Abstract:
:Reactivation of fetal hemoglobin remains a critical goal in the treatment of patients with sickle cell disease and β-thalassemia. Previously, we discovered that silencing of the fetal γ-globin gene requires the erythroid-specific eIF2α kinase heme-regulated inhibitor (HRI), suggesting that HRI might present a pharmacologic target for raising fetal hemoglobin levels. Here, via a CRISPR-Cas9-guided loss-of-function screen in human erythroblasts, we identify transcription factor ATF4, a known HRI-regulated protein, as a novel γ-globin regulator. ATF4 directly stimulates transcription of BCL11A, a repressor of γ-globin transcription, by binding to its enhancer and fostering enhancer-promoter contacts. Notably, HRI-deficient mice display normal Bcl11a levels, suggesting species-selective regulation, which we explain here by demonstrating that the analogous ATF4 motif at the murine Bcl11a enhancer is largely dispensable. Our studies uncover a linear signaling pathway from HRI to ATF4 to BCL11A to γ-globin and illustrate potential limits of murine models of globin gene regulation.
journal_name
Bloodjournal_title
Bloodauthors
Huang P,Peslak SA,Lan X,Khandros E,Yano JA,Sharma M,Keller CA,Giardine B,Qin K,Abdulmalik O,Hardison RC,Shi J,Blobel GAdoi
10.1182/blood.2020005301subject
Has Abstractpub_date
2020-06-11 00:00:00pages
2121-2132issue
24eissn
0006-4971issn
1528-0020pii
454411journal_volume
135pub_type
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