title: Genome-wide analysis identifies a functional association of Tet1 and Polycomb repressive complex 2 in mouse embryonic stem cells.
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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Neri
authors.forename: Danny
authors.initials: D
authors.lastname: Incarnato
authors.forename: Anna
authors.initials: A
authors.lastname: Krepelova
authors.forename: Stefania
authors.initials: S
authors.lastname: Rapelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Pagnani
authors.forename: Riccardo
authors.initials: R
authors.lastname: Zecchina
authors.forename: Caterina
authors.initials: C
authors.lastname: Parlato
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oliviero
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D016678:Genome; D006657:Histones / Q000235:genetics / Q000378:metabolism; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C494163:Suz12 protein, mouse; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D063151:Polycomb Repressive Complex 2; D056264:Sin3 Histone Deacetylase and Corepressor Complex