Combined loss of DNMT3A and TET2 in HSCs promotes lineage-specific transcription factor expression.
Major finding: Combined loss of DNMT3A and TET2 in HSCs promotes lineage-specific transcription factor expression.
Mechanism: DNMT3A and TET2 exhibit cooperative and competitive activity in maintaining DNA methylation.
Impact: Co-occurring DNMT3A and TET2 mutations may synergize to promote transformation by blocking differentiation.
Mutations affecting DNA methyltransferase 3A (DNMT3A), which methylates CpG dinucleotides (5mC), and ten-eleven translocation 2 (TET2), which oxidizes 5mC to 5-hydroxymethylcytosine (5hmC), frequently co-occur in lymphoma and leukemia and have similar roles in hematopoietic stem cells (HSC) despite their opposing effects on DNA methylation. To explore the roles of DNMT3A and TET2 in hematologic malignancies, Zhang, Su, Jeong, and colleagues generated single- and double-knockout mice. Bone marrow transplantation revealed that although Dnmt3a−/− hematopoietic stem and progenitor cells (HSPC) had similar rates of engraftment as wild-type cells, Tet2−/− cells exhibited higher engraftment rates, which were further enhanced by Dnmt3a deletion. Further, double-knockout mice developed hematologic disease more rapidly. Genes associated with nucleated red blood cells were upregulated in Tet2−/− cells and further upregulated in double-knockout cells, whereas they were downregulated in Dnmt3a−/− cells. In contrast, HSC-specific genes were upregulated in Dnmt3a−/− cells, downregulated in Tet2−/− cells, and further downregulated in double-knockout cells. While loss of Tet2 or Dnmt3a alone preserved the stem-cell program, the combined loss of Tet2 and Dnmt3a promoted lineage-specific regulators, but blocked differentiation. A subset of differentially methylated regions was identified in which Dnmt3a−/− cells exhibited reduced methylation, which was further decreased in double-knockout HSCs, indicating that TET2 may synergize with DNMT3A to enhance methylation, whereas other regions exhibited competitive activity. Moreover, the synergistic differentially methylated regions were most enriched for 5hmC, and in double-knockout cells, loss of 5mC and 5hmC were correlated. Loss of 5hmC in the promoter and gene bodies was associated with reduced gene expression in double-knockout cells, whereas 5hmC at the transcription start sites was associated with upregulation. These findings suggest a dual role for TET2 in maintaining HSC gene expression and generating 5hmC that, in cooperation with DNMT3A-deposited 5mC, maintains the repressed state of lineage-specific transcription factors.
Zhang X, Su J, Jeong M, Ko M, Huang Y, Park HJ, et al. DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells. Nat Genet 2016 Jul 18 [Epub ahead of print].
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.