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.

Základní údaje

Originální název

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

Autoři

BERESHCHENKO, Oxana (380 Itálie, garant), Oriana LO RE (380 Itálie, domácí), Fedor NIKULENKOV (203 Česká republika, domácí), Sara FLAMINI (380 Itálie), Jana KOTAŠKOVÁ (203 Česká republika, domácí), Tommaso MAZZA (380 Itálie), Marguerite-Mari LE PANNERER (724 Španělsko), Marcus BUSCHBECK (724 Španělsko), Cesarina GIALLONGO (380 Itálie), Giuseppe PALUMBO (380 Itálie), Giovanni LI VOLTI (380 Itálie), Valerio PAZIENZA (380 Itálie), Libor ČERVINEK (203 Česká republika, domácí), Carlo RICCARDI (380 Itálie), Lumír KREJČÍ (203 Česká republika, domácí), Šárka POSPÍŠILOVÁ (203 Česká republika, domácí), A. Francis STEWART (276 Německo) a Manlio VINCIGUERRA (380 Itálie)

Vydání

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

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 5.028

Kód RIV

RIV/00216224:14740/19:00108045

Organizační jednotka

Středoevropský technologický institut

DOI

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

UT WoS

000483304700001

Klíčová slova anglicky

Hematopoiesis; Myelodysplastic syndrome

Štítky

14110212, 14110513, CF GEN, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 15. 10. 2024 09:13, Ing. Martina Blahová

Anotace

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.

Návaznosti

EF16_013/0001818, projekt VaV

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

GA17-17720S, projekt VaV

Název: Vnitřní vlastnosti RAD51 vlákna a jeho biologické regulace

Investor: Grantová agentura ČR, Vnitřní vlastnosti RAD51 vlákna a jeho biologické regulace

MUNI/A/1087/2018, interní kód MU

Název: Molekulární a buněčná biologie pro biomedicínské vědy

Investor: Masarykova univerzita, Molekulární a buněčná biologie pro biomedicínské vědy, DO R. 2020_Kategorie A - Specifický výzkum - Studentské výzkumné projekty

206292/E/17/Z, interní kód MU

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

Investor: Wellcome Trust, Mechanics and execution of homologous recombination - biophysics to the organism

90091, velká výzkumná infrastruktura

Název: 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 a Manlio VINCIGUERRA. Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome. CLINICAL EPIGENETICS. LONDON: BMC, 2019, roč. 11, č. 1, s. 1-14. ISSN 1868-7075. Dostupné z: 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 a Manlio VINCIGUERRA. Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome. \textit{CLINICAL EPIGENETICS}. LONDON: BMC, 2019, roč.~11, č.~1, s.~1-14. ISSN~1868-7075. Dostupné z: https://dx.doi.org/10.1186/s13148-019-0724-z.

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