Centers and Institutes
Published October 16, 2018 | Version v1
Journal article Open

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

Creators

  • 1. University of California San Francisco
  • 2. Memorial Sloan Kettering Cancer Center
  • 3. Salk Institute for Biological Studies
  • 4. University of Chicago
  • 5. University of Minnesota
  • 6. University of Pennsylvania

Description

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.

Data availability

5hmC-Seal data has been uploaded to GEO under accession GSE119500. High throughput RNA-seq and WGBS data has been uploaded to GEO under accession GSE119666.

The following data sets were generated:

Nie J Cui X Hrit J Panning B He C (2018) NCBI Gene Expression Omnibus ID GSE119500. OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in development. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE119500

Wang B Hrit J Nery J Castanon R Panning B Ecker JR (2018) NCBI Gene Expression Omnibus ID GSE119666. Perturbation of the OGT-TET1 interaction in mouse embryonic stem cells. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE119666

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Additional details

Identifiers

DOI
10.7554/eLife.34870
Other
oai:uchicago.tind.io:9976

Funding

National Cancer Institute
P30 CA008748
California Institute for Regenerative Medicine
TG2-01153
National Institutes of Health
R01 GM088506
Geoffrey Beene Cancer Research Center of Memorial Sloan-Kettering Cancer Center

UChicago Information

Division(s)
Biological Sciences Division, Physical Sciences Division
Department(s)
Biochemistry and Molecular Biology, Chemistry
Center(s) or Institute(s)
Institute for Biophysical Dynamics