RRC ID 71576
Author Qin K, Huang P, Feng R, Keller CA, Peslak SA, Khandros E, Saari MS, Lan X, Mayuranathan T, Doerfler PA, Abdulmalik O, Giardine B, Chou ST, Shi J, Hardison RC, Weiss MJ, Blobel GA.
Title Dual function NFI factors control fetal hemoglobin silencing in adult erythroid cells.
Journal Nat Genet
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.
Volume 54(6)
Pages 874-884
Published 2022-6-1
DOI 10.1038/s41588-022-01076-1
PII 10.1038/s41588-022-01076-1
PMID 35618846
PMC PMC9203980
MeSH Animals Carrier Proteins / genetics Erythroid Cells / metabolism Fetal Hemoglobin* / genetics Fetal Hemoglobin* / metabolism Gene Editing Mice NFI Transcription Factors / genetics NFI Transcription Factors / metabolism Transcription Factors / genetics beta-Globins / genetics beta-Globins / metabolism gamma-Globins* / genetics gamma-Globins* / metabolism
IF 27.605
Human and Animal Cells HUDEP-2(RCB4557)