期刊
GENES & DEVELOPMENT
卷 33, 期 15-16, 页码 1048-1068出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.325100.119
关键词
regenerative medicine; cellular engineering; hematopoietic stem and progenitor cells; posttranscriptional regulation; ribonucleoprotein complexes; RNA-binding proteins; PAR-CLIP; cell fate specification; B-cell development; fetal hematopoiesis; gene regulatory networks; gene expression programs; single-cell RNA sequencing
资金
- National Institutes of Health Intramural Research Program of the National Institute of Allergy and Infectious Diseases
- National Institutes of Health Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZICAI001051, ZIAAI001185] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [ZIAAR041206, ZIAAR041205] Funding Source: NIH RePORTER
Fetal hematopoietic stem and progenitor cells (HSPCs) hold promise to cure a wide array of hematological diseases, and we previously found a role for the RNA-binding protein (RBP) Lin28b in respecifying adult HSPCs to resemble their fetal counterparts. Here we show by single-cell RNA sequencing that Lin28b alone was insufficient for complete reprogramming of gene expression from the adult toward the fetal pattern. Using proteomics and in situ analyses, we found that Lin28b (and its closely related paralog, Lin28a) directly interacted with Igf2bp3, another RBP, and their enforced co-expression in adult HSPCs reactivated fetal-like B-cell development in vivo more efficiently than either factor alone. In B-cell progenitors, Lin28b and Igf2bp3 jointly stabilized thousands of mRNAs by binding at the same sites, including those of the B-cell regulators Pax5 and Arid3a as well as Igf2bp3 mRNA itself, forming an autoregulatory loop. Our results suggest that Lin28b and Igf2bp3 are at the center of a gene regulatory network that mediates the fetal-adult hematopoietic switch. A method to efficiently generate induced fetal-like hematopoietic stem cells (ifHSCs) will facilitate basic studies of their biology and possibly pave a path toward their clinical application.
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