Controlled noise: evidence of epigenetic regulation of single-cell expression variability.

Motivation Understanding single-cell expression variability (scEV) or gene expression noise among cells of the same type and state is crucial for delineating population-level cellular function. While epigenetic mechanisms are widely implicated in gene expression regulation, a definitive link between chromatin accessibility and scEV remains elusive. Recent advances in single-cell techniques enable the study of single-cell multiomics data that include the simultaneous measurement of scATAC-seq and scRNA-seq within individual cells, presenting an unprecedented opportunity to address this gap. Results This article introduces an innovative testing pipeline to investigate the association between chromatin accessibility and scEV. With single-cell multiomics data of scATAC-seq and scRNA-seq, the pipeline hinges on comparing the prediction performance of scATAC-seq data on gene expression levels between highly variable genes (HVGs) and non-highly variable genes (non-HVGs). Applying this pipeline to paired scATAC-seq and scRNA-seq data from human hematopoietic stem and progenitor cells, we observed a significantly superior prediction performance of scATAC-seq data for HVGs compared to non-HVGs. Notably, there was a substantial overlap between well-predicted genes and HVGs. The gene pathways enriched from well-predicted genes are highly pertinent to cell type-specific functions. Our findings support the notion that scEV largely stems from cell-to-cell variability in chromatin accessibility, providing compelling evidence for the epigenetic regulation of scEV and offering promising avenues for investigating gene regulation mechanisms at the single-cell level. Availability and implementation The source code and data used in this article can be found at https://github.com/SiweiCui/EpigeneticControlOfSingle-CellExpressionVariability. [ABSTRACT FROM AUTHOR]