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BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis
Open accessAbstract
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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“The authors flow-sorted the edited cells on the basis of the BCL11A-dependent switch to fetal haemoglobin, sequenced guides enriched in cells that had or hadn’t switched, and on the basis of those enrichments, successfully identified a primate-specific GATA1 motif critical for that enhancer’s function.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [195]
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“Cas9 introduces a targeted double-strand break, which is repaired by homology-directed repair using the donor templates, resulting in the incorporation of a single variant at the endogenous genomic locus (54, 55).”
From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [54]
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“The first such screen targeted gRNAs to effectively tile small indels across a known cluster of enhancers of BCL11A195.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [195]
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“Canver et al 9 recently showed BCL11A enhancer disruption by CRISPR/Cas9 could induce fetal haemoglobin in both mice and primary human erythroblast cells.”
From What is CRISPR/Cas9? (2016) · cites this paper as [9]
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“The initial CRISPR screens of regulatory elements delivered an individual gRNA per cell195.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [195]
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“To date, all such screens use Cas9-induced perturbations, including active Cas9 for sequence disruption195, or nuclease dead-Cas9 (dCas9) tethered to an epigenetic repressor105 or activator domain92.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [195]
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“In contrast, nine recently published CRISPR screens of noncoding sequences cumulatively studied regulatory effects on a total of 17 genes (Canver et al., 2015; Diao et al., 2016, 2017; Fulco et al., 2016; Gasperini et al., 2017; Klann et al., 2017; Korkmaz et al., 2016; Rajagopal et al., 2016; Sanjana et al., 2016).”
From A Genome-wide Framework for Mapping Gene Regulation via Cellular Genetic Screens (2019) · cites this paper as Canver et al., 2015
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“First, they focus on the regulation of a single gene per experiment, typically entailing the development of a gene-specific assay.”
From A Genome-wide Framework for Mapping Gene Regulation via Cellular Genetic Screens (2019) · cites this paper as Canver et al., 2015
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Metadata
- Authors
- Canver, M. C., Smith, E. C., Sher, F., Pinello, L., Sanjana, N. E., Shalem, O., Chen, D. D., Schupp, P. G., Vinjamur, D. S., Garcia, S. P., Luc, S., Kurita, R., Nakamura, Y., Fujiwara, Y., Maeda, T., Yuan, G.-C., Zhang, F., Orkin, S. H., & Bauer, D. E.
- Affiliations
- Boston Children's Hospital (US)
- Harvard University (US)
- Broad Institute (US)
- RIKEN BioResource Research Center (JP)
- University of Tsukuba (JP)
- Brigham and Women's Hospital (US)
- Corresponding author
- Zhang, Feng
- Orkin, Stuart H.
- Bauer, Daniel E.
- ORCID
- Venue
- Nature
- Published
- 2015-09-16
- Volume
- 527
- Issue
- 7577
- Pages
- 192-197
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4644101
- OpenAlex
- W1855348513
- Cited by
- 886
- References
- 65
- Citations by year
- 2026: 43 · 2025: 72 · 2024: 76 · 2023: 79 · 2022: 68 · 2021: 91 · 2020: 85 · 2019: 92 · 2018: 87 · 2017: 94 · 2016: 89 · 2015: 8
- FWCI
- 51.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
- PMC
- Funders
- Howard Hughes Medical Institute
- U.S. Public Health Service (R01 A1084905)
- National Heart, Lung, and Blood Institute (P01HL032262, R01HL032259, R01HL119099)
- National Institute of Mental Health (DP1MH100706, R01MH110049)
- National Human Genome Research Institute (K99HG008171, R01HG005085, K99HG008399)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK049216, 5R01-DK097768, R01DK097768, F30DK103359, K08DK093705)
- National Center for Chronic Disease Prevention and Health Promotion (5DP1-MH100706)
- Topics
- Health Sciences › Medicine › Genetics (clinical) › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- BCL11A, enhancers, CRISPR/Cas9, fetal hemoglobin, sickle cell disease, beta-thalassemia, enhancer architecture, erythroblasts
- MeSH terms
- RNA, Guide, CRISPR-Cas Systems, Animals, Base Sequence, Carrier Proteins, Cells, Cultured, DNA-Binding Proteins, Enhancer Elements, Genetic, Erythroblasts, Fetal Hemoglobin, Genetic Engineering, Humans, Molecular Sequence Data, Nuclear Proteins, Organ Specificity, Repressor Proteins, Species Specificity, Reproducibility of Results, Mutagenesis, Genome, Mice, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Cas Systems, CRISPR-Associated Proteins
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