Trichloroethylene exposure alters dimethylated histone three lysine four in protein kinase A signaling pathway chromatin of rat sperm†

Abstract Histone three lysine four dimethylation (H3k4me2) in sperm is conserved across species and is linked to transgenerational epigenetic inheritance. To test whether H3K4me2 is a target for transgenerational inheritance of toxicity, a daily gavage bolus exposure of trichloroethylene (TCE) (1000 mg/kg/day) was given to rats for 14 weeks, then epididymal sperm were isolated and native chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) of H3K4me2 was performed. Differential region analysis determined there were 2608 significantly differential H3K4me2 regions after TCE exposure, 477 were significantly increased and 2131 were significantly decreased. Z-score enrichment of differential regions determined there were significantly decreased H3k4me2 in the coding and regulatory regions of genes in the PKA signaling pathway. These changes account for TCE induced spermatozoal toxicity and show H3K4me2 is a target for paternal inheritance of toxicity.

Download Full-text

Sperm histone H3 lysine 4 trimethylation is altered in a genetic mouse model of transgenerational epigenetic inheritance

Nucleic Acids Research ◽

10.1093/nar/gkaa712 ◽

2020 ◽

Vol 48 (20) ◽

pp. 11380-11393

Author(s):

Ariane Lismer ◽

Keith Siklenka ◽

Christine Lafleur ◽

Vanessa Dumeaux ◽

Sarah Kimmins

Keyword(s):

Mouse Model ◽

Chromatin Immunoprecipitation ◽

Complex Disease ◽

Histone H3 ◽

Epigenetic Inheritance ◽

Paternal Allele ◽

Chromatin Signature ◽

Transgenerational Epigenetic Inheritance ◽

Genetic Mouse Model ◽

Sperm Counts

Abstract Advancing the molecular knowledge surrounding fertility and inheritance has become critical given the halving of sperm counts in the last 40 years, and the rise in complex disease which cannot be explained by genetics alone. The connection between both these trends may lie in alterations to the sperm epigenome and occur through environmental exposures. Changes to the sperm epigenome are also associated with health risks across generations such as metabolic disorders and cancer. Thus, it is imperative to identify the epigenetic modifications that escape reprogramming during spermatogenesis and embryogenesis. Here, we aimed to identify the chromatin signature(s) involved in transgenerational phenotypes in our genetic mouse model of epigenetic inheritance that overexpresses the histone demethylase KDM1A in their germ cells. We used sperm-specific chromatin immunoprecipitation followed by in depth sequencing (ChIP-seq), and computational analysis to identify whether differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3), and histone H3 lysine 27 trimethylation (H3K27me3) serve as mechanisms for transgenerational epigenetic inheritance through the paternal germline. Our analysis on the sperm of KDM1A transgenic males revealed specific changes in H3K4me3 enrichment that predominantly occurred independently from bivalent H3K4me3/H3K27me3 regions. Many regions with altered H3K4me3 enrichment in sperm were identified on the paternal allele of the pre-implantation embryo. These findings suggest that sperm H3K4me3 functions in the transmission of non-genetic phenotypes transgenerationally.

Download Full-text

Transgenerational epigenetic inheritance: resolving uncertainty and evolving biology

BioMolecular Concepts ◽

10.1515/bmc-2015-0005 ◽

2015 ◽

Vol 6 (2) ◽

pp. 87-103 ◽

Cited By ~ 15

Author(s):

Abhay Sharma

Keyword(s):

Epigenetic Inheritance ◽

Integrative Model ◽

Evolutionary Significance ◽

Information Propagation ◽

Transgenerational Inheritance ◽

Epigenetic Memory ◽

Transgenerational Epigenetic Inheritance ◽

Fundamental Challenge ◽

Experimental Findings

AbstractTransgenerational epigenetic inheritance in animals has increasingly been reported in recent years. Controversies, however, surround this unconventional mode of heredity, especially in mammals, for several reasons. First, its existence itself has been questioned due to perceived insufficiency of available evidence. Second, it potentially implies transfer of hereditary information from soma to germline, against the established principle in biology. Third, it inherently requires survival of epigenetic memory across reprogramming, posing another fundamental challenge in biology. Fourth, evolutionary significance of epigenetic inheritance has also been under debate. This article pointwise addresses all these concerns on the basis of recent empirical, theoretical and conceptual advances. 1) Described here in detail are the key experimental findings demonstrating the occurrence of germline epigenetic inheritance in mammals. 2) Newly emerging evidence supporting soma to germline communication in transgenerational inheritance in mammals, and a role of exosome and extracellular microRNA in this transmission, is thoroughly discussed. 3) The plausibility of epigenetic information propagation across reprogramming is highlighted. 4) Analyses supporting evolutionary significance of epigenetic inheritance are briefly mentioned. Finally, an integrative model of ‘evolutionary transgenerational systems biology’ is proposed to provide a framework to guide future advancements in epigenetic inheritance.

Download Full-text

Transgenerational inheritance of epigenetic traits

Epigenetics, Nuclear Organization & Gene Function ◽

10.1093/oso/9780198831204.003.0019 ◽

2019 ◽

pp. 213-224

Author(s):

John C. Lucchesi

Keyword(s):

Cardiovascular Disease ◽

Dna Methylation ◽

Histone Methylation ◽

Physiological Stress ◽

Adult Life ◽

Epigenetic Inheritance ◽

Transgenerational Inheritance ◽

Early Postnatal Development ◽

Transgenerational Epigenetic Inheritance ◽

Non Coding Rnas

Aberrant nutrition during pregnancy or in early postnatal development can result in obesity, diabetes, cardiovascular disease, defective cognition or psychopathologies in adult life. In some cases, the epigenetic modifications responsible for these effects can be transmitted to descendants who have not been exposed to the same environmental factors as their parents. Examples range from the transgenerational inheritance of conditions caused by physiological stress and exposure to endocrine disruptors, and behavioral and psychiatric effects. Transgenerational inheritance has been correlated with changes in DNA or histone methylation. The transmission of methylated DNA signals faces the problem of reprogramming in the germline. A few of the signals that protect imprinted regions for demethylation have been identified. Small non-coding RNAs such as piwi-interacting RNAs (piRNAs) and fragments of tRNAs are clearly involved at some level in transgenerational epigenetic inheritance. This is particularly the case in organisms such as flies and worms that lack DNA methylation.

Download Full-text

Environmentally-Induced Transgenerational Epigenetic Inheritance: Implication of PIWI Interacting RNAs

Cells ◽

10.3390/cells8091108 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1108 ◽

Cited By ~ 5

Author(s):

Karine Casier ◽

Antoine Boivin ◽

Clément Carré ◽

Laure Teysset

Keyword(s):

Small Rnas ◽

Epigenetic Inheritance ◽

Disease Development ◽

Epigenetic Mechanisms ◽

Transgenerational Inheritance ◽

Epigenetic Memory ◽

Transgenerational Epigenetic Inheritance ◽

Open Questions ◽

Sporadic Disease

Environmentally-induced transgenerational epigenetic inheritance is an emerging field. The understanding of associated epigenetic mechanisms is currently in progress with open questions still remaining. In this review, we present an overview of the knowledge of environmentally-induced transgenerational inheritance and associated epigenetic mechanisms, mainly in animals. The second part focuses on the role of PIWI-interacting RNAs (piRNAs), a class of small RNAs involved in the maintenance of the germline genome, in epigenetic memory to put into perspective cases of environmentally-induced transgenerational inheritance involving piRNA production. Finally, the last part addresses how genomes are facing production of new piRNAs, and from a broader perspective, how this process might have consequences on evolution and on sporadic disease development.

Download Full-text

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

Biochemical Society Transactions ◽

10.1042/bst20190944 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1019-1034 ◽

Cited By ~ 1

Author(s):

Rachel M. Woodhouse ◽

Alyson Ashe

Keyword(s):

Histone Modifications ◽

Molecular Mechanisms ◽

Epigenetic Inheritance ◽

Nematode Caenorhabditis Elegans ◽

Histone Methyltransferases ◽

Transgenerational Epigenetic Inheritance ◽

C Elegans ◽

Recent Developments ◽

Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

Download Full-text