Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin
| Autor: | Shaina N. Porter, Phillip A. Doerfler, Merlin Crossley, Mitchell J. Weiss, Shondra M. Pruett-Miller, Henry W Bell, Yong Cheng, Lance E. Palmer, Ruopeng Feng, Yichao Li |
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| Rok vydání: | 2021 |
| Předmět: |
HBG1
Hereditary persistence of fetal hemoglobin CAAT box Repressor KLF1 Biology Article Cell Line Erythroid Cells hemic and lymphatic diseases Chlorocebus aethiops Gene expression Genetics medicine Animals Humans GATA1 Transcription Factor gamma-Globins Promoter Regions Genetic Transcription factor Fetal Hemoglobin Gene Editing Regulation of gene expression Binding Sites Gene Expression Regulation Developmental medicine.disease Cell biology Repressor Proteins CCAAT-Binding Factor COS Cells CRISPR-Cas Systems |
| Zdroj: | Nature genetics |
| ISSN: | 1546-1718 1061-4036 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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