DNMT3A and TET2 Compete and Cooperate to Repress Differentiation Lineage-Specific Factors in Hematopoietic Stem Cells

Mutations in the epigenetic modifiers DNMT3A and TET2 non-randomly co-occur in lymphoma and leukemia despite their epistasis in the methylation-hydroxymethylation pathway. Using double knock-out (DKO) mice in which malignancy development is accelerated, we show that the DKO methylome reflects regions of independent, competitive and cooperative activity. Expression of lineage-specific transcription factors, including the erythroid regulator Klf1 is upregulated in DKO HSCs. DNMT3A and TET2 both repress Klf1 suggesting a model of cooperative inhibition by the epigenetic modifiers. These data demonstrate a dual role for TET2 in promoting and inhibiting HSC differentiation, loss of which, along with DNMT3A, obstructs differentiation leading to transformation. I)Whole genome bisulfite sequencing of Tet2 conditional knockout hematopoietic stem cells, Tet2 and DNMT3a double knockout hematopoietic stem cells using Illumina HiSeq 2000.II)Whole genome CMS-enriched bisulfite sequencing of Tet2 conditional knockout hematopoietic stem cells, Tet2 and DNMT3a double knockout hematopoietic stem cells using Illumina HiSeq 2000.III)Whole genome mRNA profiles of Tet2 conditional knockout hematopoietic stem cells, Tet2 and DNMT3a double knockout hematopoietic stem cells using Illumina HiSeq 2000. IV)Genome wide histone modification H3K27me3 profiling of Tet2 conditional knockout hematopoietic stem cells, Tet2 and DNMT3a double knockout hematopoietic stem cells using Illumina HiSeq 2000