Doerfler Lab - Activation of γ-globin gene expression by GATA1 and

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

Semantic Scholar DOI PubMedCentral PubMed

Cite

APA Click to copy
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.

Chicago/Turabian Click to copy
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 Click to copy
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.

BibTeX Click to copy

@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.