Dudley, S. C. | bioRxiv Science

bioRxiv2023

Cardiac Development Long non-coding RNA (CARDEL) is activated during human heart development and contributes to cardiac specification and homeostasis

Successful heart development depends on the careful orchestration of a network of transcription factors and signaling pathways. In recent years, the in vitro cardiac differentiation using human pluripotent stem cells (hPSCs) has been used to uncover the intricate gene network regulation involved in the proper formation and function of the human heart. Here, we searched for uncharacterized cardiac developmental genes by combining a temporal evaluation of the human cardiac specification in vitro with the analysis of fetal and adult heart tissue gene expression. We discovered that CARDEL (CARdiac DEvelopment Long non-coding RNA; LINC00890; SERTM2) expression coincides with the commitment to the cardiac lineage. CARDEL knockout hPSCs differentiated poorly in cardiac cells, and hPSC-derived cardiomyocytes showed faster beating rates after CARDEL controlled overexpression during differentiation. Altogether, we demonstrate physiological and molecular evidence that CARDEL expression contributes to sculpting the cardiac program during cell-fate commitment.

developmental biology↗

bioRxiv2019

Genome-wide association study provides new insights into the genetic architecture and pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide1. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained2-4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.

genetics↗