Mathiyalagan, P. | Search bioRxiv

bioRxiv2024

Single nucleus transcriptomics supports a role for CCNA2-induced human adult cardiomyocyte cytokinesis

Cyclin A2 (CCNA2), a master cell cycle regulator silenced in postnatal cardiomyocytes, promotes cardiac repair in animal models. However, its effect on cytokinesis in adult human cardiomyocytes remains unknown. We engineered a replication-deficient adenoviral vector encoding human CCNA2 under the cardiac Troponin T promoter and delivered it to freshly isolated cardiomyocytes from adult human hearts. Time-lapse live imaging revealed induction of complete cytokinesis with preservation of sarcomeres and calcium mobilization in redifferentiated daughter cardiomyocytes. To uncover underlying transcriptional mechanisms, single-nucleus transcriptomics of CCNA2-transgenic versus non-transgenic mouse hearts identified a cardiomyocyte subpopulation enriched for cytokinesis, proliferative, and reprogramming genes. Ultra-deep bulk RNA sequencing of adult and fetal human hearts further highlighted reprogramming pathways relevant to CCNA2-induced effects. Together, these findings demonstrate that CCNA2 can reinitiate cytokinesis in adult human cardiomyocytes and illuminate conserved molecular programs, supporting its promise as a regenerative gene therapy for the heart. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/583057v7_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@b9cfa9org.highwire.dtl.DTLVardef@f0720eorg.highwire.dtl.DTLVardef@1d020b2org.highwire.dtl.DTLVardef@112c28b_HPS_FORMAT_FIGEXP M_FIG C_FIG CCNA2 Induces Cytokinesis and Drives Proliferation and Reprogramming of Adult Cardiomyocytes: An Integrative Transcriptomic Analysis across Human and Mouse Models.

cell biology↗

bioRxiv2022

Tissue-specific and tissue-agnostic effects of genome sequence variation modulating blood pressure

Genome-wide association studies (GWAS) have mapped thousands of variants for numerous polygenic traits and diseases. However, with some exceptions, mechanistic understanding of which precise variants affect which genes in which tissues to modulate trait variation is still lacking. To this end, we introduce a novel class of genomic analyses applicable to any complex trait using GWAS together with gene expression and chromatin accessibility data from multiple tissues. Here we identify the transcription factors (TFs) and regulatory variants within active enhancers regulating specific genes in individual tissues to explain trait heritability of blood pressure (BP), a classical polygenic trait. We show that kidney-, adrenal-, heart-, and arterial-specific regulatory variants contribute to 2.5%, 5.3%, 7.7%, and 11.8% of variant heritability, respectively. Collectively, [~]500,000 predicted regulatory variants across these four tissues explain 33.4% of variant heritability. We demonstrate that these variants are enriched in enhancers binding specific TFs in each tissue. Our findings suggest that gene regulatory networks perturbed by common regulatory variants in a tissue relevant to a phenotype are the primary source of interindividual variation of BP. These studies provide an approach to scan each human tissue for its physiological contribution to a trait.

genetics↗