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

J 2019

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

BERESHCHENKO, Oxana, Oriana LO RE, Fedor NIKULENKOV, Sara FLAMINI, Jana KOTAŠKOVÁ et. al.

Basic information

Original name

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

Authors

BERESHCHENKO, Oxana (380 Italy, guarantor), Oriana LO RE (380 Italy, belonging to the institution), Fedor NIKULENKOV (203 Czech Republic, belonging to the institution), Sara FLAMINI (380 Italy), Jana KOTAŠKOVÁ (203 Czech Republic, belonging to the institution), Tommaso MAZZA (380 Italy), Marguerite-Mari LE PANNERER (724 Spain), Marcus BUSCHBECK (724 Spain), Cesarina GIALLONGO (380 Italy), Giuseppe PALUMBO (380 Italy), Giovanni LI VOLTI (380 Italy), Valerio PAZIENZA (380 Italy), Libor ČERVINEK (203 Czech Republic, belonging to the institution), Carlo RICCARDI (380 Italy), Lumír KREJČÍ (203 Czech Republic, belonging to the institution), Šárka POSPÍŠILOVÁ (203 Czech Republic, belonging to the institution), A. Francis STEWART (276 Germany) and Manlio VINCIGUERRA (380 Italy)

Edition

CLINICAL EPIGENETICS, LONDON, BMC, 2019, 1868-7075

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.028

RIV identification code

RIV/00216224:14740/19:00108045

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1186/s13148-019-0724-z

UT WoS

000483304700001

Keywords in English

Hematopoiesis; Myelodysplastic syndrome

Abstract

V originále

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.

Links

EF16_013/0001818, research and development project

Name: Modernizace a podpora výzkumných aktivit národní infrastruktury pro translační medicínu EATRIS-CZ

GA17-17720S, research and development project

Name: Vnitřní vlastnosti RAD51 vlákna a jeho biologické regulace

Investor: Czech Science Foundation

MUNI/A/1087/2018, interní kód MU

Name: Molekulární a buněčná biologie pro biomedicínské vědy

Investor: Masaryk University, Category A

206292/E/17/Z, interní kód MU

Name: Mechanics and execution of homologous recombination - biophysics to the organism

Investor: Wellcome Trust

90091, large research infrastructures

Name: NCMG

Citovat

BERESHCHENKO, Oxana, Oriana LO RE, Fedor NIKULENKOV, Sara FLAMINI, Jana KOTAŠKOVÁ, Tommaso MAZZA, Marguerite-Mari LE PANNERER, Marcus BUSCHBECK, Cesarina GIALLONGO, Giuseppe PALUMBO, Giovanni LI VOLTI, Valerio PAZIENZA, Libor ČERVINEK, Carlo RICCARDI, Lumír KREJČÍ, Šárka POSPÍŠILOVÁ, A. Francis STEWART and Manlio VINCIGUERRA. Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome. CLINICAL EPIGENETICS. LONDON: BMC, 2019, vol. 11, No 1, p. 1-14. ISSN 1868-7075. Available from: https://dx.doi.org/10.1186/s13148-019-0724-z.

@article{1604822,
   author = {Bereshchenko, Oxana and Lo Re, Oriana and Nikulenkov, Fedor and Flamini, Sara and Kotašková, Jana and Mazza, Tommaso and Le Pannerer, MargueriteandMari and Buschbeck, Marcus and Giallongo, Cesarina and Palumbo, Giuseppe and Li Volti, Giovanni and Pazienza, Valerio and Červinek, Libor and Riccardi, Carlo and Krejčí, Lumír and Pospíšilová, Šárka and Stewart, A. Francis and Vinciguerra, Manlio},
   article_location = {LONDON},
   article_number = {1},
   doi = {http://dx.doi.org/10.1186/s13148-019-0724-z},
   keywords = {Hematopoiesis; Myelodysplastic syndrome},
   language = {eng},
   issn = {1868-7075},
   journal = {CLINICAL EPIGENETICS},
   title = {Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome},
   url = {https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0724-z},
   volume = {11},
   year = {2019}
}

TY  - JOUR
ID  - 1604822
AU  - Bereshchenko, Oxana - Lo Re, Oriana - Nikulenkov, Fedor - Flamini, Sara - Kotašková, Jana - Mazza, Tommaso - Le Pannerer, Marguerite-Mari - Buschbeck, Marcus - Giallongo, Cesarina - Palumbo, Giuseppe - Li Volti, Giovanni - Pazienza, Valerio - Červinek, Libor - Riccardi, Carlo - Krejčí, Lumír - Pospíšilová, Šárka - Stewart, A. Francis - Vinciguerra, Manlio
PY  - 2019
TI  - Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome
JF  - CLINICAL EPIGENETICS
VL  - 11
IS  - 1
SP  - 1-14
EP  - 1-14
PB  - BMC
SN  - 18687075
KW  - Hematopoiesis
KW  - Myelodysplastic syndrome
UR  - https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0724-z
L2  - https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0724-z
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.
ER  -

BERESHCHENKO, Oxana, Oriana LO RE, Fedor NIKULENKOV, Sara FLAMINI, Jana KOTAŠKOVÁ, Tommaso MAZZA, Marguerite-Mari LE PANNERER, Marcus BUSCHBECK, Cesarina GIALLONGO, Giuseppe PALUMBO, Giovanni LI VOLTI, Valerio PAZIENZA, Libor ČERVINEK, Carlo RICCARDI, Lumír KREJČÍ, Šárka POSPÍŠILOVÁ, A. Francis STEWART and Manlio VINCIGUERRA. Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome. \textit{CLINICAL EPIGENETICS}. LONDON: BMC, 2019, vol.~11, No~1, p.~1-14. ISSN~1868-7075. Available from: https://dx.doi.org/10.1186/s13148-019-0724-z.

Detailed Information on Publication Record