학술논문
Activation of [gamma]-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin
Document Type
Report
Author
Source
Nature Genetics. August 2021, Vol. 53 Issue 8, p1177, 10 p.
Subject
Language
English
ISSN
1061-4036
Abstract
Author(s): Phillip A. Doerfler [sup.1] , Ruopeng Feng [sup.1] , Yichao Li [sup.1] , Lance E. Palmer [sup.1] , Shaina N. Porter [sup.2] [sup.3] , Henry W. Bell [sup.4] , [...]
Hereditary persistence of fetal hemoglobin (HPFH) ameliorates [beta]-hemoglobinopathies by inhibiting the developmental switch from [gamma]-globin (HBG1/HBG2) to [beta]-globin (HBB) gene expression. Some forms of HPFH are associated with [gamma]-globin promoter variants that either disrupt binding motifs for transcriptional repressors or create new motifs for transcriptional activators. How these variants sustain [gamma]-globin gene expression postnatally remains undefined. We mapped [gamma]-globin promoter sequences functionally in erythroid cells harboring different HPFH variants. Those that disrupt a BCL11A repressor binding element induce [gamma]-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 [gamma]-globin expression in different forms of HPFH, some of which are being recreated by therapeutic genome editing. Introduction of hereditary persistence of fetal hemoglobin variants into the [gamma]-globin promoter by using CRISPR mutagenesis and editing provides insights into transcription factor interplay, with implications for gene therapies targeting this element.
Hereditary persistence of fetal hemoglobin (HPFH) ameliorates [beta]-hemoglobinopathies by inhibiting the developmental switch from [gamma]-globin (HBG1/HBG2) to [beta]-globin (HBB) gene expression. Some forms of HPFH are associated with [gamma]-globin promoter variants that either disrupt binding motifs for transcriptional repressors or create new motifs for transcriptional activators. How these variants sustain [gamma]-globin gene expression postnatally remains undefined. We mapped [gamma]-globin promoter sequences functionally in erythroid cells harboring different HPFH variants. Those that disrupt a BCL11A repressor binding element induce [gamma]-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 [gamma]-globin expression in different forms of HPFH, some of which are being recreated by therapeutic genome editing. Introduction of hereditary persistence of fetal hemoglobin variants into the [gamma]-globin promoter by using CRISPR mutagenesis and editing provides insights into transcription factor interplay, with implications for gene therapies targeting this element.