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

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.

TET enzymes: double agents in the transposable element–host genome conflict

“…Noting that the field lacked a comprehensive analysis of TET interaction with TE sequences, de la Rica and colleagues [4] mined ChIP-seq data to determine the distribution of TET1 peaks at distinct TE classes. Their analysis revealed significant enrichment of TET1 at L1s and several types of LTR retrotransposons, suggesting that TET1 may have a widespread role in TE regulation.…”

“…De la Rica and colleagues [4] also observed that TET1 peaks at LTR elements were associated with active enhancer marks, as well as the pluripotency factors NANOG, OCT4, and SOX2 (collectively referred to as NOS). This observation is consistent with the occupied TE sequences acting as enhancers, and led to the hypothesis that TET proteins have a role in TE-derived enhancer function, important for ESC gene expression networks.…”

“…De la Rica and colleagues [4] next undertook a detailed examination of TET occupancy at L1 elements in ESCs, which revealed that TET proteins preferentially bind to and participate in active demethylation of full-length, evolutionarily young L1s, but not older, inactive subfamilies. This result raised the question of whether TETs are directly responsible for the demethylation and activation of L1 promoters in ESCs.…”

“…In a new publication, de la Rica and colleagues have investigated the roles of ten-eleven translocation (TET) enzymes at TE-derived sequences in mouse embryonic stem cells (ESCs) [4]. The pluripotent cells of the early mammalian embryo are the primary milieu for the evolutionary struggle between TEs and the host genome.…”

“…The publication from de la Rica and colleagues [4] reveals unexpectedly complex scenarios for TET-mediated TE regulation, probably shaped by ongoing evolutionary conflict at the host–retrotransposon interface. Importantly, their results shed light on the importance of DNA methylation relative to other epigenetic mechanisms for TE control in pluripotent cells.…”