Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
04
06
2021
accepted:
31
03
2022
pubmed:
20
5
2022
medline:
18
6
2022
entrez:
19
5
2022
Statut:
ppublish
Résumé
Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across cell types. Genome-wide association studies have identified over 200 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements. Here, we applied single-nucleus assay for transposase-accessible chromatin with sequencing to profile 28,316 nuclei across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped ~320,000 accessible sites across all cells, identified cell-type-specific elements and transcription factors, and prioritized functional CAD risk variants. We identified elements in smooth muscle cell transition states (for example, fibromyocytes) and functional variants predicted to alter smooth muscle cell- and macrophage-specific regulation of MRAS (3q22) and LIPA (10q23), respectively. We further nominated key driver transcription factors such as PRDM16 and TBX2. Together, this single-nucleus atlas provides a critical step towards interpreting regulatory mechanisms across the continuum of CAD risk.
Identifiants
pubmed: 35590109
doi: 10.1038/s41588-022-01069-0
pii: 10.1038/s41588-022-01069-0
pmc: PMC9203933
mid: NIHMS1794783
doi:
Substances chimiques
Chromatin
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
804-816Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL125863
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL144475
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL125224
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM133712
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141425
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL148167
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139478
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL164577
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL148239
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL135093
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL123370
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130423
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL134817
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL125912
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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