Genome-wide analysis identifies a functional association of Tet1 and Polycomb repressive complex 2 in mouse embryonic stem cells

Abstract

BackgroundTen-Eleven Translocation (TETs)proteins mediate the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Tet1 is expressed at high levels in mouse embryonic stem cells (ESCs), where it mediates the induction of 5hmC decoration on gene-regulatory elements. While the function of Tet1 is known, the mechanisms of its specificity remain unclear.ResultsWe perform a genome-wide comparative analysis of 5hmC in pluripotent ESCs, as well as in differentiated embryonic and adult cells. We find that 5hmC co-localization with Polycomb repressive complex 2 (PRC2) is specific to ESCs and is absent in differentiated cells. Tet1 in ESCs is distributed on bivalent genes in two independent pools: one with Sin3a centered at non-hydroxymethylated transcription start sites and another centered downstream from these sites. This latter pool of Tet1 co-localizes with 5hmC and PRC2. Through co-immunoprecipitation experiments, we show that Tet1 forms a complex with PRC2 specifically in ESCs. Genome-wide analysis of 5hmC profiles in ESCs following knockdown of the PRC2 subunit Suz12 shows a reduction of 5hmC within promoter sequences, specifically at H3K27me3-positive regions of bivalent promoters.ConclusionsIn ESCs, PRC2 recruits Tet1 to chromatin at H3K27me3 positive regions of the genome, with 5hmC enriched in a broad peak centered 455 bp after the transcription start site and dependent on the PRC2 component Suz12. These results suggest that PRC2-dependent recruitment of Tet1 contributes to epigenetic plasticity throughout cell differentiation.

TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway

“…10,14- 16 5-Hydroxymethylcytosine (5hmC) is a recently discovered epigenetic modification catalysed by the ten eleven translocation (TET) proteins that mediate the sequential oxidation of 5-methylcytosine (5mC) to 5hmC, leading to eventual DNA demethylation. [17][18][19][20][21] 5hmC is lost in human cancers, but the functional significance of this event is not still understood. [22][23][24][25] Several mechanisms can lead to loss of 5hmC in cancers, including mutations in IDH or TET2 genes.…”

DNA Cytosine Methylation and Hydroxymethylation at the Borders

“…Not until 57 years after the discovery of 5hmC in T-even phages [5] was the existence of genomic 5hmC in mammals and its generation by TET-catalyzed oxidation of 5mC proven [6,7]. Genomic 5hmC can act as an intermediate in DNA demethy lation by replication-dependent or replication-independent pathways [8] or it can be a relatively stable component of DNA [9,10]. It is implicated in regulating gene expression in mammals as is genomic 5mC [2].…”

MicroRNAs mediated targeting on the Yin-yang dynamics of DNA methylation in disease and development

“…Importantly, EZH2 is the catalytic subunit of PRC2 complex, where it plays key role in PRC2-mediated histone modification, suggesting that miR-26 also could perform its role as an epigenetic regulator via modulating DNA methylation pathway and histone modification at the same time. Given the fact that Tet1 and PRC2 complex interacted in ESCs (Neri et al, 2013), it further confirming the possibility that miR-26 maybe functional as a dual epigenetic effector in ESCs via targeting Tet1 and PRC2 complex simultaneously.…”