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Contributed by Neal G. Copeland, October 28, 2020 (sent for review August 20, 2020; reviewed by Adam N. Goldfarb and Paul Liu)
Significance
Regulation of quiescence is critical for the maintenance of adult HSCs, and the underlying mechanisms are poorly understood. Using a novel mouse conditional knockout allele of transcription factor gene Prdm16, we show that its deletion in the adult hematopoietic system led to a gradual loss of adult HSCs over time. This loss of adult HSCs was associated with their significantly increased cycling. We further found that Prdm16 promotes the quiescence of adult HSCs by activating the transcription of HSC cell cycle inhibitors including Cdkn1a and Egr1. Our study identifies Prdm16 as a critical regulator of adult HSC quiescence.
Abstract
Regulation 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.
Footnotes
↵1Present address: Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
- ↵2To whom correspondence may be addressed. Email: ncopeland1{at}mdanderson.org or yang.du{at}usuhs.edu.
Author contributions: K.O.G. and Y.D. designed research; K.O.G., N.N., K.O., Y.H., B.G., and Y.D. performed research; L.T. and N.A.J. contributed new reagents/analytic tools; K.O.G., N.N., K.O., Y.H., B.G., P.L., N.G.C., and Y.D. analyzed data; and K.O.G., N.G.C., and Y.D. wrote the paper.
Reviewers: A.N.G., University of Virginia; and P.L., National Institutes of Health.
The authors declare no competing interest.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2017626117/-/DCSupplemental.
Data Availability.
RNA-seq data that support the findings of this study are available in the Gene Expression Omnibus (GEO) under accession number GSE154011.
Published under the PNAS license.
References
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Prdm16 is a critical regulator of adult long-term hematopoietic stem cell quiescence
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