Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome.
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/ΔMDS 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.
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.|Department of Hematology, Chiba University Hospital, Chiba, Japan.|Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
N
N
Hasegawa
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
M
M
Oshima
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.|International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
G
G
Sashida
Department of Molecular Laboratory Medicine, Kumamoto University, Kumamoto, Japan.
H
H
Matsui
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
S
S
Koide
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
A
A
Saraya
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.|College of Life Sciences, Inner Mongolia University, Hohhot, China.
C
C
Wang
Department of Hematology, Chiba University Hospital, Chiba, Japan.|Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
T
T
Muto
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
K
K
Takane
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
A
A
Kaneda
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
K
K
Shimoda
Department of Hematology, Chiba University Hospital, Chiba, Japan.|Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
C
C
Nakaseko
Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
K
K
Yokote
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
A
A
Iwama
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism; D059372:Nucleotide Motifs; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D049308:Dioxygenases; C541081:TET2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
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