Epigenetic Research Research Articles

Role and mechanism of DNA methylation and its inhibitors in hepatic fibrosis.

Liver fibrosis is a repair response to injury caused by various chronic stimuli that continually act on the liver. Among them, the activation of hepatic stellate cells (HSCs) and their transformation into a myofibroblast phenotype is a key event leading to liver fibrosis, however the mechanism has not yet been elucidated. The molecular basis of HSC activation involves changes in the regulation of gene expression without changes in the genome sequence, namely, via epigenetic regulation. DNA methylation is a key focus of epigenetic research, as it affects the expression of fibrosis-related, metabolism-related, and tumor suppressor genes. Increasing studies have shown that DNA methylation is closely related to several physiological and pathological processes including HSC activation and liver fibrosis. This review aimed to discuss the mechanism of DNA methylation in the pathogenesis of liver fibrosis, explore DNA methylation inhibitors as potential therapies for liver fibrosis, and provide new insights on the prevention and clinical treatment of liver fibrosis.

Herbal used as Epigenetic for Cancer Treatment

Patterns of chromatin accessibility, which are in turn altered by epigenetic mechanisms, are responsible for determining the interactions that take place between transcription machinery, genes, and the cis-regulatory elements of those genes. Mutations that interfere with epigenetic processes frequently have the unfortunate side effect of causing cancer. Since these mutations can be undone, numerous anticancer treatments that target epigenetic pathways are now being developed and evaluated. (Cancer) is becoming more and more common everywhere. This decline in clinical outcomes is a result of a number of factors, including late diagnosis, a lack of efficient treatments for particular cancer subtypes, and drug resistance. Treatment resistance and stemness traits have been recognised as markers of this disease, and it has been demonstrated that epigenetic changes play a role in the process of cancer growth. Understanding these alterations and how they impact cancer carcinogenesis treatment is challenging but crucial. However, it may be able to provide the special knowledge needed to use these alterations as potential diagnostic, prognostic, therapeutic agents, and predictors of treatment efficacy. This underlines the importance of continued research to advance our knowledge of cancer carcinogenesis and epigenetics and help us overcome these challenges. This review aims to provide an overview of the state of the art in epigenetics research for cancer detection and treatment and to stimulate discussion on this subject.

A Systematic Review of Progress toward Unlocking the Power of Epigenetics in NSCLC: Latest Updates and Perspectives

Epigenetic research has the potential to improve our understanding of the pathogenesis of cancer, specifically non-small-cell lung cancer, and support our efforts to personalize the management of the disease. Epigenetic alterations are expected to have relevance for early detection, diagnosis, outcome prediction, and tumor response to therapy. Additionally, epi-drugs as therapeutic modalities may lead to the recovery of genes delaying tumor growth, thus increasing survival rates, and may be effective against tumors without druggable mutations. Epigenetic changes involve DNA methylation, histone modifications, and the activity of non-coding RNAs, causing gene expression changes and their mutual interactions. This systematic review, based on 110 studies, gives a comprehensive overview of new perspectives on diagnostic (28 studies) and prognostic (25 studies) epigenetic biomarkers, as well as epigenetic treatment options (57 studies) for non-small-cell lung cancer. This paper outlines the crosstalk between epigenetic and genetic factors as well as elucidates clinical contexts including epigenetic treatments, such as dietary supplements and food additives, which serve as anti-carcinogenic compounds and regulators of cellular epigenetics and which are used to reduce toxicity. Furthermore, a future-oriented exploration of epigenetic studies in NSCLC is presented. The findings suggest that additional studies are necessary to comprehend the mechanisms of epigenetic changes and investigate biomarkers, response rates, and tailored combinations of treatments. In the future, epigenetics could have the potential to become an integral part of diagnostics, prognostics, and personalized treatment in NSCLC.

Discovery of Novel Substrate-Competitive Lysine Methyltransferase G9a Inhibitors as Anticancer Agents.

Identification of structurally novel inhibitors of lysine methyltransferase G9a has been a subject of intense research in cancer epigenetics. Starting with the high-throughput screening (HTS) hit rac-10a obtained from the chemical library of the University of Tokyo Drug Discovery Initiative, the structure-activity relationship of the unique substrate-competitive inhibitors was established with the help of X-ray crystallography and fragment molecular orbital (FMO) calculations for the ligand-protein interaction. Further optimization of the in vitro characteristics and drug metabolism and pharmacokinetics (DMPK) properties led to the identification of 26j (RK-701), which is a structurally distinct potent inhibitor of G9a/GLP (IC50 = 27/53 nM). Compound 26j exhibited remarkable selectivity against other related methyltransferases, dose-dependent attenuation of cellular H3K9me2 levels, and tumor growth inhibition in MOLT-4 cells in vitro. Moreover, compound 26j showed inhibition of tumor initiation and growth in a carcinogen-induced hepatocellular carcinoma (HCC) in vivo mouse model without overt acute toxicity.

Transgenerational Inheritance and Systemic Racism in America.

It is well established that personal experiences of trauma, adversity, and discrimination can "get under the skin" and increase risk for a whole host of negative mental and physical health outcomes. The aim of this article is to review emerging research on transgenerational epigenetic inheritance which suggests that negative exposures in one generation, can also be passed down to affect the health and well-being of future generations. This paper reviews key concepts in transgenerational epigenetic inheritance research, select animal and human studies examining the role of epigenetic mechanisms in transmitting the impact of ancestral stress and trauma, poor nutrition, and toxicant exposure across generations, and factors that can mitigate the effects of these experiences. The animal studies provide compelling evidence for a role for these mechanisms in the transmission of the negative effects associated with ancestral adversities. Animal and clinical studies also suggest that the negative impact of personal and ancestral traumas can be prevented, with a role for in humans for evidence-based trauma treatments, culturally adapted prevention and intervention programs, and enrichment opportunities strongly indicated. Although comparable definitive data is lacking in multigenerational human cohorts, preliminary data supports a potential role for transgenerational epigenetic mechanisms in explaining persistent health disparities in the absence of personal exposures, and further elucidation of these mechanisms may guide the design of novel interventions. In addressing ancestral traumas, however, true change and healing will require acknowledgement of the harms that were done, and broader systemic policy level changes.

Toward the Development of Epigenome Editing-Based Therapeutics: Potentials and Challenges

The advancement in epigenetics research over the past several decades has led to the potential application of epigenome-editing technologies for the treatment of various diseases. In particular, epigenome editing is potentially useful in the treatment of genetic and other related diseases, including rare imprinted diseases, as it can regulate the expression of the epigenome of the target region, and thereby the causative gene, with minimal or no modification of the genomic DNA. Various efforts are underway to successfully apply epigenome editing in vivo, such as improving target specificity, enzymatic activity, and drug delivery for the development of reliable therapeutics. In this review, we introduce the latest findings, summarize the current limitations and future challenges in the practical application of epigenome editing for disease therapy, and introduce important factors to consider, such as chromatin plasticity, for a more effective epigenome editing-based therapy.

Immunoepigenetic Regulation of Inflammatory Bowel Disease: Current Insights into Novel Epigenetic Modulations of the Systemic Immune Response.

The immune system and environmental factors are involved in various diseases, such as inflammatory bowel disease (IBD), through their effect on genetics, which modulates immune cells. IBD encompasses two main phenotypes, Crohn's disease, and ulcerative colitis, which are manifested as chronic and systemic relapse-remitting gastrointestinal tract disorders with rising global incidence and prevalence. The pathophysiology of IBD is complex and not fully understood. Epigenetic research has resulted in valuable information for unraveling the etiology of this immune-mediated disease. Thus, the main objective of the present review is to summarize the current findings on the role of epigenetic mechanisms in IBD to shed light on their potential clinical relevance. This review focuses on the latest evidence regarding peripheral blood mononuclear cells and epigenetic changes in histone modification, DNA methylation, and telomere shortening in IBD. The various identified epigenetic DNA profiles with clinical value in IBD could be used as biomarkers for more accurately predicting disease development, treatment response, and therapy-related adverse events. Ultimately, the information presented here could be of potential relevance for future clinical practice in developing more efficient and precise medicine to improve the quality of life for patients with IBD.

Methylation-sensitive transcription-enhanced single-molecule biosensing of DNA methylation in cancer cells and tissues

As a major epigenetic modification, DNA methylation participates in diverse cellular functions and emerges as a promising biomarker for disease diagnosis and monitoring. Herein, we developed a methylation-sensitive transcription-enhanced single-molecule biosensor to detect DNA methylation in human cells and tissues. In this biosensor, a rationally designed transcription machine is split into two parts including a promoter sequence (probe-P) for initiating transcription and a template sequence (probe-T) for RNA synthesis. The presence of specific DNA methylation leads to the formation of full-length transcription machine through sequence-specific ligation of probe-P and probe-T, initiating the synthesis of abundant ssRNA transcripts. The resultant ssRNAs can activate CRISPR/Cas12a to catalyze cyclic cleavage of fluorophore- and quencher-dual labeled signal probes, resulting in the recovery of the fluorophore signal that can be quantified by single-molecule detection. Taking advantages of the high-fidelity ligation of split transcription machine and the high efficiency of transcription- and CRISPR/Cas12a cleavage-mediated dual signal amplification, this single-molecule biosensor achieves a low detection limit of 337 aM and high selectivity. Moreover, it can distinguish 0.01% methylation level, and even accurately detect genomic DNA methylation in single cell and clinical samples, providing a powerful tool for epigenetic researches and clinical diagnostics.

Comparing DRD2 Promoter Methylation Between Blood and Brain in Alcohol Dependence.

The dopamine receptor D2 (DRD2) is substantially involved in several forms of addiction. In addition to genetic polymorphisms, epigenetic mechanisms have emerged as an important means of regulation. Previously, DRD2 hypo- and hyper-methylation have been observed in alcohol use disorder (AUD). Blood samples are commonly used as a surrogate marker of epigenetic alterations in epigenetic research, but few specific comparisons between blood and brain tissue samples in AUD exist. We used post-mortem brain tissue samples of 17 deceased patients with AUD and 31 deceased controls to investigate the relationship between blood and brain methylation of the DRD2 promoter. When investigating individual cytosine methylation sites (CpG), several significant differences were found in the nucleus accumbens and hippocampus in the study population. Investigating binding sites with significant differences in methylation levels revealed hypomethylated CpGs targeting mainly activating transcription factors. These findings support an altered transcription of the DRD2 gene in AUD specimens with a consecutively changed reward response in the brain. While methylation between specific brain regions and blood is comparable, our study further suggests that blood methylation cannot provide meaningful perspectives on DRD2 promoter methylation in the brain.

Epigenetic modifications in chronic rhinosinusitis with and without nasal polyps.

Chronic rhinosinusitis (CRS) has brought a huge socioeconomic burden. However, its mechanism is still elusive, which may involve genetic, environmental and some other factors. Epigenetic analyses have been conducted to explore the mechanisms underlying CRS. Here, we reviewed the fruits in the epigenetic studies on DNA methylation, histone modification, and non-coding RNA regulation. We concluded that the epigenetic research on CRS has made great breakthroughs, especially in the past 5years and the field of microRNAs. "Epigenetic therapies" are expected to be designed to treat CRS in the future.

Early epigenetic markers for precision medicine.

Changes in DNA methylation levels, changes in histones, and noncoding RNA functions (ncRNAs) are common among different diseases and epigenetic component mutations. The ability to distinguish between the roles of drivers and passengers in epigenetic changes will allow to identify diseases where epigenetics could influence diagnosis, prediction and treatment. In addition, by examining the interaction between epigenetic components and other pathways of disease, a combination intervention approach will be developed. A comprehensive study of the association of specific cancer types or the cancer genome atlas project has revealed frequent mutations in genes encoded by the epigenetic components. These include mutations in DNA methylase and demethylase, the cytoplasm and the change of cytoplasm, as well as genes involved in the restoration of chromatins and the structure of chromosomes, also, the metabolic genes isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) affect histone and DNA methylation, disrupting the architecture of the 3D genome, but also affect the metabolic genes IDH1 and IDH2. Repeated DNA elements also cause cancer. In the 21st century, epigenetic research has rapidly accelerated, causing legitimate excitement and hope, and causing a certain level of excitement. New epigenetic tools can be used as prevention, diagnosis and therapeutic markers. Drug development targets specific epigenetic mechanisms that regulate gene expression and promotes gene expression. The development and use of epigenetic tools is an appropriate and effective method for treating various diseases clinically.

Decoding Cancer Formation: The Impact of Epigenetic Factors

This study delves into the critical role of epigenetic factors in the formation and progression of cancer, offering a comprehensive analysis of the molecular mechanisms that drive tumorigenesis. Epigenetic modifications, including DNA methylation, histone modification, and non-coding RNA regulation, have emerged as key players in the regulation of gene expression without altering the underlying DNA sequence. These modifications can lead to the activation of oncogenes or the silencing of tumor suppressor genes, thereby contributing to the initiation and progression of cancer. The research highlights how disruptions in normal epigenetic processes can result in abnormal cell growth, metastasis, and resistance to apoptosis, which are hallmarks of cancer. By analyzing recent advancements in epigenetic research, the study underscores the importance of understanding these mechanisms to identify potential biomarkers for early cancer detection and to develop targeted therapies that can reverse epigenetic alterations. Through a detailed examination of various cancer types, the study demonstrates the widespread impact of epigenetic changes across different forms of the disease. It also explores the potential of epigenetic therapies, such as inhibitors of DNA methyltransferases and histone deacetylases, in reprogramming cancer cells to a more normal state. This study contributes to the growing body of knowledge on the molecular underpinnings of cancer and offers insights into the development of novel therapeutic strategies that target epigenetic factors, paving the way for more effective and personalized cancer treatments.

High-throughput Sequencing Technology and Its Application in Epigenetics Studies

DNA sequencing technology is one of the important tools in modern life science research, and with the development of science and technology, sequencing technology is constantly changing. High-throughput sequencing technology is known as the second generation sequencing technology. Compared with Sanger sequencing technology, high-throughput sequencing technology has the characteristics of high throughput, fast speed and low cost. In this paper, the researcher briefly introduced the emergence and development of DNA sequencing technology, and expounded the application of high-throughput sequencing in epigenetic research from the aspects of DNA methylation and histone modification.

Chromatin research and epigenetics - historical perspectives, current research, open questions, and misconceptions

The concept of chromatin as a complex of nucleic acid and proteins in the cell nucleus was developed by cytologists and biochemists in the late 19th century. It was the starting point for biochemical research on DNA and nuclear proteins. Interest in chromatin declined rapidly at the beginning of the 20th century, but a few decades later a new focus on chromatin emerged, which was not only related to its structure, but also to its function in gene regulatory processes in the development of higher organisms. Since the late 20th century, research on chromatin modifications as well as DNA methylation that emerged in the 1970s have also been conducted under the label epigenetics, a term originally introduced for the complex processes between genotype and phenotype during development. These processes - in particular gene regulation - were subsequently scrutinized by molecular biologists. Research termed epigenetics remained marginal until the end of the 20th century but experienced a rapid rise when heritability was added to its definition. This was accompanied by an increasing diversity in researchers' understanding and definitions of epigenetics. Epigenetics now includes research on histone and DNA-modifying enzymes, nucleosome remodelers, histone chaperones, chromatin-binding proteins to facilitate transcription factor and polymerase action, and the role of long non-coding RNA and small interfering RNA in transcriptional regulation. This article highlights the major phases of chromatin and epigenetics research until the present time and illuminates how different scientific contexts changed the relevance and meaning of chromatin from the 19th century. The paper also points to misconceptions and media hype about epigenetics, for example unsupported claims about transgenerational inheritance in humans or questioning of the basic biological principles of gene regulation based on specific regulatory sequences of the genome.

Multigenerational epigenetic inheritance in human: the past, present and perspectives

Nowadays, a growing body of evidence suggests that the developmental programs of each individual could be modified. The acquired new phenotypic changes could be persistent throughout the individual's life and even transmitted to the next generation. While the exact mechanism for that preservation is not well understood yet, there are many evidences showing that epigenetic alterations, which are robust and dynamic in response to the influence of the environmental factors, could be responsible for that inheritance. A growing number of external factors such as social stress, environmental pollution and climate changes make adaptation to these environmental changes rather challenging. According to the Developmental Origin of Human Disease theory, formulated by David Barker, environmental conditions experienced during the first phases of development can have long term effects on later phases of life. This phenomenon is linked to the biological plasticity of development, which allows reprogramming of physiological functions in response to different stimuli. Consequently, in utero exposure to environmental pollutants can increase predisposition to different pathologies that can occur both in early and later phases of life not only in the living generation but also in subsequent ones. Here, we have summarised some findings in human epigenetic research studies performed for the past few years which address the question whether transgenerational effects observed in model organisms could also occur in humans.

Inhibition of Class I Histone Deacetylase Enhances Self-Reprogramming of Spermatogonial Stem Cells into Pluripotent Stem Cells.

Spermatogonial stem cells (SSCs) are the most primitive cells in spermatogenesis and are the only adult stem cells capable of passing on the genome of a given species to the next generation. SSCs are the only adult stem cells known to exhibit high Oct4 expression and can be induced to self-reprogram into pluripotent cells depending on culture conditions. Epigenetic modulation is well known to be involved in the induction of pluripotency of somatic cells. However, epigenetic modulation in self-reprogramming of SSCs into pluripotent cells has not been studied. In this study, we examined the involvement of epigenetic modulation by assessing whether self-reprogramming of SSCs is enhanced by treatment with epigenetic modulators. We found that second-generation selective class I HDAC inhibitors increased SSC reprogramming efficiency, whereas non-selective HDAC inhibitors had no effect. We showed that pluripotent stem cells derived from adult SSCs by treatment with small molecules with epigenetic modulator functions exhibit pluripotency in vitro and in vivo. Our results suggest that the mechanism of SSC reprogramming by epigenetic modulator can be used for important applications in epigenetic reprogramming research.

Transgenerational inheritance of wing development defects in Drosophila melanogaster induced by cadmium

The transgenerational inheritance of phenotype induced by environmental factors is a new focus in epigenetic research. In this study, Drosophila melanogaster (F0) was cultured in the medium containing cadmium (Cd, 4.5 mg/kg) from eggs to adults, and offspring (F1-F4) were continuously kept in standard medium (without cadmium). The phenotype analysis showed that cadmium induced developmental defects on wings and apoptosis in the wing disc cells of Drosophila (F0). The wing defects were transmitted for at least four generations even without Cd afterwards. And the effect on the mRNA expression of wing development related genes (shg, omb, F-actin, Mekk1) can be maintained for at least two or three generations. More importantly, under cadmium stress, the post-translational modification (PTM) on the histones H3K4me3 in the third instar larvae and ovaries or testes of adult flies increased significantly, while the levels of H3K9me3 and H3K27me3 decreased significantly. The expression of histone methylation related genes (dSet-1, ash1, Lsd1) increased significantly and these changes can be transmitted to offspring from one or two generations in ovaries or testes. These results suggest that the phenotypic defects of wings caused by cadmium can be inherited to the offspring, and this transgenerational inheritance effect may be related to the epigenetic regulation of histone methylation. Therefore, the adaptability of offspring should be considered when evaluating the toxicity and environmental risk of cadmium.

Epigenetics applied to child and adolescent mental health: Progress, challenges and opportunities.

Epigenetic processes are fast emerging as a promising molecular system in the search for both biomarkers and mechanisms underlying human health and disease risk, including psychopathology. In this review, we discuss the application of epigenetics (specifically DNA methylation) to research in child and adolescent mental health, with a focus on the use of developmentally sensitive datasets, such as prospective, population-based cohorts. We look back at lessons learned to date, highlight current developments in the field and areas of priority for future research. We also reflect on why epigenetic research on child and adolescent mental health currently lags behind other areas of epigenetic research and what we can do to overcome existing barriers. To move the field forward, we advocate for the need of large-scale, harmonized, collaborative efforts that explicitly account for the time-varying nature of epigenetic and mental health data across development. We conclude with a perspective on what the future may hold in terms of translational applications as more robust signals emerge from epigenetic research on child and adolescent mental health.

Epigenetic Reprogramming and Landscape of Transcriptomic Interactions: Impending Therapeutic Interference of Triple-Negative Breast Cancer in Molecular Medicine.

The mechanisms governing the development and progression of cancers are believed to be the consequence of hereditary deformities and epigenetic modifications. Accordingly, epigenetics has become an incredible and progressively explored field of research to discover better prevention and therapy for neoplasia, especially triple-negative breast cancer (TNBC). It represents 15-20% of all invasive breast cancers and will, in general, have bellicose histological highlights and poor clinical outcomes. In the early phases of triple-negative breast carcinogenesis, epigenetic deregulation modifies chromatin structure and influences the plasticity of cells. It up-keeps the oncogenic reprogramming of malignant progenitor cells with the acquisition of unrestrained selfrenewal capacities. Genomic impulsiveness in TNBC prompts mutations, copy number variations, as well as genetic rearrangements, while epigenetic remodeling includes an amendment by DNA methylation, histone modification, and noncoding RNAs of gene expression profiles. It is currently evident that epigenetic mechanisms assume a significant part in the pathogenesis, maintenance, and therapeutic resistance of TNBC. Although TNBC is a heterogeneous malaise that is perplexing to describe and treat, the ongoing explosion of genetic and epigenetic research will help to expand these endeavors. Latest developments in transcriptome analysis have reformed our understanding of human diseases, including TNBC at the molecular medicine level. It is appealing to envision transcriptomic biomarkers to comprehend tumor behavior more readily regarding its cellular microenvironment. Understanding these essential biomarkers and molecular changes will propel our capability to treat TNBC adequately. This review will depict the different aspects of epigenetics and the landscape of transcriptomics in triple-negative breast carcinogenesis and their impending application for diagnosis, prognosis, and treatment decision with the view of molecular medicine.

Machine learning‐based prediction of cognitive outcomes in de novo Parkinson's disease

AbstractBackgroundCognitive impairment is a debilitating symptom in Parkinson’s disease (PD), with high variability in onset and course of progression. This present study aimed to establish an accurate multivariate machine learning model to predict cognitive outcome in newly diagnosed PD.MethodUsing baseline measures from the Parkinson’s Progression Markers Initiative (PPMI) cohort we subset clinical, biofluid and genetic/epigenetic variables. Annual cognitive assessments over an eight‐year time span were used to define two outcomes of i) dementia conversion, and ii) cognitive impairment. Outcomes and variable subsets were tested using multiple machine learning (ML) algorithms (random forest, elasticnet, SVM‐linear and cforest) to predict prognosis of individual cognitive decline in PD. Prediction was assessed using multiple measures including Area under the Curve (AUC) and Mathews Correlation Coefficient (MCC).ResultFor both cognitive outcomes, irrespective of the of ML algorithm, models consisting of clinical variables alone performed best, with high specificity and the largest AUC's (0.88 ‐ 0.92) and MCC's (0.57‐0.80). Notably, cognitive impairment outcome showed better sensitivity than dementia conversion outcome (0.72 – 0.81 vs 0.29 – 0.64, respectively). Addition of biological and genetic variables did not largely improve the model performance. However, a number of cerebrospinal fluid (CSF) proteins and epigenetic markers showed high predictive weighting in multiple models, when included alongside clinical variables.ConclusionMachine learning algorithms can accurately predict cognitive impairment development in PD. Within the generated models, clinical predictors appear to play a more prominent role than biological predictors. We further present additional future study data, expanding epigenetic research into PD dementia.