Chromatin modifier Hmga2 promotes adult hematopoietic stem cell function and blood regeneration in stress conditions.
EMBO J
; 43(13): 2661-2684, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38811851
ABSTRACT
The molecular mechanisms governing the response of hematopoietic stem cells (HSCs) to stress insults remain poorly defined. Here, we investigated effects of conditional knock-out or overexpression of Hmga2 (High mobility group AT-hook 2), a transcriptional activator of stem cell genes in fetal HSCs. While Hmga2 overexpression did not affect adult hematopoiesis under homeostasis, it accelerated HSC expansion in response to injection with 5-fluorouracil (5-FU) or in vitro treatment with TNF-α. In contrast, HSC and megakaryocyte progenitor cell numbers were decreased in Hmga2 KO animals. Transcription of inflammatory genes was repressed in Hmga2-overexpressing mice injected with 5-FU, and Hmga2 bound to distinct regions and chromatin accessibility was decreased in HSCs upon stress. Mechanistically, we found that casein kinase 2 (CK2) phosphorylates the Hmga2 acidic domain, promoting its access and binding to chromatin, transcription of anti-inflammatory target genes, and the expansion of HSCs under stress conditions. Notably, the identified stress-regulated Hmga2 gene signature is activated in hematopoietic stem progenitor cells of human myelodysplastic syndrome patients. In sum, these results reveal a TNF-α/CK2/phospho-Hmga2 axis controlling adult stress hematopoiesis.
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Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Hematopoéticas
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Cromatina
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Camundongos Knockout
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Proteína HMGA2
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Caseína Quinase II
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article