H3K36 histone methyltransferase Setd2 is required for murine embryonic stem cell differentiation toward endoderm

Cell Rep. 2014 Sep 25;8(6):1989-2002. doi: 10.1016/j.celrep.2014.08.031. Epub 2014 Sep 18.


Setd2 is known as a histone-H3K36-specific methyltransferase. However, its role in physiological function remains unclear. In this study, we show that Setd2 mainly regulates differentiation of murine embryonic stem cells (mESCs) toward primitive endoderm. Furthermore, we show that downregulated endoderm-related genes in Setd2(-/-) mESCs are associated with an aberrantly low level of Erk activity and that enforced expression of Fgfr3 can rescue the defective Erk pathway in Setd2(-/-) mESCs. Interestingly, the transcriptional initiation of Fgfr3 is directly regulated through histone H3K36me3 modification in its distal promoter region by Setd2. These results indicate that Setd2 controls the primitive endoderm differentiation of mESCs by regulating the Fgfr3-Erk signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Line
  • Chromatin Immunoprecipitation
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism
  • Embryonic Stem Cells / transplantation
  • Endoderm / cytology
  • Endoderm / pathology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • Sequence Analysis, RNA
  • Signal Transduction
  • Teratoma / pathology
  • Transcription, Genetic


  • Histone-Lysine N-Methyltransferase
  • SETD2 protein, mouse
  • Fgfr3 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 3
  • Extracellular Signal-Regulated MAP Kinases

Associated data

  • GENBANK/GSE54932