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

Oxana Bereshchenko, Oriana Lo Re, Fedor Nikulenkov, Sara Flamini, Jana Kotaskova, Tommaso Mazza, Marguerite Marie Le Pannérer, Marcus Buschbeck, Cesarina Giallongo, Giuseppe Palumbo, Giovanni Li Volti, Valerio Pazienza, Libor Cervinek, Carlo Riccardi, Lumir Krejci, Sarka Pospisilova, A. Francis Stewart, Manlio Vinciguerra

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number121
JournalClinical Epigenetics
Volume11
Issue number1
DOIs
Publication statusPublished - Aug 22 2019

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Haploinsufficiency
Myelodysplastic Syndromes
Hematopoietic Stem Cells
Histones
Hematopoiesis
Cell Differentiation
Homeostasis
Genetic Epigenesis
RNA Sequence Analysis
Mutation
Adult Stem Cells
Neoplastic Stem Cells
Gene Expression Regulation
Hematologic Neoplasms
Embryonic Stem Cells
Bone Marrow Transplantation
Epigenomics
Exons
Alleles
Messenger RNA

Keywords

  • Hematopoiesis
  • MacroH2A1
  • Myelodysplastic syndrome

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

Cite this

Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome. / Bereshchenko, Oxana; Lo Re, Oriana; Nikulenkov, Fedor; Flamini, Sara; Kotaskova, Jana; Mazza, Tommaso; Le Pannérer, Marguerite Marie; Buschbeck, Marcus; Giallongo, Cesarina; Palumbo, Giuseppe; Li Volti, Giovanni; Pazienza, Valerio; Cervinek, Libor; Riccardi, Carlo; Krejci, Lumir; Pospisilova, Sarka; Stewart, A. Francis; Vinciguerra, Manlio.

In: Clinical Epigenetics, Vol. 11, No. 1, 121, 22.08.2019.

Research output: Contribution to journalArticle

Bereshchenko, O, Lo Re, O, Nikulenkov, F, Flamini, S, Kotaskova, J, Mazza, T, Le Pannérer, MM, Buschbeck, M, Giallongo, C, Palumbo, G, Li Volti, G, Pazienza, V, Cervinek, L, Riccardi, C, Krejci, L, Pospisilova, S, Stewart, AF & Vinciguerra, M 2019, 'Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome', Clinical Epigenetics, vol. 11, no. 1, 121. https://doi.org/10.1186/s13148-019-0724-z
Bereshchenko, Oxana ; Lo Re, Oriana ; Nikulenkov, Fedor ; Flamini, Sara ; Kotaskova, Jana ; Mazza, Tommaso ; Le Pannérer, Marguerite Marie ; Buschbeck, Marcus ; Giallongo, Cesarina ; Palumbo, Giuseppe ; Li Volti, Giovanni ; Pazienza, Valerio ; Cervinek, Libor ; Riccardi, Carlo ; Krejci, Lumir ; Pospisilova, Sarka ; Stewart, A. Francis ; Vinciguerra, Manlio. / Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome. In: Clinical Epigenetics. 2019 ; Vol. 11, No. 1.
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AU - Bereshchenko, Oxana

AU - Lo Re, Oriana

AU - Nikulenkov, Fedor

AU - Flamini, Sara

AU - Kotaskova, Jana

AU - Mazza, Tommaso

AU - Le Pannérer, Marguerite Marie

AU - Buschbeck, Marcus

AU - Giallongo, Cesarina

AU - Palumbo, Giuseppe

AU - Li Volti, Giovanni

AU - Pazienza, Valerio

AU - Cervinek, Libor

AU - Riccardi, Carlo

AU - Krejci, Lumir

AU - Pospisilova, Sarka

AU - Stewart, A. Francis

AU - Vinciguerra, Manlio

PY - 2019/8/22

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N2 - 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.

AB - 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.

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