Changes In Histone Modifications Research Articles

Epigenetics and Degenerative Retinal Diseases: Prospects for New Therapeutic Approaches.

There is growing evidence that retinal degenerative diseases are accompanied by epigenetic changes in both deoxyribonucleic acid methylation and histone modification. Even in the monogenic disease retinitis pigmentosa, there is a cascade of changes in gene expression that correlate with epigenetic changes, suggesting that many of the symptoms, and degenerative changes, may be a result of epigenetic changes downstream from the genetic mutation. This is supported by data from studies of diabetic retinopathy and macular degeneration, 2 diseases where it has been difficult to define a single causative change. Initial studies with modifiers of deoxyribonucleic acid methylation suggest that they can provide therapeutic benefit. A number of drugs are available to inhibit specific epigenetic histone modifier enzymes, and these offer the possibility of new therapeutic approaches to retinal disease. Systemic treatment with inhibitors of histone demethylases and histone deacetylases have arrested rod degeneration in rodent models of retinitis pigmentosa. Some evidence has suggested that similar treatments may provide benefits for patients with diabetic retinopathy. Because differentiation of retinal stem cells is regulated in part by epigenetic mechanisms, it may also be possible to direct stem cell differentiation pathways through the use of selective epigenetic modifiers. This is predicted to provide a valuable avenue to accelerate the introduction of regenerative approaches to retinal disease. Epigenetic modifiers are poised to become a powerful new approach to treat retinal degenerative diseases.

Black carrot extract protects against hepatic injury through epigenetic modifications.

We studied the epigenetic regulation of how black carrot extract (BCE) protects against ethanol-induced hepatic damage. We have shown that the butanol-extracted fraction of BCE (BCE-BuOH) increased intracellular cyclic adenosine monophosphate (cAMP) levels by suppressing the expression of phosphodiesterase 4b (PDE4b); however, the detailed mechanism remains to be elucidated. We focused on changes in histone modifications involved in the suppression of pde4 expression. The methylation level of histone H3 lysine 9 (H3K9), which regulates gene expression of PDE4b, decreased after treatment with 100 mM ethanol but was significantly increased by treatment with 400 μg/ml BCE-BuOH. In contrast, ethanol induced an increase in H3K9 acetylation. However, treatment with BCE-BuOH inhibited the increase in acetylation through an increase in Sirtuin 1 (Sirt1), a histone deacetylase. Furthermore, BCE-BuOH treatment increased the level of methionine adenosyltransferase (MAT) 2a mRNA and increased intracellular S-adenosylmethionine. The present results indicate that BCE-BuOH is useful for protection against alcohol-induced hepatic injury. PRACTICAL APPLICATIONS: We have reported that black carrot extract (BCE) suppressed liver steatosis and liver fibrosis on a rat alcoholic liver disease model. The results from this study have shown that BCE regulated the alcoholic-induced hepatic injury at the level of epigenetic modifications. These results suggested that BCE is useful for protection against alcoholic-induced hepatic injury.

Abstract 3766: Correlating locus-specific changes in histone trimethylation and gene expression in hypoxia

Abstract Low oxygen availability (hypoxia) is a common feature of many solid tumors and is associated with poor prognosis and resistance to therapy. The main regulator of cellular responses to hypoxia is the transcription factor HIF (hypoxia-inducible factor). In addition, several histone lysine demethylases (KDMs) are 2-OG dependent dioxygenases and require oxygen for their activity. When oxygen availability is limited, the activity of these KDMs is inhibited leading to global histone hypermethylation, potentially altering gene expression. However, some KDMs are also known to be direct transcriptional targets of HIF, increasing their expression in hypoxia and counteracting this histone hypermethylation. Furthermore, HIF can facilitate recruitment of histone methyltransferase activity to chromatin in cis, leading to local increases in methylation status. Histone methylation can be associated with both gene activation and gene repression, and it remains unclear how the balance of these widespread changes relates to locus-specific regulation of gene expression. Furthermore, previous attempts to analyze regulation of histone methylation by ChIP-seq in hypoxia have not employed normalization methods that take into account global changes in histone modification. We have performed ChIP-seq analysis of histone trimethylation (H3K4me3, H3K9me3, H3K27me3 and H3K36me3) in PC3 prostate cancer cells incubated in normoxia or (16hrs, 1%) hypoxia. We have then examined the effects of the HIF-transcriptional pathway on these marks using the same cell line following deletion of HIF-1b to block the HIF response. We employ an integrated spike-in with drosophila chromatin to provide a normalization control. We then relate our findings to changes in gene expression using RNA-seq analysis, again normalized to a spike-in control. We observe global increases in all 4 histone trimethylations across the genome in hypoxia. In particular, we observe hypoxic increases in histone trimethylation at all gene loci. However, while basal levels of histone trimethylation correlated with basal transcript levels as previously reported, hypoxic increases in promoter-associated histone H3K4me3 trimethylation bore no relation to either the direction or magnitude of gene regulation in hypoxia. Although, more subtle increases were observed across the gene body at gene loci induced by hypoxia. These findings question the currently accepted model that changes in H3K4me3 instruct changes in transcription in hypoxia and suggest that the overall effect of histone trimethylation is a more subtle balance of competing effects. Citation Format: Jessica D. Kindrick, Peter J. Ratcliffe, WIlliam Doug Figg, David R. Mole. Correlating locus-specific changes in histone trimethylation and gene expression in hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3766.

Developmental Pathways Are Epigenetically Reprogrammed during Lung Cancer Brain Metastasis.

Altered DNA methylation in lung cancer brain metastases corresponds with loss of EZH2 occupancy at developmental genes, which could promote stem-like phenotypes permissive of dissemination and survival in different microenvironments.

The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review.

Anxiety is one of the most common psychiatric disorders diagnosed in the United States today. Like all mental illnesses, anxiety pathology includes genetic, molecular, somatic, and behavioral characteristics. Specific brain regions implicated in anxiety include the prefrontal cortex, amygdala, hippocampus, and hypothalamus. Together, these regions regulate fear-related learning and memory processes, and are innervated by neuronal projections that use glutamate and GABA as neurotransmitters. Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) are also implicated in anxiety. This review discusses the neuroepigenetics of the anxiety phenotype. While studying such changes is limited to postmortem brain studies or peripheral tissue acquisition in humans, the use of animals to model anxiety phenotypes has made epigenetic research possible. In this review, we summarize and discuss a plethora of DNA methylation, histone modification, and associated gene expression differences underscoring the anxiety phenotype. The findings we outline include expression changes of various DNA methyltransferases and changes in histone modifications that affect the hypothalamic pituitary adrenal axis and stress response as well as GABA, glutamate, and BDNF signaling in the PFC, amygdala, hypothalamus, and hippocampus. Furthermore, there have been studies showing that anxiety behaviors and biological scars from stress can be reversed using histone deacetylase inhibitors, and we discuss ideas for the future of treatment. In this review, we hope that by compiling much of the data pertaining to DNA methylation and histone modifications in vivo animal studies we are able to highlight potential avenues for future research despite existing limitations.

USP16-mediated histone H2A lysine-119 deubiquitination during oocyte maturation is a prerequisite for zygotic genome activation.

Maternal-to-zygotic transition (MZT) is the first and key step in the control of animal development and intimately related to changes in chromatin structure and histone modifications. H2AK119ub1, an important epigenetic modification in regulating chromatin configuration and function, is primarily catalyzed by PRC1 and contributes to resistance to transcriptional reprogramming in mouse embryos. In this study, the genome-wide dynamic distribution of H2AK119ub1 during MZT in mice was investigated using chromosome immunoprecipitation and sequencing. The results indicated that H2AK119ub1 accumulated in fully grown oocytes and was enriched at the TSSs of maternal genes, but was promptly declined after meiotic resumption at genome-wide including the TSSs of early zygotic genes, by a previously unidentified mechanism. Genetic evidences indicated that ubiquitin-specific peptidase 16 (USP16) is the major deubiquitinase for H2AK119ub1 in mouse oocytes. Conditional knockout of Usp16 in oocytes did not impair their survival, growth, or meiotic maturation. However, oocytes lacking USP16 have defects when undergoing zygotic genome activation or gaining developmental competence after fertilization, potentially associated with high levels of maternal H2AK119ub1 deposition on the zygotic genomes. Taken together, H2AK119ub1 level is declined during oocyte maturation by an USP16-dependent mechanism, which ensures zygotic genome reprogramming and transcriptional activation of essential early zygotic genes.

Potential dual protective effects of melatonin on spermatogonia against hexavalent chromium

Hexavalent chromium (Cr (VI)) is a widely used metal and has been shown to cause male reproductive abnormalities. However, the underlying mechanisms for the Cr (VI)-induced reproductive toxicity remain incompletely understood. In this study, we investigated the spermatogonial damage caused by Cr (VI) as well as the protective effect of melatonin against Cr (VI)-triggered toxicity. We observed that Cr (VI) caused spermatogonial damage in a time- and dose-dependent manner. Results further showed that melatonin could protect spermatogonia from Cr (VI)-triggered damage via elimination of reactive oxygen species (ROS) as well as via suppression of ATM-p53 phosphorylation and the mitogen-activated protein kinase (MAPK) pathway. Prior administration of melatonin also prevented the Cr (VI)-caused enrichment of H3K9me3 in the Mad1, Mad2 and Bcl2 gene promoter regions, precluding the G2/M arrest and apoptosis in spermatogonia. Taken together, this study demonstrates that melatonin can effectively protect spermatogonia against the damage and against the histone modification changes induced by Cr (VI). This, along with the uncovered molecular mechanism, provide important implications for male infertility induced by environmental pollution.

Interspecies Single-Cell RNA-Seq Analysis Reveals the Novel Trajectory of Osteoclast Differentiation and Therapeutic Targets.

ABSTRACTBone turnover is finely tuned by cells in the bone milieu, including osteoblasts, osteoclasts, and osteocytes. Osteoclasts are multinucleated giant cells with a bone‐resorbing function that play a critical role in regulating skeletal homeostasis. Osteoclast differentiation is characterized by dramatic changes in morphology and gene expression following receptor activator of nuclear factor‐kappa‐Β ligand (RANKL) stimulation. We performed single‐cell RNA‐sequencing analyses of human and murine osteoclast‐lineage cells (OLCs) and found that OLCs in the mitotic phase do not differentiate into mature osteoclasts. We also identified a guanosine triphosphatase (GTPase) family member, RAB38, as a highly expressed molecule in both human and murine osteoclast clusters; RAB38 gene expression is associated with dynamic changes in histone modification and transcriptional regulation. Silencing Rab38 expression by using short hairpin RNA (shRNA) inhibited osteoclast differentiation and maturation. In summary, we established an integrated fate map of human and murine osteoclastogenesis; this will help identify therapeutic targets in bone diseases. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Large-Scale Chromatin Rearrangements in Cancer.

Simple SummaryCancers have many genetic mutations such as nucleotide changes, deletions, amplifications, and chromosome gains or losses. Some of these genetic alterations directly contribute to the initiation and progression of tumors. In parallel to these genetic changes, cancer cells acquire modifications to their chromatin landscape, i.e., to the marks that are carried by DNA and the histone proteins it is associated with. These “epimutations” have consequences for gene expression and genome stability, and also contribute to tumoral initiation and progression. Some of these chromatin changes are very local, affecting just one or a few genes. In contrast, some chromatin alterations observed in cancer are more widespread and affect a large part of the genome. In this review, we present different types of large-scale chromatin rearrangements in cancer, explain how they may occur, and why they are relevant for cancer diagnosis and treatment.Epigenetic abnormalities are extremely widespread in cancer. Some of them are mere consequences of transformation, but some actively contribute to cancer initiation and progression; they provide powerful new biological markers, as well as new targets for therapies. In this review, we examine the recent literature and focus on one particular aspect of epigenome deregulation: large-scale chromatin changes, causing global changes of DNA methylation or histone modifications. After a brief overview of the one-dimension (1D) and three-dimension (3D) epigenome in healthy cells and of its homeostasis mechanisms, we use selected examples to describe how many different events (mutations, changes in metabolism, and infections) can cause profound changes to the epigenome and fuel cancer. We then present the consequences for therapies and briefly discuss the role of single-cell approaches for the future progress of the field.

YY1 safeguard multidimensional epigenetic landscape associated with extended pluripotency.

Although extended pluripotent stem cells (EPSCs) have the potential to form both embryonic and extraembryonic lineages, how their transcriptional regulatory mechanism differs from that of embryonic stem cells (ESCs) remains unclear. Here, we discovered that YY1 binds to specific open chromatin regions in EPSCs. Yy1 depletion in EPSCs leads to a gene expression pattern more similar to that of ESCs than control EPSCs. Moreover, Yy1 depletion triggers a series of epigenetic crosstalk activities, including changes in DNA methylation, histone modifications and high-order chromatin structures. Yy1 depletion in EPSCs disrupts the enhancer-promoter (EP) interactions of EPSC-specific genes, including Dnmt3l. Yy1 loss results in DNA hypomethylation and dramatically reduces the enrichment of H3K4me3 and H3K27ac on the promoters of EPSC-specific genes by upregulating the expression of Kdm5c and Hdac6 through facilitating the formation of CCCTC-binding factor (CTCF)-mediated EP interactions surrounding their loci. Furthermore, single-cell RNA sequencing (scRNA-seq) experiments revealed that YY1 is required for the derivation of extraembryonic endoderm (XEN)-like cells from EPSCs in vitro. Together, this study reveals that YY1 functions as a key regulator of multidimensional epigenetic crosstalk associated with extended pluripotency.

Uncovering the Epigenetic Marks Involved in Mediating Salt Stress Tolerance in Plants.

The toxic effects of salinity on agricultural productivity necessitate development of salt stress tolerance in food crops in order to meet the escalating demands. Plants use sophisticated epigenetic systems to fine-tune their responses to environmental cues. Epigenetics is the study of heritable, covalent modifications of DNA and histone proteins that regulate gene expression without altering the underlying nucleotide sequence and consequently modify the phenotype. Epigenetic processes such as covalent changes in DNA, histone modification, histone variants, and certain non-coding RNAs (ncRNA) influence chromatin architecture to regulate its accessibility to the transcriptional machinery. Under salt stress conditions, there is a high frequency of hypermethylation at promoter located CpG sites. Salt stress results in the accumulation of active histones marks like H3K9K14Ac and H3K4me3 and the downfall of repressive histone marks such as H3K9me2 and H3K27me3 on salt-tolerance genes. Similarly, the H2A.Z variant of H2A histone is reported to be down regulated under salt stress conditions. A thorough understanding of the plasticity provided by epigenetic regulation enables a modern approach to genetic modification of salt-resistant cultivars. In this review, we summarize recent developments in understanding the epigenetic mechanisms, particularly those that may play a governing role in the designing of climate smart crops in response to salt stress.

Epigenetic Mechanisms Responsible for the Transgenerational Inheritance of Intrauterine Growth Restriction Phenotypes.

A poorly functioning placenta results in impaired exchanges of oxygen, nutrition, wastes and hormones between the mother and her fetus. This can lead to restriction of fetal growth. These growth restricted babies are at increased risk of developing chronic diseases, such as type-2 diabetes, hypertension, and kidney disease, later in life. Animal studies have shown that growth restricted phenotypes are sex-dependent and can be transmitted to subsequent generations through both the paternal and maternal lineages. Altered epigenetic mechanisms, specifically changes in DNA methylation, histone modifications, and non-coding RNAs that regulate expression of genes that are important for fetal development have been shown to be associated with the transmission pattern of growth restricted phenotypes. This review will discuss the subsequent health outcomes in the offspring after growth restriction and the transmission patterns of these diseases. Evidence of altered epigenetic mechanisms in association with fetal growth restriction will also be reviewed.

Palmitate-Triggered COX2/PGE2-Related Hyperinflammation in Dual-Stressed PdL Fibroblasts Is Mediated by Repressive H3K27 Trimethylation.

The interrelationships between periodontal disease, obesity-related hyperlipidemia and mechanical forces and their modulating effects on the epigenetic profile of periodontal ligament (PdL) cells are assumed to be remarkably complex. The PdL serves as a connective tissue between teeth and alveolar bone and is involved in pathogen defense and the inflammatory responses to mechanical stimuli occurring during tooth movement. Altered inflammatory signaling could promote root resorption and tooth loss. Hyperinflammatory COX2/PGE2 signaling was reported for human PdL fibroblasts (HPdLFs) concomitantly stressed with Porphyromonas gingivalis lipopolysaccharides and compressive force after exposure to palmitic acid (PA). The aim of this study was to investigate the extent to which this was modulated by global and gene-specific changes in histone modifications. The expression of key epigenetic players and global H3Kac and H3K27me3 levels were quantitatively evaluated in dual-stressed HPdLFs exposed to PA, revealing a minor force-related reduction in repressive H3K27me3. UNC1999-induced H3K27me3 inhibition reversed the hyperinflammatory responses of dual-stressed PA cultures characterized by increased COX2 expression, PGE2 secretion and THP1 adhesion. The reduced expression of the gene encoding the anti-inflammatory cytokine IL-10 and the increased presence of H3K27me3 at its promoter-associated sites were reversed by inhibitor treatment. Thus, the data highlight an important epigenetic interplay between the different stimuli to which the PdL is exposed.

MonaLisa: an R/Bioconductor package for identifying regulatory motifs.

SummaryProteins binding to specific nucleotide sequences, such as transcription factors, play key roles in the regulation of gene expression. Their binding can be indirectly observed via associated changes in transcription, chromatin accessibility, DNA methylation and histone modifications. Identifying candidate factors that are responsible for these observed experimental changes is critical to understand the underlying biological processes. Here, we present monaLisa, an R/Bioconductor package that implements approaches to identify relevant transcription factors from experimental data. The package can be easily integrated with other Bioconductor packages and enables seamless motif analyses without any software dependencies outside of R. Availability and implementation monaLisa is implemented in R and available on Bioconductor at https://bioconductor.org/packages/monaLisa with the development version hosted on GitHub at https://github.com/fmicompbio/monaLisa.Supplementary information Supplementary data are available at Bioinformatics online.

Identification of Key Histone Modifications and Hub Genes for Colorectal Cancer Metastasis

Background: Epithelial-Mesenchymal Transition (EMT) and its reverse Mesenchymal- Epithelial Transition (MET) are essential for tumor cells metastasis. However, the effect of epigenetic modifications on this transition is unclear. Objective: We aimed to explore the key histone modifications and hub genes of EMT/MET during Colorectal Cancer (CRC) metastasis. Method: The differentially expressed genes and differentially histone modified genes were identified. Based on the histone modification features, the up- and down-regulated genes were predicted by Random Forest algorithm. Through protein-protein interaction network and Cytoscape analysis, the hub genes with histone modification changes were selected. GO, KEGG and survival analyses were performed to confirm the importance of the hub genes. Results: It was found that H3K79me3 plays an important role in EMT/MET. And the 200-300bp and 400-500bp downstream of TSS may be the key regulatory regions of H3K79me3. Moreover, we found that the expression of the hub genes was down-regulated in EMT and then up-regulated in MET. And the changes of the hub genes expression were consistent with the changes of H3K79me3 signal in the specific regions of the genome. Finally, the hub genes KRT8 and KRT18 were involved in the metastasis process and were significantly related to the survival time. Conclusion: H3K79me3 may be crucial for EMT/MET, and the hub genes KRT8 and KRT18 may be the key genes in this process.

Therapies Targeting Epigenetic Alterations in Acute Kidney Injury-to-Chronic Kidney Disease Transition.

Acute kidney injury (AKI) was previously thought to be a merely transient event; however, recent epidemiological evidence supports the existence of a causal relationship between AKI episodes and subsequent progression to chronic kidney disease (CKD). Although the pathophysiology of this AKI-to-CKD transition is not fully understood, it is mediated by the interplay among multiple components of the kidney including tubular epithelial cells, endothelial cells, pericytes, inflammatory cells, and myofibroblasts. Epigenetic alterations including histone modification, DNA methylation, non-coding RNAs, and chromatin conformational changes, are also expected to be largely involved in the pathophysiology as a “memory” of the initial injury that can persist and predispose to chronic progression of fibrosis. Each epigenetic modification has a great potential as a therapeutic target of AKI-to-CKD transition; timely and target-specific epigenetic interventions to the various temporal stages of AKI-to-CKD transition will be the key to future therapeutic applications in clinical practice. This review elaborates on the latest knowledge of each mechanism and the currently available therapeutic agents that target epigenetic modification in the context of AKI-to-CKD transition. Further studies will elucidate more detailed mechanisms and novel therapeutic targets of AKI-to-CKD transition.

Chromatin alterations during the epididymal maturation of mouse sperm refine the paternally inherited epigenome

BackgroundPaternal lifestyle choices and male exposure history have a critical influence on the health and fitness of the next generation. Accordingly, defining the processes of germline programming is essential to resolving how the epigenetic memory of paternal experiences transmits to their offspring. Established dogma holds that all facets of chromatin organization and histone posttranslational modification are complete before sperm exits the testes. However, recent clinical and animal studies suggest that patterns of DNA methylation change during epididymal maturation. In this study, we used complementary proteomic and deep-sequencing approaches to test the hypothesis that sperm posttranslational histone modifications change during epididymal transit.ResultsUsing proteomic analysis to contrast immature spermatozoa and mature sperm isolated from the mouse epididymis, we find progressive changes in multiple histone posttranslational modifications, including H3K4me1, H3K27ac, H3K79me2, H3K64ac, H3K122ac, H4K16ac, H3K9me2, and H4K20me3. Interestingly, some of these changes only occurred on histone variant H3.3, and most involve chromatin modifications associated with gene enhancer activity. In contrast, the bivalent chromatin modifications, H3K4me3, and H3K27me3 remained constant. Using chromatin immunoprecipitation coupled with deep sequencing, we find that changes in histone h3, lysine 27 acetylation (H3K27ac) involve sharpening broad diffuse regions into narrow peaks centered on the promoter regions of genes driving embryonic development. Significantly, many of these regions overlap with broad domains of H3K4me3 in oocytes and ATAC-seq signatures of open chromatin identified in MII oocytes and sperm. In contrast, histone h3, lysine 9 dimethylation (H3K9me2) becomes enriched within the promoters of genes driving meiosis and in the distal enhancer regions of tissue-specific genes sequestered at the nuclear lamina. Maturing sperm contain the histone deacetylase enzymes HDAC1 and HDAC3, suggesting the NuRD complex may drive some of these changes. Finally, using Western blotting, we detected changes in chromatin modifications between caput and caudal sperm isolated from rams (Ovis aries), inferring changes in histone modifications are a shared feature of mammalian epididymal maturation.ConclusionsThese data extend our understanding of germline programming and reveal that, in addition to trafficking noncoding RNAs, changes in histone posttranslational modifications are a core feature of epididymal maturation.

Coordinated Epigenetic Regulation in Plants: A Potent Managerial Tool to Conquer Biotic Stress.

Plants have evolved variable phenotypic plasticity to counteract different pathogens and pests during immobile life. Microbial infection invokes multiple layers of host immune responses, and plant gene expression is swiftly and precisely reprogramed at both the transcriptional level and post-transcriptional level. Recently, the importance of epigenetic regulation in response to biotic stresses has been recognized. Changes in DNA methylation, histone modification, and chromatin structures have been observed after microbial infection. In addition, epigenetic modifications may be preserved as transgenerational memories to allow the progeny to better adapt to similar environments. Epigenetic regulation involves various regulatory components, including non-coding small RNAs, DNA methylation, histone modification, and chromatin remodelers. The crosstalk between these components allows precise fine-tuning of gene expression, giving plants the capability to fight infections and tolerant drastic environmental changes in nature. Fully unraveling epigenetic regulatory mechanisms could aid in the development of more efficient and eco-friendly strategies for crop protection in agricultural systems. In this review, we discuss the recent advances on the roles of epigenetic regulation in plant biotic stress responses.

Recognition of driver genes with potential prognostic implications in lung adenocarcinoma based on H3K79me2

Lung adenocarcinoma is a malignancy with a low overall survival and a poor prognosis. Studies have shown that lung adenocarcinoma progression relates to locus-specific/global changes in histone modifications. To explore the relationship between histone modification and gene expression changes, we focused on 11 histone modifications and quantitatively analyzed their influences on gene expression. We found that, among the studied histone modifications, H3K79me2 displayed the greatest impact on gene expression regulation. Based on the Shannon entropy, 867 genes with differential H3K79me2 levels during tumorigenesis were identified. Enrichment analyses showed that these genes were involved in 16 common cancer pathways and 11 tumors and were target-regulated by trans-regulatory elements, such as Tp53 and WT1. Then, an open-source computational framework was presented (https://github.com/zlq-imu/Identification-of-potential-LUND-driver-genes). Twelve potential driver genes were extracted from the genes with differential H3K79me2 levels during tumorigenesis. The expression levels of these potential driver genes were significantly increased/decreased in tumor cells, as assayed by RT–qPCR. A risk score model comprising these driver genes was further constructed, and this model was strongly negatively associated with the overall survival of patients in different datasets. The proportional hazards assumption and outlier test indicated that this model could robustly distinguish patients with different survival rates. Immune analyses and responses to immunotherapeutic and chemotherapeutic agents showed that patients in the high and low-risk groups may have distinct tendencies for clinical selection. Finally, the regions with clear H3K79me2 signal changes on these driver genes were accurately identified. Our research may offer potential molecular biomarkers for lung adenocarcinoma treatment.

Epigenetic Mechanisms in Understanding Nanomaterial-Induced Toxicity.

The toxic effects of different forms of nanomaterials comprise a series of biological effects such as oxidative stress; DNA damage; inflammatory response; activation of nuclear transcription factors. Some of these are key characteristics of human carcinogens and have been considered for hazard identification of nanomaterials. In addition, epigenetic changes also play a key role in the multi-step sequential process of carcinogenesis. Epigenetic modifications may constitute changes in DNA methylation, histone modifications (methylation, acetylation etc), and changes in non-coding RNA, leading to an altered gene expression profile. In this chapter, we describe the state-of-the-art of epigenetic modifications induced by different nanomaterials, from a limited number of in vitro- in vivo and human studies, a majority of which is primarily focused on DNA methylation. We also highlight the potential challenges and future directions in the field of epigenetics research in nanomaterial toxicology.