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

Epigenomics 0301 basic medicine 570 QH301-705.5 Science N-Acetylglucosaminyltransferases Dioxygenases Mice 03 medical and health sciences Protein Domains stem cells Biochemistry and Chemical Biology Proto-Oncogene Proteins Animals Humans Biology (General) development Zebrafish epigenetics Q R Gene Expression Regulation, Developmental Mouse Embryonic Stem Cells DNA Methylation Zebrafish Proteins Hematopoiesis DNA-Binding Proteins Mutation OGT 5-Methylcytosine chromatin Medicine TET Protein Binding
DOI: 10.7554/elife.34870 Publication Date: 2018-10-16T12:01:30Z
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.
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