| Literature DB >> 35941187 |
Peng Huang1, Scott A Peslak2,3, Ren Ren4, Eugene Khandros2, Kunhua Qin2, Cheryl A Keller5,6, Belinda Giardine5, Henry W Bell7, Xianjiang Lan2, Malini Sharma2, John R Horton4, Osheiza Abdulmalik2, Stella T Chou2, Junwei Shi8, Merlin Crossley7, Ross C Hardison5, Xiaodong Cheng4, Gerd A Blobel9,10.
Abstract
The fetal-to-adult switch in hemoglobin production is a model of developmental gene control with relevance to the treatment of hemoglobinopathies. The expression of transcription factor BCL11A, which represses fetal β-type globin (HBG) genes in adult erythroid cells, is predominantly controlled at the transcriptional level but the underlying mechanism is unclear. We identify HIC2 as a repressor of BCL11A transcription. HIC2 and BCL11A are reciprocally expressed during development. Forced expression of HIC2 in adult erythroid cells inhibits BCL11A transcription and induces HBG expression. HIC2 binds to erythroid BCL11A enhancers to reduce chromatin accessibility and binding of transcription factor GATA1, diminishing enhancer activity and enhancer-promoter contacts. DNA-binding and crystallography studies reveal direct steric hindrance as one mechanism by which HIC2 inhibits GATA1 binding at a critical BCL11A enhancer. Conversely, loss of HIC2 in fetal erythroblasts increases enhancer accessibility, GATA1 binding and BCL11A transcription. HIC2 emerges as an evolutionarily conserved regulator of hemoglobin switching via developmental control of BCL11A.Entities:
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Year: 2022 PMID： 35941187 DOI： 10.1038/s41588-022-01152-6
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 41.307