Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome
Posted on 2019-08-23 - 04:24
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.
CITE THIS COLLECTION
DataCite
3 Biotech
3D Printing in Medicine
3D Research
3D-Printed Materials and Systems
4OR
AAPG Bulletin
AAPS Open
AAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)
Academic Medicine
Academic Pediatrics
Academic Psychiatry
Academic Questions
Academy of Management Discoveries
Academy of Management Journal
Academy of Management Learning and Education
Academy of Management Perspectives
Academy of Management Proceedings
Academy of Management Review
Bereshchenko, Oxana; Lo Re, Oriana; Nikulenkov, Fedor; Flamini, Sara; Kotaskova, Jana; Mazza, Tommaso; et al. (2019). Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.4641128.v1
or
Select your citation style and then place your mouse over the citation text to select it.
SHARE
Usage metrics
Read the peer-reviewed publication
AUTHORS (18)
OB
Oxana Bereshchenko
OL
Oriana Lo Re
FN
Fedor Nikulenkov
SF
Sara Flamini
JK
Jana Kotaskova
TM
Tommaso Mazza
ML
Marguerite-Marie Le PannĂŠrer
MB
Marcus Buschbeck
CG
Cesarina Giallongo
GP
Giuseppe Palumbo
GL
Giovanni Li Volti
VP
Valerio Pazienza
LC
Libor Cervinek
CR
Carlo Riccardi
LK
Lumir Krejci
SP
Sarka Pospisilova
AS
A. Stewart
MV
Manlio Vinciguerra