Zfp281 Coordinates Opposing Functions of Tet1 and Tet2 in Pluripotent States

Cell Stem Cell. 2016 Sep 1;19(3):355-69. doi: 10.1016/j.stem.2016.05.025. Epub 2016 Jun 23.


Pluripotency is increasingly recognized as a spectrum of cell states defined by their growth conditions. Although naive and primed pluripotency states have been characterized molecularly, our understanding of events regulating state acquisition is wanting. Here, we performed comparative RNA sequencing of mouse embryonic stem cells (ESCs) and defined a pluripotent cell fate (PCF) gene signature associated with acquisition of naive and primed pluripotency. We identify Zfp281 as a key transcriptional regulator for primed pluripotency that also functions as a barrier toward achieving naive pluripotency in both mouse and human ESCs. Mechanistically, Zfp281 interacts with Tet1, but not Tet2, and its direct transcriptional target, miR-302/367, to negatively regulate Tet2 expression to establish and maintain primed pluripotency. Conversely, ectopic Tet2 alone, but not Tet1, efficiently reprograms primed cells toward naive pluripotency. Our study reveals a molecular circuitry in which opposing functions of Tet1 and Tet2 control acquisition of alternative pluripotent states.

Keywords: ESCs; EpiSCs; ZNF281; miR-302/367 cluster; naive; primed.

MeSH terms

  • Animals
  • Base Sequence
  • Cell Lineage / genetics
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases
  • Epigenesis, Genetic
  • Gene Expression Profiling
  • Mice
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • RNA Interference
  • Transcription Factors / metabolism*
  • Transcription, Genetic


  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • TET1 protein, mouse
  • Transcription Factors
  • Zfp281 protein, mouse
  • Dioxygenases
  • Tet2 protein, mouse