TET-dependent regulation of retrotransposable elements in mouse embryonic stem cells.

Lorenzo De La Rica,Kevin C L Cheng,Christopher D Todd,Jonathan Houseley,Cristina Cruz,Miguel R Branco,Özgen Deniz

doi:10.1186/s13059-016-1096-8

Lorenzo De La Rica, Kevin C L Cheng + Show 5 more

Open Access

https://doi.org/10.1186/s13059-016-1096-8

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Abstract

BackgroundTen-eleven translocation (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.ResultsWe performed a detailed investigation of the role of TET enzymes in the regulation of TEs in mouse embryonic stem cells (ESCs). We find that TET1 and TET2 bind multiple TE classes that harbour a variety of epigenetic signatures indicative of different functional roles. TETs co-bind with pluripotency factors to enhancer-like TEs that interact with highly expressed genes in ESCs whose expression is partly maintained by TET2-mediated DNA demethylation. TETs and 5-hydroxymethylcytosine (5hmC) are also strongly enriched at the 5′ UTR of full-length, evolutionarily young LINE-1 elements, a pattern that is conserved in human ESCs. TETs drive LINE-1 demethylation, but surprisingly, LINE-1s are kept repressed through additional TET-dependent activities. We find that the SIN3A co-repressive complex binds to LINE-1s, ensuring their repression in a TET1-dependent manner.ConclusionsOur data implicate TET enzymes in the evolutionary dynamics of TEs, both in the context of exaptation processes and of retrotransposition control. The dual role of TET action on LINE-1s may reflect the evolutionary battle between TEs and the host.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1096-8) contains supplementary material, which is available to authorized users.

Highlights

Ten-eleven translocation (TET) enzymes oxidise DNA methylation as part of an active demethylation pathway
TET1 binds to repetitive elements with diverse chromatin signatures Previous studies have established that TET1 primarily binds at CpG-rich gene promoters in mouse embryonic stem cells (ESCs) [28, 30]
To test whether TET1 binds to particular repeat classes, we uniquely mapped chromatin immunoprecipitation (ChIP) sequencing data [28] and calculated the proportion of TET1 peaks that overlapped each repeat class within the RepeatMasker annotation

Summary

Introduction

Ten-eleven translocation (TET) enzymes oxidise DNA methylation as part of an active demethylation pathway. Somatic retrotransposition of L1s has been linked to disease, especially in the context of cancer [9, 10] Mobility restriction of these de la Rica et al Genome Biology (2016) 17:234 elements is of paramount importance to maintain genome stability, especially during the crucial developmental windows of germline establishment and early embryogenesis. Both human ESCs and induced pluripotent stem cells (iPSCs) support L1 mobility [11] and de novo retrotransposition events from endogenous TEs have been detected in clonally derived iPSCs [12], with important implications for regenerative medicine strategies

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