Single-cell multiome study maps how cellular senescence reshapes genetic regulation of chromatin and gene expression

A preprint posted to bioRxiv reports single-cell multiome ATAC-RNA profiling from proliferating and replicatively senescent primary human umbilical vein endothelial cells (HUVECs) derived from 100 genotyped donors. The study maps expression quantitative trait loci (eQTLs) and chromatin accessibility QTLs (caQTLs) separately in each cellular state, allowing direct comparison of how the inherited regulatory landscape changes as cells undergo senescence.

The authors additionally implement a covariance-aware multivariate QTL mapping approach to identify chromatin accessibility-expression QTLs (caeQTLs), which model accessibility and expression jointly rather than treating them as independent phenotypes. The joint analysis recovers regulatory signals not captured by either univariate approach alone.

Senescence — the state in which cells cease dividing in response to stress or replicative exhaustion — is increasingly recognised as a contributor to ageing-related disease and tissue dysfunction. By characterising how this state alters the effects of inherited genetic variants on chromatin and transcription, the work provides a framework for understanding why some disease-associated variants identified through GWAS may exert their effects specifically in aged or stressed cell populations rather than in proliferating cells.

The preprint does not yet carry peer-reviewed status. The HUVEC system, while tractable for QTL mapping, represents a single endothelial cell type, and the generalisability to other tissues remains to be established.