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Genes Dev. 2019 Jun 20. doi: 10.1101/gad.325100.119. [Epub ahead of print]

Enhancement of LIN28B-induced hematopoietic reprogramming by IGF2BP3.

Author information

1
Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
2
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA.
3
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
4
Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
#
Contributed equally

Abstract

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.

KEYWORDS:

B-cell development; PAR-CLIP; RNA-binding proteins; cell fate specification; cellular engineering; fetal hematopoiesis; gene expression programs; gene regulatory networks; hematopoietic stem and progenitor cells; posttranscriptional regulation; regenerative medicine; ribonucleoprotein complexes; single-cell RNA sequencing

PMID:
31221665
DOI:
10.1101/gad.325100.119

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