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 nonneoplastic tissues and cancer cell lines, we reveal a comprehensive catalog of DoG RNA signatures. Through separate lines of evidence, we support the biological importance of DoG RNAs in carcinogenesis. First, we show tissue-specific and stage-specific differential expression of DoG RNAs in tumors versus paired normal tissues with their respective host genes involved in tumor-promoting versus tumor-suppressor pathways. Second, we identify that differential DoG RNA expression is associated with poor patient survival. Third, we identify that DoG RNA induction is a consequence of treating colon cancer cells with the topoisomerase I (TOP1) poison camptothecin and following TOP1 depletion. Our results underlie the significance of DoG RNAs and TOP1-dependent regulation of DoG RNAs in diversifying and modulating the cancer transcriptome.
| Original language | English (US) |
|---|---|
| Article number | adh9613 |
| Journal | Science Advances |
| Volume | 10 |
| Issue number | 27 |
| DOIs | |
| State | Published - Jul 2024 |
Funding
We thank the Lauberth laboratory members, A. Shilatifard, R. Shiekhattar, and M. Morgan for discussions and M. Bhola and M. Iwanaszko for advice on NGS data analysis. We want to thank M. Parren for review and editing of the manuscript and S. Lauberth for helping with figure design and layout. This research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, Feinberg's Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University's high-performance Computing facility, with the purpose to advance research in genomics. Funding: This work was supported by NIH/National Institute of General Medical Sciences (R35 GM128900) to S.M.L, the Robert H. Lurie Comprehensive Cancer Center to S.M.L. and Y.L., and NIH/National Institute of General Medical Sciences (R35 GM147283) to Y.L. Author contributions: Conceptualization: S.M.L.. Methodology: K.A., B.M., J.X., P.-A. L., and N.M. Investigation: K.A., B.M., J.X., P.-A. L., and N.M. Computational analysis: J.X., P.-A. L., D.K., and Y.L. Writing-original draft: S.M.L. Writing- review and editing: S.M.L., G.-Y. Y., D.K., Y.L., K.A., and B.M. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. RNA-seq, PRO-seq, ChIP-seq, and TOP1-seq data have been deposited and are accessible at the Gene Expression Omnibus with the accession number (GSE202408). This paper analyzes existing, publicly available TC GA data (accession number: phs000178.v10.p8). facility, with the purpose to advance research in genomics. Funding: this work was supported by nih/national institute of General Medical Sciences (R35 GM128900) to S.M.l, the Robert h. lurie comprehensive cancer center to S.M.l. and Y.l., and nih/national institute of General Medical Sciences (R35 GM147283) to Y.l. Author contributions: conceptualization: S.M.l.. Methodology: K.A., B.M., J.X., P.-A.l., and n.M. investigation: K.A., B.M., J.X., P.-A.l., and n.M. computational analysis: J.X., P.-A.l., d.K., and Y.l. Writing\u2014original draft: S.M.l. Writing\u2014 review and editing: S.M.l., G.-Y.Y., d.K., Y.l., K.A., and B.M. Competing interests: the authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. RnA-seq, PRO-seq, chiP-seq, and tOP1-seq data have been deposited and are accessible at the Gene expression Omnibus with the accession number (GSe202408). this paper analyzes existing, publicly available tcGA data (accession number: phs000178.v10.p8).
ASJC Scopus subject areas
- General
