Downstream-of-gene (DoG) transcripts contribute to an imbalance in the cancer cell transcriptome

Abstract

Downstream-of-gene (DoG) transcripts are an emerging class of noncoding RNAs. However, it remains largely unknown how DoG RNA production is regulated and whether alterations in DoG RNA signatures exist in major cancers. Here, through transcriptomic analyses of matched tumors and non-neoplastic tissues and cancer cell lines, we reveal a comprehensive catalogue of DoG RNA signatures. Through separate lines of evidence, we support the biological importance of DoG RNAs in carcinogenesis. First, we reveal DoG RNAs are tissue-specific and differentially expressed in tumors versus paired normal tissues with their respective host genes involved in tumor promoting versus tumor suppressor pathways. Second, increased DoG RNA number and length is associated with poor patient prognosis. Third, depletion of essential enzyme Topoisomerase I in colon cancer alters RNA polymerase II chromatin engagement leading to termination defects and induction of DoG RNAs. Our results underlie the significance of DoG RNAs in diversifying the cancer transcriptome.