Betti, M. J. | bioRxiv Science

bioRxiv2025

A role of extracellular vesicle-mediated inter-organ communication in obesity-related arrhythmia

Obesity contributes to the risk of cardiac arrhythmias, but the exact mechanism remains unclear. Here, we show visceral adipose tissue-derived extracellular vesicles (VAT EVs) from individuals with obesity prolong action potential duration (APD) and impair calcium handling in stem cell-derived cardiomyocytes, in addition to activating fibroblasts and macrophages towards a pro-fibrotic/inflammatory state, thereby creating pro-arrhythmic substrate. Adipose-derived EVs target the heart in obese mice, suggesting the potential for direct communication. Transcriptome-wide genetic association (TWAS) and epigenetic studies anchored on genes differentially expressed in cardiomyocytes, fibroblasts, and macrophages after VAT-EV exposure identified genes significantly associated with QT interval and atrial fibrillation. Finally, as a proof-of-principle, we pharmacologically blocked TRPC3 (a VAT-EV-induced ion channel) in cardiomyocytes, restoring the APD towards normality. This molecular genetic evidence supports an EV-mediated direct communication pathway between adipose tissue and the heart in arrhythmogenesis, offering a new paradigm to identify mediators of cardiovascular disease in obesity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/676027v1_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@114b230org.highwire.dtl.DTLVardef@1be7926org.highwire.dtl.DTLVardef@3d6b0org.highwire.dtl.DTLVardef@3ef15_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Minimum entropy framework identifies a novel class of genomic functional elements and reveals regulatory mechanisms at human disease loci

We introduce CoRE-BED, a framework trained using 19 epigenomic features in 33 major cell and tissue types to predict cell-type-specific regulatory function. CoRE-BED identifies nine functional classes de-novo, capturing both known and new regulatory categories. Notably, we describe a previously undercharacterized class that we term Development Associated Elements (DAEs), which are highly enriched in cell types with elevated regenerative potential and distinguished by the dual presence of either H3K4me2 and H3K9ac (an epigenetic signature associated with kinetochore assembly) or H3K79me3 and H4K20me1 (a signature associated with transcriptional pause release). Unlike bivalent promoters, which represent a transitory state between active and silenced promoters, DAEs transition directly to or from a non-functional state during stem cell differentiation and are proximal to highly expressed genes. CoRE-BEDs interpretability facilitates causal inference and functional prioritization. Across 70 complex traits, distal insulators account for the largest mean proportion of SNP heritability ([~]49%) captured by the GWAS. Collectively, our results demonstrate the value of exploring non-conventional ways of regulatory classification that enrich for trait heritability, to complement existing approaches for cis-regulatory prediction.

genomics↗