@article{e417fdfbc00a4a19b87e38dd1071b021,
title = "Dual function NFI factors control fetal hemoglobin silencing in adult erythroid cells",
abstract = "The mechanisms by which the fetal-type β-globin-like genes HBG1 and HBG2 are silenced in adult erythroid precursor cells remain a fundamental question in human biology and have therapeutic relevance to sickle cell disease and β-thalassemia. Here, we identify via a CRISPR–Cas9 genetic screen two members of the NFI transcription factor family—NFIA and NFIX—as HBG1/2 repressors. NFIA and NFIX are expressed at elevated levels in adult erythroid cells compared with fetal cells, and function cooperatively to repress HBG1/2 in cultured cells and in human-to-mouse xenotransplants. Genomic profiling, genome editing and DNA binding assays demonstrate that the potent concerted activity of NFIA and NFIX is explained in part by their ability to stimulate the expression of BCL11A, a known silencer of the HBG1/2 genes, and in part by directly repressing the HBG1/2 genes. Thus, NFI factors emerge as versatile regulators of the fetal-to-adult switch in β-globin production.",
author = "Kunhua Qin and Peng Huang and Ruopeng Feng and Keller, {Cheryl A.} and Peslak, {Scott A.} and Eugene Khandros and Saari, {Megan S.} and Xianjiang Lan and Thiyagaraj Mayuranathan and Doerfler, {Phillip A.} and Osheiza Abdulmalik and Belinda Giardine and Chou, {Stella T.} and Junwei Shi and Hardison, {Ross C.} and Weiss, {Mitchell J.} and Blobel, {Gerd A.}",
note = "Funding Information: We thank the staff of CHOP Flow Cytometry Core Facility for assistance with cell sorting, and members of the Blobel laboratory for helpful discussions. HUDEP2 cells were a gift from R. Kurita and Y. Nakamura (RIKEN BioResource Center). The Fred Hutchinson Cancer Research Center Cooperative Center of Excellence in Hematology was supported by NIDDK Grant no. DK106829. This work was supported by NIH grants from the National Heart, Lung, and Blood Institute (grant no. HL119479) and research funding from Pfizer (G.A.B.); the National Institute of Diabetes and Digestive and Kidney Diseases (grant no. R24DK106766) (G.A.B., M.J.W. and R.C.H.); grant no. P01HL053749 (to M.J.W.), grant no. R01HL156647 (to M.J.W.), the Assisi Foundation of Memphis (to M.J.W.); the Doris Duke Charitable Foundation grant no. 2017093 (to M.J.W.); grant no. R01HL147879 (to S.T.C.); a K08 training grant (no. K08-DK129716) and the Doris Duke Charitable Foundation Physician Scientist Fellowship grant no. 2020062 (S.A.P.); a T32 training grant (no. HL007150-42) and an American Society of Hematology Research Training Award for Fellows (E.K.); NIDDK grant no. F32DK118822 and Cooley{\textquoteright}s Anemia Foundation (to P.A.D.); and the St. Jude Children{\textquoteright}s Research Hospital Collaborative Research Consortium on Novel Gene Therapies for Sickle Cell Disease. We thank the DiGaetano family for their generous support. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = jun,
doi = "10.1038/s41588-022-01076-1",
language = "English (US)",
volume = "54",
pages = "874--884",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "6",
}