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

Francesco Neri1, Danny Incarnato12, Anna Krepelova12, Stefania Rapelli12, Andrea Pagnani13, Riccardo Zecchina13, Caterina Parlato1 and Salvatore Oliviero12*

Author Affiliations

1 Human Genetics Foundation (HuGeF), via Nizza 52, 10126, Torino, Italy

2 Dipartimento di Biotecnologie Chimica e Farmacia Università degli Studi di Siena. Via Fiorentina 1, 53100 Siena, Italy

3 Politecnico di Torino, Corso Duca degli Abruzzi 24, I-10129 Torino, Italy

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Genome Biology 2013, 14:R91  doi:10.1186/gb-2013-14-8-r91

Published: 29 August 2013

Abstract

Background

Ten-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.

Results

We 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.

Conclusions

In 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.

Keywords:
DNA-hydrossymethylation; Chip-Seq; PRC2; Stem Cells; Liver; Brain;Fibroblasts