Dataset Information

Tertiary Epimutations - A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability.

ABSTRACT: Exposure to environmental factors can induce the epigenetic transgenerational inheritance of disease. Alterations to the epigenome termed "epimutations" include "primary epimutations" which are epigenetic alterations in the absence of genetic change and "secondary epimutations" which form following an initial genetic change. To determine if secondary epimutations contribute to transgenerational transmission of disease following in utero exposure to the endocrine disruptor vinclozolin, we exposed pregnant female rats carrying the lacI mutation-reporter transgene to vinclozolin and assessed the frequency of mutations in kidney tissue and sperm recovered from F1 and F3 generation progeny. Our results confirm that vinclozolin induces primary epimutations rather than secondary epimutations, but also suggest that some primary epimutations can predispose a subsequent accelerated accumulation of genetic mutations in F3 generation descendants that have the potential to contribute to transgenerational phenotypes. We therefore propose the existence of "tertiary epimutations" which are initial primary epimutations that promote genome instability leading to an accelerated accumulation of genetic mutations.

SUBMITTER: McCarrey JR

PROVIDER: S-EPMC5167269 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Tertiary Epimutations - A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability.

McCarrey John R JR Lehle Jake D JD Raju Seetha S SS Wang Yufeng Y Nilsson Eric E EE Skinner Michael K MK

PloS one 20161219 12

Exposure to environmental factors can induce the epigenetic transgenerational inheritance of disease. Alterations to the epigenome termed "epimutations" include "primary epimutations" which are epigenetic alterations in the absence of genetic change and "secondary epimutations" which form following an initial genetic change. To determine if secondary epimutations contribute to transgenerational transmission of disease following in utero exposure to the endocrine disruptor vinclozolin, we exposed ...[more]

PMID: 27992467

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Project description:Epigenetic inheritance is the transmission of altered gene expression states across dividing cells without DNA sequence variation. Induced epigenetic changes (epimutations) have been extensively studied, but importantly, epimutations also occur spontaneously in a manner reminiscent of DNA sequence change. Small RNAs are established as a source of spontaneous epimutations which transmit gene expression changes over multiple generations in C.elegans. These changes are generally short lived, but rarely long-lived changes occur. Given that chromatin state is a critical regulator of gene expression, we explored whether chromatin states also undergo spontaneous change and whether this could be a potential alternative mechanism for transgenerational epigenetic inheritance. We compared the chromatin profiles and gene expression profiles at matched time points from a twenty generation bottlenecked lineage of C.elegans. We found that heritable changes in gene expression arose at a higher rate than the estimate for DNA sequence variation, indicating that these were true epigenetic events. In addition to recapitulating the known role for small RNAs, we provide evidence for chromatin mediated epimutations as an alternative mechanism driving epigenetic inheritance. Chromatin epimutations were heritable, enriched in the germline and synchronised with inherited gene expression changes. As with small RNA mediated epimutations, they were generally short lived with a tendency to resolve to baseline after 2-3 generations. A subset of chromatin epimutations however were long lasting, and these were uniquely enriched in piRNA clusters. Genes with long lived epimutations were implicated in multiple components of xenobiotic response pathways. This points to a mechanism for epigenetic ‘anticipation’ of environmental stressors. Adaptive traits driven by epimutations may be selected for under adverse conditions and lost on return to normal conditions, enabling soft adaptation in the absence of genetic sequence change.

Dataset Information

Tertiary Epimutations - A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability.

Publications

Tertiary Epimutations - A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability.

Similar Datasets

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