Regulation Ratio: A Singular Multi-Omic Measurement of Gene Regulatory Mechanisms

Gene expression is regulated through a complex interplay between transcriptional and post-transcriptional mechanisms, yet their relative contributions and relationships remain incompletely understood. In this study, we propose normalized metrics to quantify regulatory density at each of these 2 levels by integrating assay for transposase-accessible chromatin sequencing (ATAC-seq), RNA sequencing (RNA-seq), and protein occupancy profiling sequencing (POP-seq) data across 3 human cell lines-HEK293, HepG2, and K562-to assess gene-specific regulatory variations. This analysis revealed 3 distinct regulatory classes: predominantly post-transcriptionally regulated, predominantly transcriptionally regulated, and balanced genes. Using this metric, prominent associations between regulatory strategies and gene properties were uncovered, with transcriptionally regulated genes exhibiting greater length, post-transcriptionally regulated genes displaying higher isoform diversity and expression levels, and specific transcript types showing consistent enrichment patterns across regulatory categories. Remarkably, 55.8% of genes maintained identical regulatory classification across the 3 cell lines examined, with functional pathway analysis demonstrating high conservation of regulatory-functional relationships despite different cellular origins. This study provides a novel framework for understanding gene regulatory strategies and demonstrates that the relationship between gene properties and regulatory mechanisms represents a fundamental organizational principle that could transcend cell type specificity, with important implications for understanding dysregulation in disease states.