期刊
CELL STEM CELL
卷 27, 期 5, 页码 732-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2020.08.001
关键词
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资金
- National Heart, Lung, and Blood Institute (NHLBI) [R01 HL136504, R01 HL152180]
- Alex's Lemonade Stand Foundation (A'' Award)
- Gabrielle's Angel Foundation
- V Foundation
- American Society of Hematology
- Children's Discovery Institute of Washington University
- St. Louis Children's Hospital
- National Institute of General Medical Sciences (NIGMS) [R01 GM126112]
- Silicon Valley Community Foundation
- Chan Zuckerberg Initiative [HCA2-A-1708-02799]
- Allen Distinguished Investigator Award (Paul G. Allen Frontiers Group)
- Vallee Scholar Award
- Sloan Research Fellowship
Fetal and adult hematopoietic stem cells (HSCs) have distinct proliferation rates, lineage biases, gene expression profiles, and gene dependencies. Although these differences are widely recognized, it is not clear how the transition from fetal to adult identity is coordinated. Here we show that murine HSCs and committed hematopoietic progenitor cells (HPCs) undergo a gradual, rather than precipitous, transition from fetal to adult transcriptional states. The transition begins prior to birth and is punctuated by a late prenatal spike in type I interferon signaling that promotes perinatal HPC expansion and sensitizes progenitors to the leukemogenic FLT3(ITD) mutation. Most other changes in gene expression and enhancer activation are imprecisely timed and poorly coordinated. Thus, heterochronic enhancer elements, and their associated transcripts, are activated independently of one another rather than as part of a robust network. This simplifies the regulatory programs that guide neonatal HSC/HPC ontogeny, but it creates heterogeneity within these populations.
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