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10.1128/MCB.01172-14

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suck abstract from ncbi


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pmid25582196
      Mol+Cell+Biol 2015 ; 35 (6 ): 1026-42
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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.
  • |Animals [MESH]
  • |Cell Differentiation/*genetics [MESH]
  • |Cell Line [MESH]
  • |CpG Islands/genetics [MESH]
  • |DNA Methylation/genetics [MESH]
  • |DNA-Binding Proteins/*genetics/*metabolism [MESH]
  • |Embryonic Stem Cells/metabolism [MESH]
  • |Gene Expression Regulation, Developmental/genetics [MESH]
  • |HEK293 Cells [MESH]
  • |Humans [MESH]
  • |Mice [MESH]
  • |Mice, Inbred C57BL [MESH]
  • |NIH 3T3 Cells [MESH]
  • |Pluripotent Stem Cells/*metabolism [MESH]
  • |Promoter Regions, Genetic/*genetics [MESH]
  • |Proto-Oncogene Proteins/*genetics/*metabolism [MESH]
  • |Regulatory Sequences, Nucleic Acid/*genetics [MESH]
  • |Transcription Initiation Site/physiology [MESH]


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