TIF1beta regulates the pluripotency of embryonic stem cells in a phosphorylation-dependent manner

Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10926-31. doi: 10.1073/pnas.0907601107. Epub 2010 May 27.

Abstract

Transcription networks composed of various transcriptional factors specifically expressed in undifferentiated embryonic stem (ES) cells have been implicated in the regulation of pluripotency in ES cells. However, the molecular mechanisms responsible for self-renewal, maintenance of pluripotency, and lineage specification during differentiation of ES cells are still unclear. The results of this study demonstrate that a phosphorylation-dependent chromatin relaxation factor, transcriptional intermediary factor-1beta (TIF1beta), is a unique regulator of the pluripotency of ES cells and regulates Oct3/4-dependent transcription in a phosphorylation-dependent manner. TIF1beta is specifically phosphorylated in pluripotent mouse ES cells at the C-terminal serine 824, which has been previously shown to induce chromatin relaxation. Phosphorylated TIF1beta is partially colocalized at the activated chromatin markers, and forms a complex with the pluripotency-specific transcription factor Oct3/4 and subunits of the switching defective/sucrose nonfermenting, ATP-dependent chromatin remodeling complex, Smarcd1 [corrected], Brg-1, and BAF155, all of which are components of an ES-specific chromatin remodeling complex, esBAF. Phosphorylated TIF1beta specifically induces ES cell-specific genes and enables prolonged maintenance of an undifferentiated state in mouse ES cells. Moreover, TIF1beta regulates the reprogramming process of somatic cells in a phosphorylation-dependent manner. Our results suggest that TIF1beta provides a phosphorylation-dependent, bidirectional platform for specific transcriptional factors and chromatin remodeling enzymes that regulate the cell differentiation process and the pluripotency of stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Cell Differentiation
  • Chromatin Assembly and Disassembly
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism*
  • Mice
  • Mutagenesis, Site-Directed
  • Neurons / cytology
  • Neurons / metabolism
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Octamer Transcription Factor-3 / metabolism
  • Phosphorylation
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Serine / chemistry
  • Transcription Factors / metabolism
  • Tripartite Motif-Containing Protein 28

Substances

  • Nuclear Proteins
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • Recombinant Proteins
  • Repressor Proteins
  • Transcription Factors
  • Serine
  • Trim28 protein, mouse
  • Tripartite Motif-Containing Protein 28