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CRISPR screening uncovers a long-range enhancer for ONECUT1 in pancreatic differentiation and links a diabetes risk variant.
- Source :
-
Cell reports [Cell Rep] 2024 Aug 27; Vol. 43 (8), pp. 114640. Date of Electronic Publication: 2024 Aug 21. - Publication Year :
- 2024
-
Abstract
- Functional enhancer annotation is critical for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants. However, unbiased enhancer discovery in disease-relevant contexts remains challenging. To identify enhancers pertinent to diabetes, we conducted a CRISPR interference (CRISPRi) screen in the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among the enhancers identified, we focused on an enhancer we named ONECUT1e-664kb, ∼664 kb from the ONECUT1 promoter. Previous studies have linked ONECUT1 coding mutations to pancreatic hypoplasia and neonatal diabetes. We found that homozygous deletion of ONECUT1e-664kb in hPSCs leads to a near-complete loss of ONECUT1 expression and impaired pancreatic differentiation. ONECUT1e-664kb contains a type 2 diabetes-associated variant (rs528350911) disrupting a GATA motif. Introducing the risk variant into hPSCs reduced binding of key pancreatic transcription factors (GATA4, GATA6, and FOXA2), supporting its causal role in diabetes. This work highlights the utility of unbiased enhancer discovery in disease-relevant settings for understanding monogenic and complex disease.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Diabetes Mellitus, Type 2 genetics
Diabetes Mellitus, Type 2 metabolism
Diabetes Mellitus, Type 2 pathology
Clustered Regularly Interspaced Short Palindromic Repeats genetics
Pluripotent Stem Cells metabolism
CRISPR-Cas Systems genetics
GATA6 Transcription Factor metabolism
GATA6 Transcription Factor genetics
Enhancer Elements, Genetic genetics
Cell Differentiation genetics
Pancreas metabolism
Pancreas pathology
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 43
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 39163202
- Full Text :
- https://doi.org/10.1016/j.celrep.2024.114640