TET1 is controlled by pluripotency-associated factors in ESCs and downmodulated by PRC2 in differentiated cells and tissues

Abstract

Ten-eleven translocation (Tet) genes encode for afamily of hydroxymethylase enzymes involved in regulatingDNA methylation dynamics. Tet1 is highlyexpressed in mouse embryonic stem cells (ESCs) where it plays a critical role the pluripotency maintenance.Tet1 is also involved in cell reprogrammingevents and in cancer progression. Although the functionalrole of Tet1 has been largely studied, its regulationis poorly understood. Here we show that Tet1gene is regulated, both in mouse and human ESCs, by the stemness specific factors Oct3/4, Nanog andby Myc. Thus Tet1 is integrated in the pluripotencytranscriptional network of ESCs. We found that Tet1is switched of f by cell proliferation in adult cells andtissues with a consequent genome-wide reductionof 5hmC, which is more evident in hypermethylatedregions and promoters. Tet1 downmodulation is mediatedby the Polycomb repressive complex 2 (PRC2) through H3K27me3 histone mark deposition. Thisstudy expands the knowledge about Tet1 involvementin stemness circuits in ESCs and provides evidencefor a transcriptional relationship between Tet1and PRC2 in adult proliferating cells improving ourunderstanding of the crosstalk between the epigeneticevents mediated by these factors.