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Article: Prdm16 is a critical regulator of adult long-term hematopoietic stem cell quiescence

TitlePrdm16 is a critical regulator of adult long-term hematopoietic stem cell quiescence
Authors
Keywordshematopoietic stem cells
Prdm16
quiescence
Issue Date2020
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings of the National Academy of Sciences, 2020, v. 117 n. 50, p. 31945-31953 How to Cite?
AbstractRegulation of quiescence is critical for the maintenance of adult hematopoietic stem cells (HSCs). Disruption of transcription factor gene Prdm16 during mouse embryonic development has been shown to cause a severe loss of fetal liver HSCs; however, the underlying mechanisms and the function of Prdm16 in adult HSCs remain unclear. To investigate the role of Prdm16 in adult HSCs, we generated a novel conditional knockout mouse model and deleted Prdm16 in adult mouse hematopoietic system using the IFN-inducible Mx1-Cre. Our results show that Prdm16 deletion in the adult mouse hematopoietic system has a less severe effect on HSCs, causing a gradual decline of adult HSC numbers and a concomitant increase in the multipotent progenitor (MPP) compartment. Prdm16 deletion in the hematopoietic system following transplantation produced the same phenotype, indicating that the defect is intrinsic to adult HSCs. This HSC loss was also exacerbated by stress induced by 5-fluorouracil injections. Annexin V staining showed no difference in apoptosis between wild-type and knockout adult HSCs. In contrast, Bromodeoxyuridine analysis revealed that loss of Prdm16 significantly increased cycling of long-term HSCs (LT-HSCs) with the majority of the cells found in the S to G2/M phase. Consistently, RNA sequencing analysis of mouse LT-HSCs with and without Prdm16 deletion showed that Prdm16 loss induced a significant decrease in the expression of several known cell cycle regulators of HSCs, among which Cdkn1a and Egr1 were identified as direct targets of Prdm16. Our results suggest that Prdm16 preserves the function of adult LT-HSCs by promoting their quiescence.
Persistent Identifierhttp://hdl.handle.net/10722/306206
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorGudmundsson, KO-
dc.contributor.authorNguyen, N-
dc.contributor.authorOakley, K-
dc.contributor.authorHan, Y-
dc.contributor.authorGudmundsdottir, B-
dc.contributor.authorLiu, P-
dc.contributor.authorTessarollo, L-
dc.contributor.authorJenkins, NA-
dc.contributor.authorCopeland, NG-
dc.contributor.authorDu, Y-
dc.date.accessioned2021-10-20T10:20:18Z-
dc.date.available2021-10-20T10:20:18Z-
dc.date.issued2020-
dc.identifier.citationProceedings of the National Academy of Sciences, 2020, v. 117 n. 50, p. 31945-31953-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/306206-
dc.description.abstractRegulation of quiescence is critical for the maintenance of adult hematopoietic stem cells (HSCs). Disruption of transcription factor gene Prdm16 during mouse embryonic development has been shown to cause a severe loss of fetal liver HSCs; however, the underlying mechanisms and the function of Prdm16 in adult HSCs remain unclear. To investigate the role of Prdm16 in adult HSCs, we generated a novel conditional knockout mouse model and deleted Prdm16 in adult mouse hematopoietic system using the IFN-inducible Mx1-Cre. Our results show that Prdm16 deletion in the adult mouse hematopoietic system has a less severe effect on HSCs, causing a gradual decline of adult HSC numbers and a concomitant increase in the multipotent progenitor (MPP) compartment. Prdm16 deletion in the hematopoietic system following transplantation produced the same phenotype, indicating that the defect is intrinsic to adult HSCs. This HSC loss was also exacerbated by stress induced by 5-fluorouracil injections. Annexin V staining showed no difference in apoptosis between wild-type and knockout adult HSCs. In contrast, Bromodeoxyuridine analysis revealed that loss of Prdm16 significantly increased cycling of long-term HSCs (LT-HSCs) with the majority of the cells found in the S to G2/M phase. Consistently, RNA sequencing analysis of mouse LT-HSCs with and without Prdm16 deletion showed that Prdm16 loss induced a significant decrease in the expression of several known cell cycle regulators of HSCs, among which Cdkn1a and Egr1 were identified as direct targets of Prdm16. Our results suggest that Prdm16 preserves the function of adult LT-HSCs by promoting their quiescence.-
dc.languageeng-
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org-
dc.relation.ispartofProceedings of the National Academy of Sciences-
dc.rightsProceedings of the National Academy of Sciences. Copyright © National Academy of Sciences.-
dc.subjecthematopoietic stem cells-
dc.subjectPrdm16-
dc.subjectquiescence-
dc.titlePrdm16 is a critical regulator of adult long-term hematopoietic stem cell quiescence-
dc.typeArticle-
dc.identifier.emailLiu, P: pliu88@hku.hk-
dc.identifier.authorityLiu, P=rp02328-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.2017626117-
dc.identifier.pmid33268499-
dc.identifier.pmcidPMC7749346-
dc.identifier.scopuseid_2-s2.0-85098470943-
dc.identifier.hkuros327330-
dc.identifier.volume117-
dc.identifier.issue50-
dc.identifier.spage31945-
dc.identifier.epage31953-
dc.identifier.isiWOS:000600608300052-
dc.publisher.placeUnited States-

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