Enhancement of LIN28B-induced hematopoietic reprogramming by IGF2BP3

• Published in: Genes & development Vol. 33; no. 15-16; pp. 1048 - 1068
• Main Authors: Wang, Saifeng, Chim, Bryan, Su, Yijun, Khil, Pavel, Wong, Madeline, Wang, Xiantao, Foroushani, Amir, Smith, Patrick T, Liu, Xiuhuai, Li, Rui, Ganesan, Sundar, Kanellopoulou, Chrysi, Hafner, Markus, Muljo, Stefan A
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01-08-2019
• Subjects: Animals; Binding Sites; Cells, Cultured; Cellular Reprogramming - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Regulatory Networks; Hematopoietic Stem Cells - physiology; Mice; MicroRNAs - metabolism; Models, Animal; Research Paper; RNA, Messenger - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; single-cell RNA sequencing; ribonucleoprotein complexes; PAR-CLIP; regenerative medicine; RNA-binding proteins; fetal hematopoiesis; gene expression programs; B-cell development; posttranscriptional regulation; cellular engineering; gene regulatory networks; cell fate specification; hematopoietic stem and progenitor cells
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.325100.119

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
and
as well as
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.