An atlas of human dsRNAome: cell-specific expression of endogenous double-stranded RNAs

Abstract

Endogenous double-stranded RNAs (dsRNAs) form structure-specific interactions with various dsRNA-binding proteins (dsRBP) to regulate cellular signaling by activating the innate immune response. Recent studies show that dsRNAs are closely associated with several human diseases that feature aberrant immune activation and tissue degeneration. However, our understanding on the regulation of cellular dsRNAs and their biological function is hampered by an incomplete annotation of tissue-specific profiles of dsRNAs. Here, we combine experimental and computational approaches to define the endogenous dsRNA repertoire in multiple cell types, including monocyte, neuronal progenitor cells, and several cancer cell lines of different tissue origins. We conduct formaldehyde cross-linking and immunoprecipitation followed by high-throughput sequencing (fCLIP-seq) using anti-dsRNA J2 antibody to capture and profile dsRNAs longer than 40 bp. A combination of alignment strategy to map unique reads with dsRNA-producing features is employed to characterize cellular dsRNAomes of each cell type and discover a population of endogenous dsRNAs with particular importance to cell specificity and disease context. Our comprehensive data on human dsRNAome provide a revised view of RNA-mediated cellular responses to overcome intractable immune disorders.