Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome

• Published in: Leukemia Vol. 31; no. 4; pp. 861 - 871
• Main Authors: Hasegawa, N, Oshima, M, Sashida, G, Matsui, H, Koide, S, Saraya, A, Wang, C, Muto, T, Takane, K, Kaneda, A, Shimoda, K, Nakaseko, C, Yokote, K, Iwama, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2017; Nature Publishing Group
• Subjects: 38/39; 38/91; 631/532/71; 631/67/1990/1673; Analysis; Animals; Base Sequence; Binding Sites; Cancer; Cancer Research; Care and treatment; Cells (biology); Combinatorial analysis; CpG Islands; Critical Care Medicine; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA Methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enhancer Elements, Genetic; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenesis, Genetic; Epigenetics; Gene Expression Regulation; Gene silencing; Genomes; Hematology; Hematopoiesis - genetics; Hematopoietic stem cells; Intensive; Internal Medicine; Laboratory animals; Leukemia; Medicine; Medicine & Public Health; Methylation; Mice; Mice, Knockout; Mice, Transgenic; Mutation; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - metabolism; Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism; Nucleotide Motifs; Oncology; original-article; Pathogenesis; Polycomb group proteins; Progenitor cells; Protein Binding; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Repressor Proteins - metabolism; Stem cells; Transcription Factors - metabolism; Japan
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2016.268

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 ( Tet2 KD/KD Ezh2 Δ/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 Tet2 KD/KD Ezh2 Δ/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.