Integrative Analysis of Epigenetic, Transcriptomic, and Metabolomic Responses to Arsenic Exposure Using Coupled Matrix Factorization

Abstract: Arsenic (As), a widespread environmental toxin, poses major health risks due to its inorganic forms (iAs), which are linked to cancer, cardiovascular disease, and endocrine disruption. Although its toxic effects have been extensively studied, the molecular mechanisms underlying arsenic-induced perturbations remain incompletely understood. This complexity arises from its ability to reprogram epigenetic landscapes, alter gene expression, and disrupt metabolic balance through interconnected regulatory networks. Existing studies often analyze epigenomic, transcriptomic, and metabolomic datasets independently, overlooking their interdependence. Here, we present a coupled matrix factorization (CMF) framework based on the PARAFAC2-AOADMM model for joint integration of DNA methylation (RRBS), RNA-seq, and metabolomics data from mouse embryonic stem cells (ESCs) and epiblast-like cells (EpiLCs) exposed to arsenic. By jointly decomposing multi-omics matrices, our approach identifies shared and dataset-specific components that capture coordinated molecular responses to arsenic exposure. This integrative methodology demonstrates the potential of CMF-based models in computational toxicology and offers a generalizable framework for dissecting complex multi-layered biological perturbations.