Impacts of combinatorial dysfunction of epigenetic regulators Tet2 and Ezh2 on epigenome in the pathogenesis of myelodysplastic syndrome. Mus musculus

Somatic inactivating mutations of epigenetic regulators are frequently found in combination in myelodysplastic syndrome (MDS). However, it remains unknown how combinatory mutations in epigenetic regulators promote development of MDS. Here, we performed epigenomic profilings of hematopoietic stem and progenitor cells (HSPCs) from MDS mice hypomorphic for Tet2 followed by the loss of polycomb-group gene Ezh2 (Tet2KD/KDEzh2d/d). Aberrant DNA methylation propagated in a sequential manner from a Tet2 insufficient state followed by Ezh2 loss, and further to advanced MDS. Hyper-differentially methylated regions (hyper-DMRs) in Tet2KD/KDEzh2d/d MDS HSPCs were largely distinct from those in each single mutant and significantly correlated with transcriptional repression. Hyper-DMRs in Tet2KD/KDEzh2d/d HSPCs were enriched for PRC2 targets, among which Ezh2-specific targets losing H3K27me3 mark were more dependent on DNA methylation to keep the transcriptionally repressed state and responded to a DNA demethylating agent better than Ezh1 targets, which retained H3K27me3 mark. Hyper-DMR genes included many hematopoietic regulator genes, such as Gata2, Gata3, Bcor and Nr4a2. Among these, Nr4a2 was shown to act as a tumor suppressor in Tet2KD/KDEzh2d/d cells. Our findings provide a detailed trail of the epigenetic drift in a well-defined MDS model and/demonstrate that the combined/dysfunction of epigenetic regulators cooperatively remodels epigenome in the pathogenesis of MDS.