RRC ID 67334
Author Doerfler PA, Feng R, Li Y, Palmer LE, Porter SN, Bell HW, Crossley M, Pruett-Miller SM, Cheng Y, Weiss MJ.
Title Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin.
Journal Nat Genet
Abstract Hereditary persistence of fetal hemoglobin (HPFH) ameliorates β-hemoglobinopathies by inhibiting the developmental switch from γ-globin (HBG1/HBG2) to β-globin (HBB) gene expression. Some forms of HPFH are associated with γ-globin promoter variants that either disrupt binding motifs for transcriptional repressors or create new motifs for transcriptional activators. How these variants sustain γ-globin gene expression postnatally remains undefined. We mapped γ-globin promoter sequences functionally in erythroid cells harboring different HPFH variants. Those that disrupt a BCL11A repressor binding element induce γ-globin expression by facilitating the recruitment of nuclear transcription factor Y (NF-Y) to a nearby proximal CCAAT box and GATA1 to an upstream motif. The proximal CCAAT element becomes dispensable for HPFH variants that generate new binding motifs for activators NF-Y or KLF1, but GATA1 recruitment remains essential. Our findings define distinct mechanisms through which transcription factors and their cis-regulatory elements activate γ-globin expression in different forms of HPFH, some of which are being recreated by therapeutic genome editing.
Volume 53(8)
Pages 1177-1186
Published 2021-8-1
DOI 10.1038/s41588-021-00904-0
PII 10.1038/s41588-021-00904-0
PMID 34341563
PMC PMC8610173
MeSH Animals Binding Sites CCAAT-Binding Factor / genetics* COS Cells CRISPR-Cas Systems Cell Line Chlorocebus aethiops Erythroid Cells Fetal Hemoglobin / genetics* GATA1 Transcription Factor / genetics* Gene Editing / methods Gene Expression Regulation, Developmental Humans Promoter Regions, Genetic Repressor Proteins / genetics Repressor Proteins / metabolism gamma-Globins / genetics*
IF 27.605
Human and Animal Cells HUDEP-2(RCB4557)