OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in development
- University of California, San Francisco, United States
- Memorial Sloan Kettering Cancer Center, United States
- Salk Institute for Biological Studies, United States
- University of Chicago, United States
- University of Minnesota, United States
- University of Pennsylvania, United States
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.
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.
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OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in developmentPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE119500).
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Perturbation of the OGT-TET1 interaction in mouse embryonic stem cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE119666).
Article and author information
Author details
Funding
National Cancer Institute (P30 CA008748)
- Cheng Li
- Mary Goll
California Institute for Regenerative Medicine (TG2-01153)
- Joel Hrit
- Barbara Panning
National Institutes of Health (R01 GM088506)
- Joel Hrit
- Leeanne Goodrich
- Barbara Panning
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Hrit et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in development
eLife 7:e34870.
https://doi.org/10.7554/eLife.34870
