Single-cell chromatin accessibility identifies pancreatic islet cell type- and state-specific regulatory programs of diabetes risk.
Blood Glucose
/ metabolism
Cell Differentiation
Chromatin
/ chemistry
Diabetes Mellitus, Type 2
/ genetics
Epigenomics
Fasting
Gene Expression Profiling
Genome-Wide Association Study
Glucagon-Secreting Cells
/ metabolism
High-Throughput Nucleotide Sequencing
Human Embryonic Stem Cells
/ cytology
Humans
Insulin-Secreting Cells
/ metabolism
KCNQ1 Potassium Channel
/ genetics
Multigene Family
Pancreatic Polypeptide-Secreting Cells
/ metabolism
Polymorphism, Genetic
Single-Cell Analysis
Somatostatin-Secreting Cells
/ metabolism
Transcription Factors
/ classification
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
24
05
2019
accepted:
18
02
2021
pubmed:
3
4
2021
medline:
21
4
2021
entrez:
2
4
2021
Statut:
ppublish
Résumé
Single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) creates new opportunities to dissect cell type-specific mechanisms of complex diseases. Since pancreatic islets are central to type 2 diabetes (T2D), we profiled 15,298 islet cells by using combinatorial barcoding snATAC-seq and identified 12 clusters, including multiple alpha, beta and delta cell states. We cataloged 228,873 accessible chromatin sites and identified transcription factors underlying lineage- and state-specific regulation. We observed state-specific enrichment of fasting glucose and T2D genome-wide association studies for beta cells and enrichment for other endocrine cell types. At T2D signals localized to islet-accessible chromatin, we prioritized variants with predicted regulatory function and co-accessibility with target genes. A causal T2D variant rs231361 at the KCNQ1 locus had predicted effects on a beta cell enhancer co-accessible with INS and genome editing in embryonic stem cell-derived beta cells affected INS levels. Together our findings demonstrate the power of single-cell epigenomics for interpreting complex disease genetics.
Identifiants
pubmed: 33795864
doi: 10.1038/s41588-021-00823-0
pii: 10.1038/s41588-021-00823-0
pmc: PMC9037575
mid: NIHMS1675458
doi:
Substances chimiques
Blood Glucose
0
Chromatin
0
KCNQ1 Potassium Channel
0
KCNQ1 protein, human
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
455-466Subventions
Organisme : NIDDK NIH HHS
ID : U01 DK105541
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK114650
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK120429
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK068471
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK105554
Pays : United States
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