Find Paper, Faster
Example:10.1021/acsami.1c06204 or Chem. Rev., 2007, 107, 2411-2502
Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin
Nature Genetics  (IF38.33),  Pub Date : 2021-08-02, DOI: 10.1038/s41588-021-00904-0
Doerfler, Phillip A., Feng, Ruopeng, Li, Yichao, Palmer, Lance E., Porter, Shaina N., Bell, Henry W., Crossley, Merlin, Pruett-Miller, Shondra M., Cheng, Yong, Weiss, Mitchell J.

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.