Large-scale single-nuclei profiling identifies role for ATRNL1 in atrial fibrillation
Atrial fibrillation (AF) is the most common sustained arrhythmia in humans, yet the molecular basis of AF remains incompletely understood. To determine the cell type-specific transcriptional changes underlying AF, we perform single-nucleus RNA-seq (snRNA-seq) on left atrial (LA) samples from patients with AF and controls. From more than 175,000 nuclei we find that only cardiomyocytes (CMs) and macrophages (MΦs) have a significant number of differentially expressed genes in patients with AF. Attractin Like 1 (ATRNL1) was overexpressed in CMs among patients with AF and localized to the intercalated disks. Further, in both knockdown and overexpression experiments we identify a potent role for ATRNL1 in cell stress response, and in the modulation of the cardiac action potential. Finally, we detect an unexpected expression pattern for a leading AF candidate gene, KCNN3. In sum, we uncover a role for ATRNL1 which may serve as potential therapeutic target for this common arrhythmia.
Authors
- Kenneth B. Margulies (ORCID: https://orcid.org/0000-0002-8093-4465)
- Matthew C. Hill (ORCID: https://orcid.org/0000-0003-4578-3873)
- Ondine Atwa
- Carla Klattenhoff
- Kenneth C Bedi (ORCID: https://orcid.org/0000-0003-3588-9324)
- Yasmine Guedira
- Nathan R. Tucker (ORCID: https://orcid.org/0000-0002-5071-4218)
- Harshit Bhasin (ORCID: https://orcid.org/0000-0001-9687-9344)
- Mark D. Chaffin (ORCID: https://orcid.org/0000-0002-1234-5562)
- Patrick T. Ellinor (ORCID: https://orcid.org/0000-0002-2067-0533)
- Bridget Simonson (ORCID: https://orcid.org/0009-0003-5601-0953)
- Carolina Roselli (ORCID: https://orcid.org/0000-0001-5267-6756)
- Helene Mantineo
- Ling Xiao (ORCID: https://orcid.org/0000-0003-3025-467X)
- Caroline N. Herndon
Institutions
- Broad Institute (US)
- Bayer (United States) (US)
- SUNY Upstate Medical University (US)
- Cardiovascular Institute of the South (US)
- Massachusetts General Hospital (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-19
- DOI
- https://doi.org/10.1038/s41467-024-54296-w
- Citations
- 11
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 2.57
Funders
- American Heart Association
- Massachusetts General Hospital
- European Commission
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Human Genome Research Institute
- NIH Office of the Director
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- Common Fund