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HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription
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HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription
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Journal Article
HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription
2022
Overview
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
.
HIC2 regulates the fetal-to-adult hemoglobin switch. It inactivates an enhancer of the
BCL11A
gene, a fetal globin repressor, by reducing chromatin accessibility and displacing the transcription factor GATA1.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animal Genetics and Genomics
/ Binding
/ Biomedical and Life Sciences
/ CRISPR
/ Erythroid Cells - metabolism
/ Fetuses
/ Humans
/ Kruppel-Like Transcription Factors - metabolism
/ Proteins
/ Repressor Proteins - genetics
/ Repressor Proteins - metabolism
/ Transcription Factors - genetics
