title: Dynamic switching of active promoter and enhancer domains regulates Tet1 and Tet2 expression during cell state transitions between pluripotency and differentiation.
abstract: The Tet 5-methylcytosine dioxygenases catalyze DNA demethylation by producing 5-hydroxymethylcytosine and further oxidized products. Tet1 and Tet2 are highly expressed in mouse pluripotent cells and downregulated to different extents in somatic cells, but the transcriptional mechanisms are unclear. Here we defined the promoter and enhancer domains in Tet1 and Tet2. Within a 15-kb "superenhancer" of Tet1, there are two transcription start sites (TSSs) with different activation patterns during development. A 6-kb promoter region upstream of the distal TSS is highly active in naive pluripotent cells, autonomously reports Tet1 expression in a transgenic system, and rapidly undergoes DNA methylation and silencing upon differentiation in cultured cells and native epiblast. A second TSS downstream, associated with a constitutively weak CpG-rich promoter, is activated by a neighboring enhancer in naive embryonic stem cells (ESCs) and primed epiblast-like cells (EpiLCs). Tet2 has a CpG island promoter with pluripotency-independent activity and an ESC-specific distal intragenic enhancer; the latter is rapidly downregulated in EpiLCs. Our study reveals distinct modes of transcriptional regulation at Tet1 and Tet2 during cell state transitions of early development. New transgenic reporters using Tet1 and Tet2 cis-regulatory domains may serve to distinguish nuanced changes in pluripotent states and the underlying epigenetic variations.
authors.affiliation: KU Leuven Department of Development and Regeneration, Stem Cell Institute Leuven, Leuven, Belgium.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Sohni
authors.affiliation: KU Leuven Department of Development and Regeneration, Stem Cell Institute Leuven, Leuven, Belgium.
authors.forename: Michela
authors.initials: M
authors.lastname: Bartoccetti
authors.affiliation: KU Leuven Department of Development and Regeneration, Stem Cell Institute Leuven, Leuven, Belgium.
authors.forename: Rita
authors.initials: R
authors.lastname: Khoueiry
authors.affiliation: KU Leuven Department of Cellular and Molecular Medicine, Laboratory of Molecular Endocrinology, Leuven, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Spans
authors.affiliation: KU Leuven Department of Development and Regeneration, Stem Cell Institute Leuven, Leuven, Belgium.
authors.forename: Joris
authors.initials: J
authors.lastname: Vande Velde
authors.affiliation: KU Leuven Department of Development and Regeneration, Stem Cell Institute Leuven, Leuven, Belgium.
authors.forename: Linde
authors.initials: L
authors.lastname: De Troyer
authors.affiliation: Blood Center of Wisconsin, Blood Research Institute, Milwaukee, Wisconsin, USA.
authors.forename: Kirthi
authors.initials: K
authors.lastname: Pulakanti
authors.affiliation: KU Leuven Department of Cellular and Molecular Medicine, Laboratory of Molecular Endocrinology, Leuven, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Claessens
authors.affiliation: Blood Center of Wisconsin, Blood Research Institute, Milwaukee, Wisconsin, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Rao
authors.affiliation: KU Leuven Department of Development and Regeneration, Stem Cell Institute Leuven, Leuven, Belgium kian.koh@med.kuleuven.be.
authors.forename: Kian Peng
authors.initials: KP
authors.lastname: Koh
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D024363:Transcription Initiation Site / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins