TET1 is controlled by pluripotency-associated factors in ESCs and downmodulated by PRC2 in differentiated cells and tissues.
Ten-eleven translocation (Tet) genes encode for a family of hydroxymethylase enzymes involved in regulating DNA methylation dynamics. Tet1 is highly expressed in mouse embryonic stem cells (ESCs) where it plays a critical role the pluripotency maintenance. Tet1 is also involved in cell reprogramming events and in cancer progression. Although the functional role of Tet1 has been largely studied, its regulation is poorly understood. Here we show that Tet1 gene is regulated, both in mouse and human ESCs, by the stemness specific factors Oct3/4, Nanog and by Myc. Thus Tet1 is integrated in the pluripotency transcriptional network of ESCs. We found that Tet1 is switched off by cell proliferation in adult cells and tissues with a consequent genome-wide reduction of 5hmC, which is more evident in hypermethylated regions and promoters. Tet1 downmodulation is mediated by the Polycomb repressive complex 2 (PRC2) through H3K27me3 histone mark deposition. This study expands the knowledge about Tet1 involvement in stemness circuits in ESCs and provides evidence for a transcriptional relationship between Tet1 and PRC2 in adult proliferating cells improving our understanding of the crosstalk between the epigenetic events mediated by these factors.
Human Genetics Foundation (HuGeF), via Nizza 52, Torino, 10126, Italy.
Francesco
F
Neri
Human Genetics Foundation (HuGeF), via Nizza 52, Torino, 10126, Italy Dipartimento di Scienze della Vita e Biologia dei Sistemi, Università di Torino, Via Accademia Albertina 13, 10123, Torino, Italy.
Danny
D
Incarnato
Human Genetics Foundation (HuGeF), via Nizza 52, Torino, 10126, Italy.
Anna
A
Krepelova
Human Genetics Foundation (HuGeF), via Nizza 52, Torino, 10126, Italy.
Daniela
D
Dettori
Human Genetics Foundation (HuGeF), via Nizza 52, Torino, 10126, Italy Dipartimento di Scienze della Vita e Biologia dei Sistemi, Università di Torino, Via Accademia Albertina 13, 10123, Torino, Italy.
Stefania
S
Rapelli
Human Genetics Foundation (HuGeF), via Nizza 52, Torino, 10126, Italy.
Mara
M
Maldotti
Human Genetics Foundation (HuGeF), via Nizza 52, Torino, 10126, Italy.
Caterina
C
Parlato
Human Genetics Foundation (HuGeF), via Nizza 52, Torino, 10126, Italy.
Francesca
F
Anselmi
Dipartimento di Scienze della Vita e Biologia dei Sistemi, Università di Torino, Via Accademia Albertina 13, 10123, Torino, Italy.
Federico
F
Galvagni
Human Genetics Foundation (HuGeF), via Nizza 52, Torino, 10126, Italy Dipartimento di Biotecnologie Chimica e Farmacia, Università di Siena, Via Aldo Moro 2, 53100, Siena, Italy salvatore.oliviero@hugef-torino.org.
Salvatore
S
Oliviero
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases; D039904:Pluripotent Stem Cells / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; D014157:Transcription Factors; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D063151:Polycomb Repressive Complex 2