Abstract
BackgroundEpigenetic regulation is important in hematopoiesis, but the involvement of histone variants is poorly understood. Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic stem cell (HSC) disorders characterized by ineffective hematopoiesis. MacroH2A1.1 is a histone H2A variant that negatively correlates with the self-renewal capacity of embryonic, adult, and cancer stem cells. MacroH2A1.1 is a target of the frequent U2AF1 S34F mutation in MDS. The role of macroH2A1.1 in hematopoiesis is unclear.ResultsMacroH2A1.1 mRNA levels are significantly decreased in patients with low-risk MDS presenting with chromosomal 5q deletion and myeloid cytopenias and tend to be decreased in MDS patients carrying the U2AF1 S34F mutation. Using an innovative mouse allele lacking the macroH2A1.1 alternatively spliced exon, we investigated whether macroH2A1.1 regulates HSC homeostasis and differentiation. The lack of macroH2A1.1 decreased while macroH2A1.1 haploinsufficiency increased HSC frequency upon irradiation. Moreover, bone marrow transplantation experiments showed that both deficiency and haploinsufficiency of macroH2A1.1 resulted in enhanced HSC differentiation along the myeloid lineage. Finally, RNA-sequencing analysis implicated macroH2A1.1-mediated regulation of ribosomal gene expression in HSC homeostasis.ConclusionsTogether, our findings suggest a new epigenetic process contributing to hematopoiesis regulation. By combining clinical data with a discrete mutant mouse model and in vitro studies of human and mouse cells, we identify macroH2A1.1 as a key player in the cellular and molecular features of MDS. These data justify the exploration of macroH2A1.1 and associated proteins as therapeutic targets in hematological malignancies.
Highlights
Epigenetic regulation is important in hematopoiesis, but the involvement of histone variants is poorly understood
Yip et al recently demonstrated that bone marrow (BM) progenitor cells from Myelodysplastic syndromes (MDS) patients with an endogenous U2AF1 S34F mutation showed aberrantly spliced H2AFY, resulting in reduced macroH2A1.1, but not macroH2A1.2, isoform expression in both erythroid and granulomonocytic derived colonies [6]. shRNA-mediated silencing of macroH2A1.1 in BM progenitor cells led to increased apoptosis and decreased differentiation when cells were cultured under erythroid and granulomonocytic conditions [6]
Here, we show that the histone variant macroH2A1.1, which is downregulated in a subset of patients with MDS, profoundly affects the survival and differentiation of murine hematopoietic stem cell (HSC)/hematopoietic progenitor cells (HPC) in vivo and human leukemic cell lines in vitro
Summary
Epigenetic regulation is important in hematopoiesis, but the involvement of histone variants is poorly understood. Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic stem cell (HSC) disorders characterized by ineffective hematopoiesis. The healthy hematopoietic stem cell (HSC) pool is maintained by genetically and epigenetically regulated gene expression [1, 2]. When these systems go awry, aberrant hematopoietic stem and progenitor cells may emerge (reviewed in [3]), which are implicated in the development of a heterogeneous group of disorders called myelodysplastic syndromes (MDS). Yip et al recently demonstrated that bone marrow (BM) progenitor cells from MDS patients with an endogenous U2AF1 S34F mutation showed aberrantly spliced H2AFY, resulting in reduced macroH2A1.1, but not macroH2A1.2, isoform expression in both erythroid and granulomonocytic derived colonies [6]. Yip et al recently demonstrated that bone marrow (BM) progenitor cells from MDS patients with an endogenous U2AF1 S34F mutation showed aberrantly spliced H2AFY, resulting in reduced macroH2A1.1, but not macroH2A1.2, isoform expression in both erythroid and granulomonocytic derived colonies [6]. shRNA-mediated silencing of macroH2A1.1 in BM progenitor cells led to increased apoptosis and decreased differentiation when cells were cultured under erythroid and granulomonocytic conditions [6]
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