Genomics

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Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis (eRRBS)


ABSTRACT: DNA methylation is tightly regulated throughout mammalian development and altered methylation patterns are a hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in acute myeloid leukemia (AML) and has been suggested to protect CpG islands and promoters from aberrant methylation. By generating a novel mouse model of Tet2-deficient AML we show that loss of Tet2 in hematopoietic cells leads to progressive hypermethylation of active enhancer elements and altered expression of genes implicated in tumorigenesis. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner. Furthermore, we confirm this specific enhancer hypermethylation phenotype in human AML patients. Thus, we propose that TET2 prevents leukemic transformation of hematopoietic cells by protecting enhancers from aberrant DNA methylation. Enhanced Reduced Representation Bisulfite Sequencing (eRRBS) analysis of in vitro-grown hematopoietic cells transduced with AML1-ETO or MLL-AF9

ORGANISM(S): Mus musculus  

SUBMITTER: Jens V Johansen   Kristian Helin  Kasper D Rasmussen  Kasper Dindler Rasmussen  Guangshuai Jia  Olivier A Bernard 

PROVIDER: E-GEOD-59584 | ArrayExpress | 2015-04-22

SECONDARY ACCESSION(S): GSE59584SRP044646PRJNA255664

REPOSITORIES: GEO, ArrayExpress, ENA

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Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis.

Rasmussen Kasper D KD   Jia Guangshuai G   Johansen Jens V JV   Pedersen Marianne T MT   Rapin Nicolas N   Bagger Frederik O FO   Porse Bo T BT   Bernard Olivier A OA   Christensen Jesper J   Helin Kristian K  

Genes & development 20150417 9


DNA methylation is tightly regulated throughout mammalian development, and altered DNA methylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in hematological disorders, including acute myeloid leukemia (AML), and has been suggested to protect CG dinucleotide (CpG) islands and promoters from aberrant DNA methylation. In this study, we present a novel Tet2-dependent leukemia mouse model that closely recapitulates gene expression profiles a  ...[more]

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