NatureSep 17, 2015

Detailed study of BCL11A gene control regions using targeted Cas9 gene editing

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 11, 2026

Abstract

In situ saturating mutagenesis of human and mouse enhancers reveals critical features and vulnerabilities.

Enhancers are essential for determining cellular identity and are identified by chromatin marks and gain-of-function potential.
Common genetic variations in a human BCL11A enhancer are linked to fetal hemoglobin levels.
The mouse version of this enhancer is necessary for BCL11A expression in erythroid cells.
Despite functional similarities, the structure of composite enhancers in humans and mice shows significant divergence.
The identified human enhancer sequences are primarily unique to primates.
Editing of human progenitor cells and mouse models validates the BCL11A erythroid enhancer as a potential target for inducing fetal hemoglobin.

Simplified

Enhancers, critical determinants of cellular identity, are commonly recognized by correlative chromatin marks and gain-of-function potential, although only loss-of-function studies can demonstrate their requirement in the native genomic context. Previously, we identified an erythroid enhancer of human BCL11A, subject to common genetic variation associated with the fetal haemoglobin level, the mouse orthologue of which is necessary for erythroid BCL11A expression. Here we develop pooled clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 guide RNA libraries to perform in situ saturating mutagenesis of the human and mouse enhancers. This approach reveals critical minimal features and discrete vulnerabilities of these enhancers. Despite conserved function of the composite enhancers, their architecture diverges. The crucial human sequences appear to be primate-specific. Through editing of primary human progenitors and mouse transgenesis, we validate the BCL11A erythroid enhancer as a target for fetal haemoglobin reinduction. The detailed enhancer map will inform therapeutic genome editing, and the screening approach described here is generally applicable to functional interrogation of non-coding genomic elements.

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Detailed study of BCL11A gene control regions using targeted Cas9 gene editing

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