Journal
NATURE
Volume 527, Issue 7577, Pages 192-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature15521
Keywords
-
Categories
Funding
- Jane Coffin Childs Memorial Fund for Medical Research Fellowship
- NHGRI Career Development Award [K99HG008399]
- Simons Center for the Social Brain Postdoctoral Fellowship
- NIH NHGRI [K99-HG008171]
- Klarman Family Foundation
- Leukemia & Lymphoma Society Fellow Award
- NIH [R01 A1084905, R01HL119099, R01HG005085]
- NIMH [5DP1-MH100706]
- NIDDK [5R01-DK097768]
- Waterman award from the National Science Foundation
- Keck Foundation
- McKnight Foundation
- Damon Runyon Foundation
- Searle Scholars Foundation
- Merkin Foundation
- Vallee Foundation
- Simons Foundation
- Bob Metcalfe
- Center of Excellence in Molecular Hematology [P01HL032262, P30DK049216]
- NIDDK Career Development Award [K08DK093705]
- Doris Duke Charitable Foundation Innovations in Clinical Research Award [2013137]
- Charles H. Hood Foundation Child Health Research Award
- [F30DK103359-01A1]
Ask authors/readers for more resources
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 eiythroid BCL11A expression. Here we develop pooled clustered regularly interspaced paiindromic 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
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available