Journal article
Phillip A. Doerfler, Ruopeng Feng, Yichao Li, L. Palmer, Shaina N. Porter, Henry W. Bell, M. Crossley, S. Pruett-Miller, Yong Cheng, M. Weiss
Nature Genetics, 2021
Nature Genetics, 2021
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APA
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Doerfler, P. A., Feng, R., Li, Y., Palmer, L., Porter, S. N., Bell, H. W., … Weiss, M. (2021). Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin. Nature Genetics.
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Doerfler, Phillip A., Ruopeng Feng, Yichao Li, L. Palmer, Shaina N. Porter, Henry W. Bell, M. Crossley, S. Pruett-Miller, Yong Cheng, and M. Weiss. “Activation of γ-Globin Gene Expression by GATA1 and NF-Y in Hereditary Persistence of Fetal Hemoglobin.” Nature Genetics (2021).
MLA
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Doerfler, Phillip A., et al. “Activation of γ-Globin Gene Expression by GATA1 and NF-Y in Hereditary Persistence of Fetal Hemoglobin.” Nature Genetics, 2021.
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@article{phillip2021a,
title = {Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin},
year = {2021},
journal = {Nature Genetics},
author = {Doerfler, Phillip A. and Feng, Ruopeng and Li, Yichao and Palmer, L. and Porter, Shaina N. and Bell, Henry W. and Crossley, M. and Pruett-Miller, S. and Cheng, Yong and Weiss, M.}
}
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. Introduction of hereditary persistence of fetal hemoglobin variants into the γ-globin promoter by using CRISPR mutagenesis and editing provides insights into transcription factor interplay, with implications for gene therapies targeting this element.