Genomics

Dataset Information

144

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


ABSTRACT: 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. Overall design: 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

INSTRUMENT(S): Illumina HiSeq 2000 (Mus musculus)

SUBMITTER: Jianzhong Su  

PROVIDER: GSE72148 | GEO | 2016-05-20

SECONDARY ACCESSION(S): PRJNA293214

REPOSITORIES: GEO

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Publications

DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells.

Zhang Xiaotian X   Su Jianzhong J   Jeong Mira M   Ko Myunggon M   Huang Yun Y   Park Hyun Jung HJ   Guzman Anna A   Lei Yong Y   Huang Yung-Hsin YH   Rao Anjana A   Li Wei W   Goodell Margaret A MA  

Nature genetics 20160718 9


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 Dnmt3a and Tet2 double-knockout mice in which the development of malignancy is accelerated, we show that the double-knockout methylome reflects regions of independent, competitive and cooperative activity. Expression of lineage-specific transcription factors, including the erythroid regulators Klf1 and Epor, is upregulat  ...[more]

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