HIC2 Controls Developmental Hemoglobin Switching by Repressing BCL11A Transcription

Authors

Peng Huang
Scott A Peslak
Ren Ren
Eugene Khandros
Kunhua Qin
Cheryl A Keller
Belinda Giardine
Henry W Bell
Xianjiang Lan
Malini Sharma
John R Horton
Osheiza Abdulmalik
Stella T Chou
Junwei Shi
Merlin Crossley
Ross C Hardison
Xiaodong Cheng
Gerd A Blobel

Publication Date

9-1-2022

Journal

Nature Genetics

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

Carrier Proteins, Erythroid Cells, Hemoglobins, Humans, Kruppel-Like Transcription Factors, Repressor Proteins, Transcription Factors, Tumor Suppressor Proteins, beta-Globins, gamma-Globins

Comments

This article has been corrected. See Nat Genet. 2023 Jul 31.

DOI

10.1038/s41588-022-01152-6

PMID

35941187

PMCID

PMC9940634

PubMedCentral® Posted Date

2-20-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes