Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome
Bereshchenko, O. (Department of Medicine. Department of Philosophy. Social Sciences and Education. University of Perugia)
Lo Re, O. (Department of Biology. Faculty of Medicine. Masaryk University)
Nikulenkov, F. (Department of Biology. Faculty of Medicine. Masaryk University)
Flamini, S. (Department of Medicine. Department of Philosophy. Social Sciences and Education. University of Perugia)
Kotaskova, J. (University Hospital Brno (República Txeca))
Mazza, T. (IRCCS Casa Sollievo della Sofferenza. Bioinformatics Unit)
Le Pannérer, Marguerite Marie (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Buschbeck, Marcus (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Giallongo, C. (Division of Hematology. A.O.U. Policlinico-OVE. University of Catania)
Palumbo, G. (Department of Medical and Surgical Sciences and Advanced Technologies GF Ingrassia. University of Catania)
Li Volti, G. (Department of Biomedical and Biotechnological Sciences. University of Catania)
Pazienza, V. (Gastroenterology Unit. IRCCS Casa Sollievo della Sofferenza)
Cervinek, L. (University Hospital Brno (República Txeca))
Riccardi, C. (Department of Medicine. Department of Philosophy. Social Sciences and Education. University of Perugia)
Krejci, L. (Department of Biology. Faculty of Medicine. Masaryk University)
Pospisilova, S. (University Hospital Brno (República Txeca))
Stewart, A. F. (Genomics. Biotechnology Center. Center for Molecular and Cellular Bioengineering. Technische Universität Dresden)
Vinciguerra, M. (International Clinical Research Center. St'Anne University Hospital)
Universitat Autònoma de Barcelona

Fecha:	2019
Resumen:	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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Hematopoiesis ; MacroH2A1 ; Myelodysplastic syndrome
Publicado en:	Clinical Epigenetics, Vol. 11 Núm. 1 (22 2019) , p. 121, ISSN 1868-7083

DOI: 10.1186/s13148-019-0724-z
PMID: 31439048

14 p, 3.9 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Instituto de Investigación contra la Leucemia Josep Carreras
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