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Clin Epigenetics. 2019 Aug 22;11(1):121. doi: 10.1186/s13148-019-0724-z.

Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome.

Author information

1
Department of Medicine, Department of Philosophy, Social Sciences and Education, University of Perugia, Perugia, Italy. oxana.bereshchenko@unipg.it.
2
International Clinical Research Center, St'Anne University Hospital, Brno, Czech Republic.
3
Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
4
Department of Medicine, Department of Philosophy, Social Sciences and Education, University of Perugia, Perugia, Italy.
5
Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
6
Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, University Hospital Brno and Masaryk University, Brno, Czech Republic.
7
IRCCS Casa Sollievo della Sofferenza, Bioinformatics unit, San Giovanni Rotondo, Italy.
8
Josep Carreras Leukemia Research Institute (IJC), Universitat Autònoma de Barcelona, Campus ICO-Germans Trias I Pujol, Badalona, Spain.
9
Programme of Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), Badalona, Spain.
10
Division of Hematology, A.O.U. Policlinico-OVE, University of Catania, Catania, Italy.
11
Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", University of Catania, Catania, Italy.
12
Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
13
Gastroenterology unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
14
Genomics, Biotechnology Center, Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany.
15
International Clinical Research Center, St'Anne University Hospital, Brno, Czech Republic. manlio.vinciguerra@fnusa.cz.

Abstract

BACKGROUND:

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. 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.

RESULTS:

MacroH2A1.1 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.

CONCLUSIONS:

Together, 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.

KEYWORDS:

Hematopoiesis; MacroH2A1; Myelodysplastic syndrome

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