OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in development

Elife. 2018 Oct 16;7:e34870. doi: 10.7554/eLife.34870.

Abstract

TET enzymes convert 5-methylcytosine to 5-hydroxymethylcytosine and higher oxidized derivatives. TETs stably associate with and are post-translationally modified by the nutrient-sensing enzyme OGT, suggesting a connection between metabolism and the epigenome. Here, we show for the first time that modification by OGT enhances TET1 activity in vitro. We identify a TET1 domain that is necessary and sufficient for binding to OGT and report a point mutation that disrupts the TET1-OGT interaction. We show that this interaction is necessary for TET1 to rescue hematopoetic stem cell production in tet mutant zebrafish embryos, suggesting that OGT promotes TET1's function during development. Finally, we show that disrupting the TET1-OGT interaction in mouse embryonic stem cells changes the abundance of TET2 and 5-methylcytosine, which is accompanied by alterations in gene expression. These results link metabolism and epigenetic control, which may be relevant to the developmental and disease processes regulated by these two enzymes.

Keywords: OGT; TET; biochemistry; cell biology; chemical biology; chromatin; development; epigenetics; mouse; stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / analogs & derivatives
  • 5-Methylcytosine / metabolism
  • Animals
  • DNA Methylation / genetics
  • DNA-Binding Proteins / genetics*
  • Dioxygenases / genetics*
  • Epigenomics
  • Gene Expression Regulation, Developmental / genetics
  • Hematopoiesis / genetics
  • Humans
  • Mice
  • Mouse Embryonic Stem Cells / metabolism*
  • Mutation
  • N-Acetylglucosaminyltransferases / genetics*
  • Protein Binding / genetics
  • Protein Domains / genetics
  • Proto-Oncogene Proteins / genetics*
  • Zebrafish / genetics
  • Zebrafish / growth & development
  • Zebrafish Proteins / genetics*

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • TET1 protein, mouse
  • Zebrafish Proteins
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Tet1 protein, zebrafish
  • Dioxygenases
  • N-Acetylglucosaminyltransferases
  • ogt.1 protein, zebrafish