HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription
- 8 August 2022
- journal article
- research article
- Published by Springer Nature in Nature Genetics
- Vol. 54 (9) , 1417-1426
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R24DK106766, R24DK106766)
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (HL119479, HL007439, HL007150-42)
- The St Jude Children’s Research Hospital Collaborative Research Consortium on Novel Gene Therapies for Sickle Cell Disease
- Doris Duke Charitable Foundation (2020062)
- American Society of Hematology
- Cooley's Anemia Foundation
- Cancer Prevention and Research Institute of Texas (RR160029)
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35GM134744)
- Australian Government Research Training Program Scholarship
- National Health and Medical Research Council Australia Grant
This publication has 54 references indexed in Scilit:
- Establishment of Immortalized Human Erythroid Progenitor Cell Lines Able to Produce Enucleated Red Blood CellsPLOS ONE, 2013
- Combinatorial Assembly of Developmental Stage-Specific Enhancers Controls Gene Expression Programs during Human ErythropoiesisDevelopmental Cell, 2012
- KLF1 regulates BCL11A expression and γ- to β-globin gene switchingNature Genetics, 2010
- DNA polymorphisms at the BCL11A , HBS1L-MYB , and β- globin loci associate with fetal hemoglobin levels and pain crises in sickle cell diseaseProceedings of the National Academy of Sciences, 2008
- A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15Nature Genetics, 2007
- Proximity among Distant Regulatory Elements at the β-Globin Locus Requires GATA-1 and FOG-1Molecular Cell, 2005
- Coot: model-building tools for molecular graphicsActa Crystallographica Section D Structural Biology, 2004
- Global regulation of erythroid gene expression by transcription factor GATA-1Blood, 2004
- Formation of a Tissue-Specific Histone Acetylation Pattern by the Hematopoietic Transcription Factor GATA-1Molecular and Cellular Biology, 2003
- β-Globin gene inactivation by DNA translocation in γβ-thalassaemiNature, 1983