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2015 ; 35
(6
): 1026-42
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gab.com Text
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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
#MMPMID25582196
Sohni A
; Bartoccetti M
; Khoueiry R
; Spans L
; Vande Velde J
; De Troyer L
; Pulakanti K
; Claessens F
; Rao S
; Koh KP
Mol Cell Biol
2015[Mar]; 35
(6
): 1026-42
PMID25582196
show ga
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.