scholarly journals Integration of sperm ncRNA-directed DNA methylation and DNA methylation-directed histone retention in epigenetic transgenerational inheritance

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Daniel Beck ◽  
Millissia Ben Maamar ◽  
Michael K. Skinner
Keyword(s):  
Dna Methylation ◽  
Potential Role ◽  
Epigenetic Alterations ◽  
Adult Males ◽  
Transgenerational Inheritance ◽  
Non Coding Rna ◽  
F2 Generation ◽  
Genetic Form ◽  
F1 Generation ◽  
Epigenetic Processes

Abstract Background Environmentally induced epigenetic transgenerational inheritance of pathology and phenotypic variation has been demonstrated in all organisms investigated from plants to humans. This non-genetic form of inheritance is mediated through epigenetic alterations in the sperm and/or egg to subsequent generations. Although the combined regulation of differential DNA methylated regions (DMR), non-coding RNA (ncRNA), and differential histone retention (DHR) have been shown to occur, the integration of these different epigenetic processes remains to be elucidated. The current study was designed to examine the integration of the different epigenetic processes. Results A rat model of transiently exposed F0 generation gestating females to the agricultural fungicide vinclozolin or pesticide DDT (dichloro-diphenyl-trichloroethane) was used to acquire the sperm from adult males in the subsequent F1 generation offspring, F2 generation grand offspring, and F3 generation great-grand offspring. The F1 generation sperm ncRNA had substantial overlap with the F1, F2 and F3 generation DMRs, suggesting a potential role for RNA-directed DNA methylation. The DMRs also had significant overlap with the DHRs, suggesting potential DNA methylation-directed histone retention. In addition, a high percentage of DMRs induced in the F1 generation sperm were maintained in subsequent generations. Conclusions Many of the DMRs, ncRNA, and DHRs were colocalized to the same chromosomal location regions. Observations suggest an integration of DMRs, ncRNA, and DHRs in part involve RNA-directed DNA methylation and DNA methylation-directed histone retention in epigenetic transgenerational inheritance.

scholarly journals Transgenerational inheritance of BPA-induced obesity correlates with transmission of new CTCF sites in the Fto gene

2020 ◽  
Author(s):  
Victor Corces ◽  
Yoon Jung ◽  
Brianna Bixler ◽  
Daniel Ruiz ◽  
Hsiao-Lin Wang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Pregnant Mouse ◽  
Chromatin Accessibility ◽  
Epigenetic Alterations ◽  
Transgenerational Inheritance ◽  
Fto Gene ◽  
Intergenic Regions ◽  
F2 Progeny ◽  
Additional Exposure ◽  
F1 Generation

Abstract The mechanisms by which epiphenotypes are transmitted transgenerationally through the parental germlines are poorly understood. Here we show that exposure of pregnant mouse F0 females during E7.5-E13.5 to bisphenol A results in obesity in the F2 progeny in the absence of additional exposure. This epiphenotype can be transmitted through the male and female germlines up to the F5 generation, decreases in F6, and disappears in F7. Analyses of chromatin changes in the sperm of the F1 generation reveal a widespread increase in chromatin accessibility at binding sites for CTCF and other transcription factors accompanied by alterations in 3D organization. Comparison of the transmission of obesity between F2 and F5 and its disappearance in F7 with alterations in the binding of these transcription factors points to the activation of two enhancers located in intronic and intergenic regions of the Fto gene as the cause of transgenerational inheritance. These enhancers form an autoregulatory feedback loop that, in combination with a decrease of m6A in sperm RNAs, may cause alterations of gene expression in the embryo after fertilization. Given the established involvement of SNPs in FTO in human obesity, the results suggest that both genetic and epigenetic alterations of the same gene can lead to the same phenotypic outcomes on human health.

scholarly journals The Epigenetic Landscape of Vascular Calcification: An Integrative Perspective

2020 ◽  
Vol 21 (3) ◽  
pp. 980 ◽  
Author(s):  
Yi-Chou Hou ◽  
Chien-Lin Lu ◽  
Tzu-Hang Yuan ◽  
Min-Tser Liao ◽  
Chia-Ter Chao ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Histone Modification ◽  
Vascular Calcification ◽  
Calcium Deposition ◽  
Non Coding Rna ◽  
Physico Chemical ◽  
Variable Combination ◽  
Epigenetic Signatures ◽  
Epigenetic Processes

Vascular calcification (VC) is an important complication among patients of advanced age, those with chronic kidney disease, and those with diabetes mellitus. The pathophysiology of VC encompasses passive occurrence of physico-chemical calcium deposition, active cellular secretion of osteoid matrix upon exposure to metabolically noxious stimuli, or a variable combination of both processes. Epigenetic alterations have been shown to participate in this complex environment, through mechanisms including DNA methylation, non-coding RNAs, histone modifications, and chromatin changes. Despite such importance, existing reviews fail to provide a comprehensive view of all relevant reports addressing epigenetic processes in VC, and cross-talk between different epigenetic machineries is rarely examined. We conducted a systematic review based on PUBMED and MEDLINE databases up to 30 September 2019, to identify clinical, translational, and experimental reports addressing epigenetic processes in VC; we retrieved 66 original studies, among which 60.6% looked into the pathogenic role of non-coding RNA, followed by DNA methylation (12.1%), histone modification (9.1%), and chromatin changes (4.5%). Nine (13.6%) reports examined the discrepancy of epigenetic signatures between subjects or tissues with and without VC, supporting their applicability as biomarkers. Assisted by bioinformatic analyses blending in each epigenetic component, we discovered prominent interactions between microRNAs, DNA methylation, and histone modification regarding potential influences on VC risk.

scholarly journals CRUCIAL CHALLENGES IN EPIGENETIC CANCER THERAPEUTIC STRATEGY YET TO BE RESOLVED

2016 ◽  
Vol 8 (12) ◽  
pp. 1 ◽  
Author(s):  
Md. Torequl Islam
Keyword(s):  
Dna Methylation ◽  
Therapeutic Strategy ◽  
Short Note ◽  
Therapeutic Interventions ◽  
Epigenetic Alterations ◽  
Genetic Pathways ◽  
Non Coding Rna ◽  
Small Ncrnas ◽  
Epigenetic Machinery ◽  
Novel Strategy

<p>Cancer is considered by both genetic and epigenetic pathways. Although, genetic pathways are straightforward, but the reversibility and numerous unclear talks make epigenetic pathway complicated. DNA methylation, histone modifications and non-coding RNA (ncRNA) mediated gene silencing are the three known consequences in epigenetic alterations. In this context, small ncRNAs such as microRNA are known to regulate various components of cellular epigenetic machinery by up or down-regulating in pathogenesis; those are already known in a number of pathophysiological states. These types of biomarkers can be used in the diagnosis and therapeutic interventions in some instances. Although some epigenetic therapies have been introduced, but a number of challenges in each case are remarkable, encouraging more researchers in this field of novel strategy. This paper will discuss a short note on epigenetics and epigenetic therapeutic interventions along with crucial challenges yet to be resolved.</p>

scholarly journals Alterations in sperm DNA methylation, non-coding RNA and histone retention associate with DDT-induced epigenetic transgenerational inheritance of disease

2018 ◽  
Vol 11 (1) ◽  
Author(s):  
Michael K. Skinner ◽  
Millissia Ben Maamar ◽  
Ingrid Sadler-Riggleman ◽  
Daniel Beck ◽  
Eric Nilsson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transgenerational Inheritance ◽  
Non Coding Rna ◽  
Sperm Dna ◽  
Sperm Dna Methylation

scholarly journals Ovarian cancer: epigenetics, drug resistance, and progression

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Weiwei Xie ◽  
Huizhen Sun ◽  
Xiaoduan Li ◽  
Feikai Lin ◽  
Ziliang Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Methylation ◽  
Dna Sequences ◽  
Histone Deacetylase Inhibitors ◽  
Malignant Tumors ◽  
Clinical Investigation ◽  
Cancer Epigenetics ◽  
Novel Approach ◽  
Non Coding Rna ◽  
Epigenetic Processes

AbstractOvarian cancer (OC) is one of the most common malignant tumors in women. OC is associated with the activation of oncogenes, the inactivation of tumor suppressor genes, and the activation of abnormal cell signaling pathways. Moreover, epigenetic processes have been found to play an important role in OC tumorigenesis. Epigenetic processes do not change DNA sequences but regulate gene expression through DNA methylation, histone modification, and non-coding RNA. This review comprehensively considers the importance of epigenetics in OC, with a focus on microRNA and long non-coding RNA. These types of RNA are promising molecular markers and therapeutic targets that may support precision medicine in OC. DNA methylation inhibitors and histone deacetylase inhibitors may be useful for such targeting, with a possible novel approach combining these two therapies. Currently, the clinical application of such epigenetic approaches is limited by multiple obstacles, including the heterogeneity of OC, insufficient sample sizes in reported studies, and non-optimized methods for detecting potential tumor markers. Nonetheless, the application of epigenetic approaches to OC patient diagnosis, treatment, and prognosis is a promising area for future clinical investigation.

scholarly journals Epigenetic Biomarkers for the Diagnosis and Treatment of Liver Disease

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1265
Author(s):  
María Arechederra ◽  
Miriam Recalde ◽  
María Gárate-Rascón ◽  
Maite G. Fernández-Barrena ◽  
Matías A. Ávila ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Liver Disease ◽  
Therapeutic Strategy ◽  
Therapeutic Strategies ◽  
Epigenetic Alterations ◽  
Post Translational Modifications ◽  
Epigenetic Marks ◽  
Diagnosis And Prognosis ◽  
Epigenetic Biomarkers ◽  
Non Coding Rna

Research in the last decades has demonstrated the relevance of epigenetics in controlling gene expression to maintain cell homeostasis, and the important role played by epigenome alterations in disease development. Moreover, the reversibility of epigenetic marks can be harnessed as a therapeutic strategy, and epigenetic marks can be used as diagnosis biomarkers. Epigenetic alterations in DNA methylation, histone post-translational modifications (PTMs), and non-coding RNA (ncRNA) expression have been associated with the process of hepatocarcinogenesis. Here, we summarize epigenetic alterations involved in the pathogenesis of chronic liver disease (CLD), particularly focusing on DNA methylation. We also discuss their utility as epigenetic biomarkers in liquid biopsy for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Finally, we discuss the potential of epigenetic therapeutic strategies for HCC treatment.

scholarly journals Generational comparisons (F1 versus F3) of vinclozolin induced epigenetic transgenerational inheritance of sperm differential DNA methylation regions (epimutations) using MeDIP-Seq

2017 ◽  
Vol 3 (3) ◽  
Author(s):  
Daniel Beck ◽  
Ingrid Sadler-Riggleman ◽  
Michael K. Skinner
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Bioinformatic Analysis ◽  
Female Rat ◽  
Transgenerational Inheritance ◽  
Methylated Dna ◽  
Epigenetic Programming ◽  
Direct Exposure ◽  
Generation Sequencing ◽  
F1 Generation

Abstract Environmentally induced epigenetic transgenerational inheritance of disease and phenotypic variation has been shown to involve DNA methylation alterations in the germline (e.g. sperm). These differential DNA methylation regions (DMRs) are termed epimutations and in part transmit the transgenerational phenotypes. The agricultural fungicide vinclozolin exposure of a gestating female rat has previously been shown to promote transgenerational disease and epimutations in F3 generation (great-grand-offspring) animals. The current study was designed to investigate the actions of direct fetal exposure on the F1 generation rat sperm DMRs compared to the F3 transgenerational sperm DMRs. A protocol involving methylated DNA immunoprecipitation (MeDIP) followed by next-generation sequencing (Seq) was used in the current study. Bioinformatics analysis of the MeDIP-Seq data was developed and several different variations in the bioinformatic analysis were evaluated. Observations indicate needs to be considered. Interestingly, the F1 generation DMRs were found to be fewer in number and for the most part distinct from the F3 generation epimutations. Observations suggest the direct exposure induced F1 generation sperm DMRs appear to promote in subsequent generations alterations in the germ cell developmental programming that leads to the distinct epimutations in the F3 generation. This may help explain the differences in disease and phenotypes between the direct exposure F1 generation and transgenerational F3 generation. Observations demonstrate a distinction between the direct exposure versus transgenerational epigenetic programming induced by environmental exposures and provide insights into the molecular mechanisms involved in the epigenetic transgenerational inheritance phenomenon.

scholarly journals Transgenerational inheritance of BPA-induced obesity correlates with transmission of new CTCF sites in the Fto gene

2020 ◽  
Author(s):  
Yoon Hee Jung ◽  
Brianna J. Bixler ◽  
Daniel Ruiz ◽  
Hsiao-Lin V. Wang ◽  
Hannah Linsenbaum ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Binding Sites ◽  
Pregnant Mouse ◽  
Chromatin Accessibility ◽  
Epigenetic Alterations ◽  
Transgenerational Inheritance ◽  
Fto Gene ◽  
F2 Progeny ◽  
Additional Exposure ◽  
F1 Generation

AbstractThe mechanisms by which epiphenotypes are transmitted transgenerationally through the parental germlines are poorly understood. Here we show that exposure of pregnant mouse F0 females during E7.5-E13.5 to bisphenol A results in obesity in the F2 progeny in the absence of additional exposure. This epiphenotype can be transmitted through the male and female germlines up to the F5 generation, decreases in F6, and disappears in F7. Analysis of chromatin changes in the sperm of the F1 generation reveals a widespread increase in chromatin accessibility at binding sites for CTCF and other transcription factors accompanied by alterations in 3D organization. Comparison of the transmission of obesity between F2 and F5 and its disappearance in F7 with alterations in the binding of these transcription factors points to the activation of an enhancer in an intron of the Fto gene as the cause of transgenerational inheritance. Activation of the Fto enhancer results in a decrease of m6A in sperm RNAs, which may result in alterations of gene expression in the embryo after fertilization. Given the established involvement of SNPs in FTO in human obesity, the results suggest that both genetic and epigenetic alterations of the same gene can lead to the same phenotypic outcomes on human health.

scholarly journals Targeting Epigenetic Modifications in Uveal Melanoma

2020 ◽  
Vol 21 (15) ◽  
pp. 5314
Author(s):  
Pooneh Chokhachi Baradaran ◽  
Zuzana Kozovska ◽  
Alena Furdova ◽  
Bozena Smolkova
Keyword(s):  
Dna Methylation ◽  
Uveal Melanoma ◽  
Histone Modifications ◽  
Tumor Suppressor Genes ◽  
Primary Therapy ◽  
Epigenetic Alterations ◽  
Combination Therapies ◽  
Non Coding Rna ◽  
Aberrant Dna Methylation ◽  
New Generation

Uveal melanoma (UM), the most common intraocular malignancy in adults, is a rare subset of melanoma. Despite effective primary therapy, around 50% of patients will develop the metastatic disease. Several clinical trials have been evaluated for patients with advanced UM, though outcomes remain dismal due to the lack of efficient therapies. Epigenetic dysregulation consisting of aberrant DNA methylation, histone modifications, and small non-coding RNA expression, silencing tumor suppressor genes, or activating oncogenes, have been shown to play a significant role in UM initiation and progression. Given that there is no evidence any approach improves results so far, adopting combination therapies, incorporating a new generation of epigenetic drugs targeting these alterations, may pave the way for novel promising therapeutic options. Furthermore, the fusion of effector enzymes with nuclease-deficient Cas9 (dCas9) in clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) system equips a potent tool for locus-specific erasure or establishment of DNA methylation as well as histone modifications and, therefore, transcriptional regulation of specific genes. Both, CRISPR-dCas9 potential for driver epigenetic alterations discovery, and possibilities for their targeting in UM are highlighted in this review.

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