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Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome
- Source :
- Leukemia. 31(4)
- Publication Year :
- 2016
-
Abstract
- Somatic inactivating mutations in epigenetic regulators are frequently found in combination in myelodysplastic syndrome (MDS). However, the mechanisms by which combinatory mutations in epigenetic regulators promote the development of MDS remain unknown. Here we performed epigenomic profiling of hematopoietic progenitors in MDS mice hypomorphic for Tet2 following the loss of the polycomb-group gene Ezh2 (Tet2KD/KDEzh2Δ/Δ). Aberrant DNA methylation propagated in a sequential manner from a Tet2-insufficient state to advanced MDS with deletion of Ezh2. Hyper-differentially methylated regions (hyper-DMRs) in Tet2KD/KDEzh2Δ/Δ MDS hematopoietic stem/progenitor cells were largely distinct from those in each single mutant and correlated with transcriptional repression. Although Tet2 hypomorph was responsible for enhancer hypermethylation, the loss of Ezh2 induced hyper-DMRs that were enriched for CpG islands of polycomb targets. Notably, Ezh2 targets largely lost the H3K27me3 mark while acquiring a significantly higher level of DNA methylation than Ezh1 targets that retained the mark. These findings indicate that Ezh2 targets are the major targets of the epigenetic switch in MDS with Ezh2 insufficiency. Our results provide a detailed trail for the epigenetic drift in a well-defined MDS model and demonstrate that the combined dysfunction of epigenetic regulators cooperatively remodels the epigenome in the pathogenesis of MDS.
- Subjects :
- 0301 basic medicine
Cancer Research
Mice, Transgenic
macromolecular substances
Biology
Dioxygenases
Epigenesis, Genetic
03 medical and health sciences
Mice
hemic and lymphatic diseases
Proto-Oncogene Proteins
Nuclear Receptor Subfamily 4, Group A, Member 2
Animals
Enhancer of Zeste Homolog 2 Protein
Epigenetics
Nucleotide Motifs
Epigenomics
Genetics
Regulation of gene expression
Mice, Knockout
Binding Sites
Base Sequence
EZH2
Hematology
Epigenome
DNA Methylation
Hematopoiesis
DNA-Binding Proteins
Repressor Proteins
Disease Models, Animal
030104 developmental biology
Enhancer Elements, Genetic
Oncology
CpG site
Gene Expression Regulation
Myelodysplastic Syndromes
DNA methylation
Cancer research
CpG Islands
Stem cell
Protein Binding
Transcription Factors
Subjects
Details
- ISSN :
- 14765551
- Volume :
- 31
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi.dedup.....1ddcb0cbbdef68b05f8f755a319a0a5b