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Dynamic switching of active promoter and enhancer domains regulates Tet1 and Tet2 expression during cell state transitions between pluripotency and differentiation. Mol Cell Biol 2015 Mar;35(6):1026-42

Date

01/15/2015

Pubmed ID

25582196

Pubmed Central ID

PMC4333094

DOI

10.1128/MCB.01172-14

Scopus ID

2-s2.0-84923197447   37 Citations

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.

Author List

Sohni A, Bartoccetti M, Khoueiry R, Spans L, Vande Velde J, De Troyer L, Pulakanti K, Claessens F, Rao S, Koh KP

Author

Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Differentiation
Cell Line
CpG Islands
DNA Methylation
DNA-Binding Proteins
Embryonic Stem Cells
Gene Expression Regulation, Developmental
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
NIH 3T3 Cells
Pluripotent Stem Cells
Promoter Regions, Genetic
Proto-Oncogene Proteins
Regulatory Sequences, Nucleic Acid
Transcription Initiation Site
Transcription, Genetic