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Genome-wide hydroxymethylcytosine pattern changes in response to oxidative stress

ABSTRACT: The TET-family enzymes (TETs) convert methylcytosine to hydroxymethylcytosine, a lately discovered epigenetic modification that can modulate transcription. While recent reports suggest that TETs may play a role in response to oxidative stress, this role remains uncertain. Here we show that Tet1 is sensitive to peroxide and report a global decrease in hydroxymethylcytosine in cells treated with BSO and in the intestinal epithelium of mice lacking the major antioxidant enzymes glutathione peroxidases 1 and 2. Furthermore, genome-wide profiling revealed differentially hydroxymethylated regions in genes involved in responses to oxidative stress. Intriguingly, a considerable proportion of these regions lie in genes encoding microRNAs predicted to target transcripts involved in oxidative stress response. This work thus demonstrates a profound effect of oxidative stress on the hydroxymethylome and opens exciting new avenues of research by highlighting a set of microRNAs that may participate in the prevention or etiology of oxidative-stress-related diseases. Examination of DNA hydroxymethylation landscape in SY5Y cell lines and in intestinal epithelium of mice.

ORGANISM(S): Homo sapiens

SUBMITTER: Matthieu Defrance

PROVIDER: E-GEOD-59718 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genome-wide hydroxymethylcytosine pattern changes in response to oxidative stress

Project description:The TET-family enzymes (TETs) convert methylcytosine to hydroxymethylcytosine, a lately discovered epigenetic modification that can modulate transcription. While recent reports suggest that TETs may play a role in response to oxidative stress, this role remains uncertain. Here we show that Tet1 is sensitive to peroxide and report a global decrease in hydroxymethylcytosine in cells treated with BSO and in the intestinal epithelium of mice lacking the major antioxidant enzymes glutathione peroxidases 1 and 2. Furthermore, genome-wide profiling revealed differentially hydroxymethylated regions in genes involved in responses to oxidative stress. Intriguingly, a considerable proportion of these regions lie in genes encoding microRNAs predicted to target transcripts involved in oxidative stress response. This work thus demonstrates a profound effect of oxidative stress on the hydroxymethylome and opens exciting new avenues of research by highlighting a set of microRNAs that may participate in the prevention or etiology of oxidative-stress-related diseases.

2016-01-14 | GSE59718 | GEO

Expression data from intestinal epithelium

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Autophagy maintains intestinal stem cell integrity

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5-hydroxymethylcytosine and gene activity in mouse intestinal differentiation (RNA-Seq).

Project description:Background: Cytosine hydroxymethylation (5hmC) was recently identified in mammalian DNA as the product of oxidation of methylated cytosines (5mC) by Ten-Eleven-Translocation (TET) enzymes. The TETs have been shown to influence 5mC metabolism, pluripotency and differentiation during early embryonic development. However, a functional relationship between gene expression and 5hmC in adult (somatic) stem cell differentiation is however mainly unknown. To explore the role of this novel DNA modification in adult stem cell differentiation we profiled 5hmC and gene activity in purified mouse intestinal progenitors and differentiated progeny. Results: We show that the hydroxymethylome is highly dynamic with tens of thousands of differentially hydroxymethylated regions between progenitors and differentiated progeny. In progenitors 5hmC does not correlate with gene expression levels, however, upon differentiation a global increase in 5hmC is observed with an overall positive correlation between 5hmC and gene expression together with prominent associations with histone modifications that typify active genes and enhancer elements. Conclusions: In the context of recent evidence of near identical methylomes between mouse intestinal stem and differentiated cells, our data imply that a gene regulatory role for 5hmC is predominant over its role in controlling DNA methylation states. Our study provides an insight into the dynamics of 5hmC and of epigenetic machineries in differentiation of the mouse intestine.

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5-hydroxymethylcytosine and gene activity in mouse intestinal differentiation (hmeDIP-seq).

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Intestinal stem cell differentiation is associated with dynamic changes in the chromatin landscape [5hmc-seal-seq]

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TET-dependent regulation of retrotransposable elements in mouse embryonic stem cells [small RNA-seq]

Project description:TET enzymes oxidise DNA methylation as part of an active demethylation pathway. Despite extensive research into the role of TETs in genome regulation, little is known about their effect on transposable elements (TEs), which make up nearly half of the mouse and human genomes. Epigenetic mechanisms controlling TEs have the potential to affect their mobility and to drive the co-adoption of TEs for the benefit of the host. We have performed a detailed investigation of the role of TET enzymes in the regulation of TEs in mouse embryonic stem cells (ESCs). We found that TET1 and TET2 bind multiple TE classes that harbour a variety of epigenetic signatures indicative of different functional roles. Namely, TETs co-bind with pluripotency factors to enhancer-like TEs that interact with highly expressed genes in ESCs, whose expression is partly maintained by the demethylating action of TET2. TETs and 5-hydroxymethylcytosine are also strongly enriched at the 5’ UTR of full-length, evolutionarily young LINE1 elements, a pattern that is conserved in human embryonic stem cells. TET depletion leads to a marked increase in DNA methylation levels at LINE1s, but surprisingly their expression is stably maintained through additional TET-dependent activities. Specifically, we find that TET1 recruits the SIN3A co-repressive complex to LINE1s, ensuring their repression upon TET-driven hypomethylation. This dual nature of TET action may reflect the evolutionary battle between TEs and the host. Our data implicate TET enzymes in the evolutionary dynamics of TEs, both in the context of exaptation processes and of retrotransposition control.

2016-10-28 | GSE84459 | GEO

TET-dependent regulation of retrotransposable elements in mouse embryonic stem cells [RNA-seq]

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Exploring the epigenetic landscape of spermatozoa: impact of oxidative stress and antioxidant supplementation on DNA methylation and hydroxymethylation

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Genome-wide hydroxymethylcytosine pattern changes in response to oxidative stress

Project description:Genome-wide hydroxymethylcytosine pattern changes in response to oxidative stress

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