reduction of CYP1A1 protein expression by siRNA or inhibition of its activity by rhapontigenin attenuated MRSA-induced EC permeability and inflammatory responses. In a mouse model of MRSA-induced acute lung injury (ALI), inhibition of CYP1A1 activity by rhapontigenin improved multiple indices of ALI, including bronchoalveolar lavage (BAL) protein concentration, cytokine levels, and markers of endothelial damage. Analysis of publicly available data suggests upregulation of CYP1A1 expression in ARDS patients compared to ICU controls. In summary, these studies provide new insights into MRSA-induced lung injury and identify a novel functional role for epigenetic upregulation of CYP1A1 in lung EC during ARDS pathogenesis.

Epigenetics of Hypertensive Nephropathy.

Hypertensive nephropathy (HN) is a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD), contributing to significant morbidity, mortality, and rising healthcare costs. In this review article, we explore the role of epigenetic mechanisms in HN progression and their potential therapeutic implications. We begin by examining key epigenetic modifications-DNA methylation, histone modifications, and non-coding RNAs-observed in kidney disease. Next, we discuss the underlying pathophysiology of HN and highlight current in vitro and in vivo models used to study the condition. Finally, we compare various types of HN-induced renal injury and their associated epigenetic mechanisms with those observed in other kidney injury models, drawing inferences on potential epigenetic therapies for HN. The information gathered in this work indicate that epigenetic mechanisms can drive the progression of HN by regulating key molecular signaling pathways involved in renal damage and fibrosis. The limitations of Renin-Angiotensin-Aldosterone System (RAAS) inhibitors underscore the need for alternative treatments targeting epigenetic pathways. This review emphasizes the importance of further research into the epigenetic regulation of HN to develop more effective therapies and preventive strategies. Identifying novel epigenetic markers could provide new therapeutic opportunities for managing CKD and reducing the burden of ESRD.

Tracking induced pluripotent stem cell differentiation with a fluorescent genetically encoded epigenetic probe

Epigenetic modifications (methylation, acetylation, etc.) of core histones play a key role in regulation of gene expression. Thus, the epigenome changes strongly during various biological processes such as cell differentiation and dedifferentiation. Classical methods of analysis of epigenetic modifications such as mass-spectrometry and chromatin immuno-precipitation, work with fixed cells only. Here we present a genetically encoded fluorescent probe, MPP8-Green, for detecting H3K9me3, a histone modification associated with inactive chromatin. This probe, based on the chromodomain of MPP8, allows for visualization of H3K9me3 epigenetic landscapes in single living cells. We used this probe to track changes in H3K9me3 landscapes during the differentiation of induced pluripotent stem cells (iPSCs) into induced neurons. Our findings revealed two major waves of global H3K9me3 reorganization during 4-day differentiation, namely on the first and third days, whereas nearly no changes occurred on the second and fourth days. The proposed method LiveMIEL (Live-cell Microscopic Imaging of Epigenetic Landscapes), which combines genetically encoded epigenetic probes and machine learning approaches, enables classification of multiparametric epigenetic signatures of single cells during stem cell differentiation and potentially in other biological models.

Integrative analysis of transcriptome and metabolome reveals the heterogeneity of ovarian follicles between high-altitude Yak (Bos grunniens) and Low-altitude cattle (Bos taurus)

Differences including reproductive efficiency have been proved existence between high-altitude yak (Bos grunniens) and low-altitude cattle (Bos taurus), however, the discrepancies of ovarian follicles across them are still elusive. In the present study, RNA-seq results exhibited an obvious separation of yak and cattle granulosa cells (GCs), and 2329 differently expressed genes (DEGs) was obtained, with 1297 upregulated and 1032 downregulated DEGs in yaks. Advanced analysis revealed that DEGs were mainly enriched in cellular structure, DNA packaging and remodeling (GO and GSEA), hypoxia adaptability, energy metabolism (KEGG and GSEA), and epigenetic modification of histones (Reactome and GSEA). Metabolite profiles of yak and cattle follicular fluid (FF) were depicted by LC-MS/MS non-target metabolomics, and 350 different metabolites (DMs) were acquired, with 242 upregulated and 108 downregulated DMs in yaks. The KEGG pathway enrichment results demonstrated that DMs were primarily enriched in metabolism including lipid, carbohydrate and nucleic acid metabolism. Finally, twenty-nine pathways were significant enriched via integrative analysis, most of which were associated with metabolism including carbohydrate metabolism (e.g. Glycolysis / Gluconeogenesis) and lipid metabolism (e.g. Sphingolipid metabolism). Of note, the key hypoxia adaptation pathway, HIF-1 signaling pathway, was predominant enriched. Overall, we ascertained that the heterogeneity in ovarian follicles of yaks and cattle was existence, which were mainly reflected on hypoxia adaptation and energy metabolism. These results implied that the above processes were evolved specifically for the normal development of yak follicles under plateau atmosphere.

Establishment and Maintenance of Heat-Stress Memory in Plants.

Among the rich repertoire of strategies that allow plants to adapt to high-temperature stress is heat-stress memory. The mechanisms underlying the establishment and maintenance of heat-stress memory are poorly understood, although the chromatin opening state appears to be an important structural basis for maintaining heat-stress memory. The chromatin opening state is influenced by epigenetic modifications, making DNA and histone modifications important entry points for understanding heat-shock memory. Current research suggests that traditional heat-stress signaling pathway components might be involved in chromatin opening, thereby promoting the establishment of heat-stress memory in plants. In this review, we discuss the relationship between chromatin structure-based maintenance and the establishment of heat-stress memory. We also discuss the association between traditional heat-stress signals and epigenetic modifications. Finally, we discuss potential research ideas for exploring plant adaptation to high-temperature stress in the future.

Metabolic conditioning enhances human bmMSC therapy of doxorubicin-induced heart failure.

The therapeutic potential of bone marrow mesenchymal stromal cells (bmMSCs) to address heart failure needs improvement for better engraftment and survival. This study explores the role of metabolic sorting for human bmMSCs in coculture in vitro and on doxorubicin-induced heart failure mice models. Using functional, epigenetic, and gene expression approaches on cells sorted for mitochondrial membrane potential in terms of their metabolic status, we demonstrated that bmMSCs selected for their glycolytic metabolism presented proliferative advantage and resistance to oxidative stress thereby favoring cell engraftment. Therapeutic use of glycolytic bmMSCs rescued left ventricular ejection fraction and decreased fibrosis in mice models of acute heart failure. Metabolic changes were also related to epigenetic histone modifications such as lysine methylation. By targeting LSD1 (lysine-specific demethylase 1) as a conditioning agent to enhance the metabolic profile of bmMSCs, we deciphered the interplay between glycolysis and bmMSC functionality. Our study elucidates novel strategies for optimizing bmMSC-based treatments for heart failure, highlighting the metabolic properties of bmMSCs as a promising target for more effective cardiovascular regenerative therapies.

DeepEpi: Deep Learning Model for Predicting Gene Expression Regulation Based on Epigenetic Histone Modifications

Background: Histone modification is a vital element in gene expression regulation. The way in which these proteins bind to the DNA impacts whether or not a gene may be expressed. Although those factors cannot influence DNA construction, they can influence how it is transcribed. Objective: Each spatial location in DNA has its function, so the spatial arrangement of chromatin modifications affects how the gene can express. Also, gene regulation is affected by the type of histone modification combinations that are present on the gene and depends on the spatial distributional pattern of these modifications and how long these modifications read on a gene region. So, this study aims to know how to model Long-range spatial genome data and model complex dependencies among Histone reads. Methods: The Convolution Neural Network (CNN) is used to model all data features in this paper. It can detect patterns in histones signals and preserve the spatial information of these patterns. It also uses the concept of memory in long short-term memory (LSTM), using vanilla LSTM, Bi-Directional LSTM, or Stacked LSTM to preserve long-range histones signals. Additionally, it tries to combine these methods using ConvLSTM or uses them together with the aid of a self-attention. Results: Based on the results, the combination of CNN, LSTM with the self-attention mechanism obtained an Area under the Curve (AUC) score of 88.87% over 56 cell types. Conclusion: The result outperforms the present state-of-the-art model and provides insight into how combinatorial interactions between histone modification marks can control gene expression. The source code is available at https://github.com/RaniaHamdy/DeepEpi.

Unveiling nuclear chromatin distribution using IsoConcentraChromJ: A flourescence imaging plugin for IsoRegional and IsoVolumetric based ratios analysis.

Chromatin exhibits non-random distribution within the nucleus being arranged into discrete domains that are spatially organized throughout the nuclear space. Both the spatial distribution and structural rearrangement of chromatin domains in the nucleus depend on epigenetic modifications of DNA and/or histones and structural elements such as the nuclear envelope. These components collectively contribute to the organization and rearrangement of chromatin domains, thereby influencing genome architecture and functional regulation. This study develops an innovative, user-friendly, ImageJ-based plugin, called IsoConcentraChromJ, aimed quantitatively delineating the spatial distribution of chromatin regions in concentric patterns. The IsoConcentraChromJ can be applied to quantitative chromatin analysis in both two- and three-dimensional spaces. After DNA and histone staining with fluorescent probes, high-resolution images of nuclei have been obtained using advanced fluorescence microscopy approaches, including confocal and stimulated emission depletion (STED) microscopy. IsoConcentraChromJ workflow comprises the following sequential steps: nucleus segmentation, thresholding, masking, normalization, and trisection with specified ratios for either 2D or 3D acquisitions. The effectiveness of the IsoConcentraChromJ has been validated and demonstrated using experimental datasets consisting in nuclei images of pre-adipocytes and mature adipocytes, encompassing both 2D and 3D imaging. The outcomes allow to characterize the nuclear architecture by calculating the ratios between specific concentric nuclear areas/volumes of acetylated chromatin with respect to total acetylated chromatin and/or total DNA. The novel IsoConcentrapChromJ plugin could represent a valuable resource for researchers investigating the rearrangement of chromatin architecture driven by epigenetic mechanisms using nuclear images obtained by different fluorescence microscopy methods.

Epigenetic Histone Modifications H3K36me3 and H4K5/8/12/16ac Induce Open Polynucleosome Conformations via Different Mechanisms

Nucleosomes are the basic compaction unit of chromatin and nucleosome structure and their higher-order assemblies regulate genome accessibility. Many post-translational modifications alter nucleosome dynamics, nucleosome-nucleosome interactions, and ultimately chromatin structure and gene expression. Here, we investigate the role of two post-translational modifications associated with actively transcribed regions, H3K36me3 and H4K5/8/12/16ac, in the contexts of tri-nucleosome arrays that provide a tractable model system for quantitative single-molecule analysis, while enabling us to probe nucleosome-nucleosome interactions. Direct visualization by AFM imaging reveals that H3K36me3 and H4K5/8/12/16ac nucleosomes adopt significantly more open and loose conformations than unmodified nucleosomes. Similarly, magnetic tweezers force spectroscopy shows a reduction in DNA outer turn wrapping and nucleosome-nucleosome interactions for the modified nucleosomes. The results suggest that for H3K36me3 the increased breathing and outer DNA turn unwrapping seen in mononucleosomes propagates to more open conformations in nucleosome arrays. In contrast, the even more open structures of H4K5/8/12/16ac nucleosome arrays do not appear to derive from the dynamics of the constituent mononucleosomes, but are driven by reduced nucleosome-nucleosome interactions, suggesting that stacking interactions can overrule DNA breathing of individual nucleosomes. We anticipate that our methodology will be broadly applicable to reveal the influence of other post-translational modifications and to observe the activity of nucleosome remodelers.

Epigenetic remodeling in insect immune memory.

The innate immune system of insects can respond more swiftly and efficiently to pathogens based on previous experience of encountering antigens. The understanding of molecular mechanisms governing immune priming, a form of immune memory in insects, including its transgenerational inheritance, remains elusive. It is still unclear if the enhanced expression of immune genes observed in primed insects can persist and be regulated through changes in chromatin structure via epigenetic modifications of DNA or histones, mirroring observations in mammals. Increasing experimental evidence suggests that epigenetic changes at the level of DNA/RNA methylation and histone acetylation can modulate the activation of insects' immune responses to pathogen exposure. Moreover, transgenerational inheritance of certain epigenetic modifications in model insect hosts can influence the transmission of pre-programmed immune responses to the offspring, leading to the development of evolved resistance. Epigenetic research in model insect hosts is on the brink of significant progress in the mechanistic understanding of chromatin remodeling within innate immunity, particularly the direct relationships between immunological priming and epigenetic alterations. In this review, we discuss the latest discoveries concerning the involvement of DNA methylation and histone acetylation in shaping the development, maintenance, and inheritance of immune memory in insects, culminating in the evolution of resistance against pathogens.

Histone acylation at a glance.

An important mechanism of gene expression regulation is the epigenetic modification of histones. The cofactors and substrates for these modifications are often intermediary metabolites, and it is becoming increasingly clear that the metabolic and nutritional state of cells can influence these marks. These connections between the balance of metabolites, histone modifications and downstream transcriptional changes comprise a metabolic signaling program that can enable cells to adapt to changes in nutrient availability. Beyond acetylation, there is evidence now that histones can be modified by other acyl groups. In this Cell Science at a Glance article and the accompanying poster, we focus on these histone acylation modifications and provide an overview of the players that govern these acylations and their connections with metabolism.

Unraveling the Epigenetic Landscape: Insights into Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis.

Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) are examples of neurodegenerative movement disorders (NMDs), which are defined by a gradual loss of motor function that is frequently accompanied by cognitive decline. Although genetic abnormalities have long been acknowledged as significant factors, new research indicates that epigenetic alterations are crucial for the initiation and development of disease. This review delves into the complex interactions that exist between the pathophysiology of NMDs and epigenetic mechanisms such DNA methylation, histone modifications, and non-coding RNAs. Here, we examine how these epigenetic changes could affect protein aggregation, neuroinflammation, and gene expression patterns, thereby influencing the viability and functionality of neurons. Through the clarification of the epigenetic terrain underpinning neurodegenerative movement disorders, this review seeks to enhance comprehension of the underlying mechanisms of the illness and augment the creation of innovative therapeutic strategies.

VRK1 Regulates Sensitivity to Oxidative Stress by Altering Histone Epigenetic Modifications and the Nuclear Phosphoproteome in Tumor Cells.

The chromatin organization and its dynamic remodeling determine its accessibility and sensitivity to DNA damage oxidative stress, the main source of endogenous DNA damage. We studied the role of the VRK1 chromatin kinase in the response to oxidative stress. which alters the nuclear pattern of histone epigenetic modifications and phosphoproteome pathways. The early effect of oxidative stress on chromatin was studied by determining the levels of 8-oxoG lesions and the alteration of the epigenetic modification of histones. Oxidative stress caused an accumulation of 8-oxoG DNA lesions that were increased by VRK1 depletion, causing a significant accumulation of DNA strand breaks detected by labeling free 3'-DNA ends. In addition, oxidative stress altered the pattern of chromatin epigenetic marks and the nuclear phosphoproteome pathways that were impaired by VRK1 depletion. Oxidative stress induced the acetylation of H4K16ac and H3K9 and the loss of H3K4me3. The depletion of VRK1 altered all these modifications induced by oxidative stress and resulted in losses of H4K16ac and H3K9ac and increases in the H3K9me3 and H3K4me3 levels. All these changes were induced by the oxidative stress in the epigenetic pattern of histones and impaired by VRK1 depletion, indicating that VRK1 plays a major role in the functional reorganization of chromatin in the response to oxidative stress. The analysis of the nuclear phosphoproteome in response to oxidative stress detected an enrichment of the phosphorylated proteins associated with the chromosome organization and chromatin remodeling pathways, which were significantly decreased by VRK1 depletion. VRK1 depletion alters the histone epigenetic pattern and nuclear phosphoproteome pathways in response to oxidative stress. The enzymes performing post-translational epigenetic modifications are potential targets in synthetic lethality strategies for cancer therapies.

Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress

BackgroundRegulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses of RNA-Seq data uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT.ResultsMotivated to understand how BAT function is regulated epigenetically, we developed a novel method for the first-ever unbiased top-down proteomic quantitation of histone modifications in BAT and validated our results with a multi-omic approach. To test our hypothesis, wildtype male C57BL/6J mice were housed under chronic conditions of thermoneutral temperature (TN, 28°C), mild cold/room temperature (RT, 22°C), or severe cold (SC, 8°C) and BAT was analyzed for DNA methylation and histone modifications. Methylation of promoters and intragenic regions in genomic DNA decrease in response to chronic cold exposure. Integration of DNA methylation and RNA expression datasets suggest a role for epigenetic modification of DNA in regulation of gene expression in response to cold. In response to cold housing, we observe increased bulk acetylation of histones H3.2 and H4, increased histone H3.2 proteoforms with di- and trimethylation of lysine 9 (K9me2 and K9me3), and increased histone H4 proteoforms with acetylation of lysine 16 (K16ac) in BAT.ConclusionsOur results reveal global epigenetically-regulated transcriptional “on” and “off” signals in murine BAT in response to varying degrees of chronic cold stimuli and establish a novel methodology to quantitatively study histones in BAT, allowing for direct comparisons to decipher mechanistic changes during the thermogenic response. Additionally, we make histone PTM and proteoform quantitation, RNA splicing, RRBS, and transcriptional footprint datasets available as a resource for future research.

A critical role for Pol II CTD phosphorylation in heterochromatic gene activation

How gene activation works in heterochromatin, and how the mechanism might differ from the one used in euchromatin, has been largely unexplored. Previous work has shown that in SIR-regulated heterochromatin of Saccharomyces cerevisiae, gene activation occurs in the absence of covalent histone modifications and other alterations of chromatin commonly associated with transcription.Here we demonstrate that such activation occurs in a substantial fraction of cells, consistent with frequent transcriptional bursting, and this raises the possibility that an alternative activation pathway might be used. We address one such possibility, Pol II CTD phosphorylation, and explore this idea using a natural telomere-linked gene, YFR057w, as a model. Unlike covalent histone modifications, we find that Ser2, Ser5 and Ser7 CTD phosphorylated Pol II is prevalent at the drug-induced heterochromatic gene. Particularly enriched relative to the euchromatic state is Ser2 phosphorylation. Consistent with a functional role for Ser2P, YFR057w is negligibly activated in cells deficient in the Ser2 CTD kinases Ctk1 and Bur1 even though the gene is strongly stimulated when it is placed in a euchromatic context. Collectively, our results are consistent with a critical role for Ser2 CTD phosphorylation in driving Pol II recruitment and transcription of a natural heterochromatic gene – an activity that may supplant the need for histone epigenetic modifications.

Abstract 859: Development of non-smoking lung cancers by indoor carcinogenic aerosols through epigenetic reprogramming of lung stem cells: Bioinformatics and artificial intelligence analysis

Abstract Several scientific studies discovered the toxic effects of indoor aerosols on different organs’ adult stem cells of the human body. The most importantly, the indoor toxic aerosols comprised of numerous carcinogens namely, sodium dodecyl sulfate, phthalic acids from floor cleaners, formaldehyde, acetaldehyde, benzene, toluene, ethyl benzene, xylenes, from air fresheners, Hydramethylnon, Pyrethrins, imiprothrin, cypermethrin, tetramethrin, prallethrin and permethrin from ant and roach Killer. However, there was a lack of analysis revealing the mechanism of toxic effects and epigenetic reprogramming of human lung stem cells and development of non-smoking lung cancers. In this study, we analyzed the toxic effects of these chemicals and the mechanism of epigenetic reprograming on lung epithelial cells using Comparative Toxico-genomics Database (CTD), database of Environmental Health Perspectives (EHP), National Institute of Environmental Health Sciences (NIEHS), Google search browser with generative artificial intelligence (AI) and other biological informatics methods (Reactome, Cytoscape PSICQUIC services, and ChEMBL database). We observed from CTD analysis that the chemical gene interactions as risk factors from indoor aerosols showed transcriptionally highly expressed of 31 common genes, by phthalic acids, sodium dodecyl sulfate, from the total of 1347 genes, 107 common genes by formaldehyde, acetaldehyde from the total of 4193 genes and all other toxic ingredients of indoor aerosols. The epigenetic mechanism of histone modifications (H3K4me3, H3K9me3, H3K27me3, H3K27ac, H3K36me3, H3K4me1, Hsa-mir-1301 of lung epithelial, and miRNAs have been revealed by NIH Roadmap Epigenomics Mapping Consortium and the lung tissue arrays were analyzed with AI and matplotlib program. The heterogenic adult stem cell reprogramming is regulated by epigenetic bivalent histone modifications at transcript starts sequences (TSS) of target genes and our current study revealed that CD44, CD80, ALDH2, ALDH3A1, ALDH3B2 are epigenetically reprogrammed with close interaction of other genes by these toxic ingredients of indoor aerosols. Therefore, our results are significant for the carcinogenic effects of indoor aerosols causing for development of lung cancer epigenetically, which may give a clue for the prevention and treatment of nonsmoking lung cancer. Citation Format: Juan Anderson, Mariah Delgado, Malcolm Lovett, Maya Saunders, Geovannie Lake, Samuel Darko, Rose M. Stiffin, Ayivi Huisso, Marilyn Sherman, Latoya Appleton, Amalya Mihnea, Swarnava Das, Mohammad M. Algahtani, Ravi Vadapalli, Biswarup Basu, Arunima Biswas, Noor Neha, Madhumita Das, Marco A. Ruiz, Mayur Doke, Jayanta K. Das. Development of non-smoking lung cancers by indoor carcinogenic aerosols through epigenetic reprogramming of lung stem cells: Bioinformatics and artificial intelligence analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 859.

JMJD3 regulate H3K27me3 modification via interacting directly with TET1 to affect spermatogonia self-renewal and proliferation

BackgroundIn epigenetic modification, histone modification and DNA methylation coordinate the regulation of spermatogonium. Not only can methylcytosine dioxygenase 1 (TET1) function as a DNA demethylase, converting 5-methylcytosine to 5-hydroxymethylcytosine, it can also form complexes with other proteins to regulate gene expression. H3K27me3, one of the common histone modifications, is involved in the regulation of stem cell maintenance and tumorigenesis by inhibiting gene transcription.Methodswe examined JMJD3 at both mRNA and protein levels and performed Chip-seq sequencing of H3K27me3 in TET1 overexpressing cells to search for target genes and signaling pathways of its action.ResultsThis study has found that JMJD3 plays a leading role in spermatogonia self-renewal and proliferation: at one extreme, the expression of the self-renewal gene GFRA1 and the proliferation-promoting gene PCNA was upregulated following the overexpression of JMJD3 in spermatogonia; at the other end of the spectrum, the expression of differentiation-promoting gene DAZL was down-regulated. Furthermore, the fact that TET1 and JMJD3 can form a protein complex to interact with H3K27me3 has also been fully proven. Then, through analyzing the sequencing results of CHIP-Seq, we found that TET1 targeted Pramel3 when it interacted with H3K27me3. Besides, TET1 overexpression not only reduced H3K27me3 deposition at Pramel3, but promoted its transcriptional activation as well, and the up-regulation of Pramel3 expression was verified in JMJD3-overexpressing spermatogonia.ConclusionIn summary, our study identified a novel link between TET1 and H3K27me3 and established a Tet1-JMJD3-H3K27me3-Pramel3 axis to regulate spermatogonia self-renewal and proliferation. Judging from the evidence offered above, we can safely conclude that this study provides new ideas for further research regarding the mechanism of spermatogenesis and spermatogenesis disorders on an apparent spectrum.

MicroRNA-93-5p regulates odontogenic differentiation and dentin formation via KDM6B

BackgroundEpigenetic factors influence the odontogenic differentiation of dental pulp stem cells and play indispensable roles during tooth development. Some microRNAs can epigenetically regulate other epigenetic factors like DNA methyltransferases and histone modification enzymes, functioning as epigenetic-microRNAs. In our previous study, microarray analysis suggested microRNA-93-5p (miR-93-5p) was differentially expressed during the bell stage in human tooth germ. Prediction tools indicated that miR-93-5p may target lysine-specific demethylase 6B (KDM6B). Therefore, we explored the role of miR-93-5p as an epi-miRNA in tooth development and further investigated the underlying mechanisms of miR-93-5p in regulating odontogenic differentiation and dentin formation.MethodsThe expression pattern of miR-93-5p and KDM6B of dental pulp stem cells (DPSCs) was examined during tooth development and odontogenic differentiation. Dual luciferase reporter and ChIP-qPCR assay were used to validate the target and downstream regulatory genes of miR-93-5p in human DPSCs (hDPSCs). Histological analyses and qPCR assays were conducted for investigating the effects of miR-93-5p mimic and inhibitor on odontogenic differentiation of hDPSCs. A pulpotomy rat model was further established, microCT and histological analyses were performed to explore the effects of KDM6B-overexpression and miR-93-5p inhibition on the formation of tertiary dentin.ResultsThe expression level of miR-93-5p decreased as odontoblast differentiated, in parallel with elevated expression of histone demethylase KDM6B. In hDPSCs, miR-93-5p overexpression inhibited the odontogenic differentiation and vice versa. MiR-93-5p targeted 3′ untranslated region (UTR) of KDM6B, thereby inhibiting its protein translation. Furthermore, KDM6B bound the promoter region of BMP2 to demethylate H3K27me3 marks and thus upregulated BMP2 transcription. In the rat pulpotomy model, KDM6B-overexpression or miR-93-5p inhibition suppressed H3K27me3 level in DPSCs and consequently promoted the formation of tertiary dentin.ConclusionsMiR-93-5p targets epigenetic regulator KDM6B and regulates H3K27me3 marks on BMP2 promoters, thus modulating the odontogenic differentiation of DPSCs and dentin formation.