Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, United States; TETRAD Graduate Program, University of California San Francisco, San Francisco, United States
Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, United States; TETRAD Graduate Program, University of California San Francisco, San Francisco, United States
Cheng Li
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States; Program in Biochemistry and Structural Biology, Cell and Developmental Biology, and Molecular Biology (BCMB Allied program), Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, United States
Genomic Analysis Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, United States
Ji Nie
Department of Chemistry, Howard Hughes Medical Institute, University of Chicago, Chicago, United States; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States; Institute for Biophysical Dynamics, University of Chicago, Chicago, United States
Xiaolong Cui
Department of Chemistry, Howard Hughes Medical Institute, University of Chicago, Chicago, United States; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States; Institute for Biophysical Dynamics, University of Chicago, Chicago, United States
Elizabeth Allene Martin
Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, United States; TETRAD Graduate Program, University of California San Francisco, San Francisco, United States
Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, United States; TETRAD Graduate Program, University of California San Francisco, San Francisco, United States
Jenna Fernandez
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, United States
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Joseph R Nery
Genomic Analysis Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, United States
Rosa Castanon
Genomic Analysis Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, United States
Rahul M Kohli
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Department of Chemistry, Howard Hughes Medical Institute, University of Chicago, Chicago, United States; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States; Institute for Biophysical Dynamics, University of Chicago, Chicago, United States
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.
