Integration of transcriptomes of senescent cell models with multi-tissue patient samples reveals reduced COL6A3 as an inducer of senescence
Radoslav Savić,
Jialiang Yang,
Simon Koplev,
Mahru C. An,
Priyanka L. Patel,
Robert N. O’Brien,
Brittany N. Dubose,
Tetyana Dodatko,
Eduard Rogatsky,
Katyayani Sukhavasi,
Raili Ermel,
Arno Ruusalepp,
Sander M. Houten,
Jason C. Kovacic,
Andrew F. Stewart,
Christopher B. Yohn,
Eric E. Schadt,
Remi-Martin Laberge,
Johan L.M. Björkegren,
Zhidong Tu,
Carmen Argmann
Affiliations
Radoslav Savić
Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA
Jialiang Yang
Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA
Simon Koplev
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK
Mahru C. An
UNITY Biotechnology, South San Francisco, CA 94080, USA
Priyanka L. Patel
UNITY Biotechnology, South San Francisco, CA 94080, USA
Robert N. O’Brien
UNITY Biotechnology, South San Francisco, CA 94080, USA
Brittany N. Dubose
UNITY Biotechnology, South San Francisco, CA 94080, USA
Tetyana Dodatko
Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA
Eduard Rogatsky
Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA
Katyayani Sukhavasi
Department of Cardiac Surgery and The Heart Clinic, Tartu University Hospital, Tartu, Estonia
Raili Ermel
Department of Cardiac Surgery and The Heart Clinic, Tartu University Hospital, Tartu, Estonia
Arno Ruusalepp
Department of Cardiac Surgery and The Heart Clinic, Tartu University Hospital, Tartu, Estonia; Clinical Gene Networks AB, Stockholm, Sweden
Sander M. Houten
Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA
Jason C. Kovacic
Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia; St. Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia
Andrew F. Stewart
Diabetes Obesity Metabolism Institute, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Christopher B. Yohn
UNITY Biotechnology, South San Francisco, CA 94080, USA
Eric E. Schadt
Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA
Remi-Martin Laberge
UNITY Biotechnology, South San Francisco, CA 94080, USA
Johan L.M. Björkegren
Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Clinical Gene Networks AB, Stockholm, Sweden; Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden
Zhidong Tu
Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA
Carmen Argmann
Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Corresponding author
Summary: Senescent cells are a major contributor to age-dependent cardiovascular tissue dysfunction, but knowledge of their in vivo cell markers and tissue context is lacking. To reveal tissue-relevant senescence biology, we integrate the transcriptomes of 10 experimental senescence cell models with a 224 multi-tissue gene co-expression network based on RNA-seq data of seven tissues biopsies from ∼600 coronary artery disease (CAD) patients. We identify 56 senescence-associated modules, many enriched in CAD GWAS genes and correlated with cardiometabolic traits—which supports universality of senescence gene programs across tissues and in CAD. Cross-tissue network analyses reveal 86 candidate senescence-associated secretory phenotype (SASP) factors, including COL6A3. Experimental knockdown of COL6A3 induces transcriptional changes that overlap the majority of the experimental senescence models, with cell-cycle arrest linked to modulation of DREAM complex-targeted genes. We provide a transcriptomic resource for cellular senescence and identify candidate biomarkers, SASP factors, and potential drivers of senescence in human tissues.
