The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression

Peng Huang, Scott A. Peslak, Xianjiang Lan, Eugene Khandros, Jennifer A. Yano, Malini Sharma, Cheryl A. Keller, Belinda Giardine, Kunhua Qin, Osheiza Abdulmalik, Ross C. Hardison, Junwei Shi, Gerd A. Blobel

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Reactivation of fetal hemoglobin remains a critical goal in the treatment of patients with sickle cell disease and b-thalassemia. Previously, we discovered that silencing of the fetal g-globin gene requires the erythroid-specific eIF2a 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 g-globin regulator. ATF4 directly stimulates transcription of BCL11A, a repressor of g-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 g-globin and illustrate potential limits of murine models of globin gene regulation.

Original languageEnglish (US)
Pages (from-to)2121-2132
Number of pages12
JournalBlood
Volume135
Issue number24
DOIs
StatePublished - Jun 11 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression'. Together they form a unique fingerprint.

Cite this