tRNA-overlapping long non-coding RNA loci repress codon-biased genes

Sameen Ahmed; Jacob L Fine; Jordan J Chalmers; Katerina Kiriakopulos; Lindsay A Clarke; Carla Casanova Suárez; Katty Soleimanpour; Winona Oliveros; Kate Delfosse; Milad Mokhtaridoost; Cassandra J Wong; Anne-Claude Gingras; Brian Ciruna; Marc R Fabian; Benjamin J Blencowe; Philipp G Maass

doi:10.1016/j.celrep.2025.116417

tRNA-overlapping long non-coding RNA loci repress codon-biased genes

Cell Rep. 2025 Oct 28;44(10):116417. doi: 10.1016/j.celrep.2025.116417. Epub 2025 Oct 9.

Authors

Sameen Ahmed¹, Jacob L Fine², Jordan J Chalmers¹, Katerina Kiriakopulos¹, Lindsay A Clarke³, Carla Casanova Suárez⁴, Katty Soleimanpour⁵, Winona Oliveros⁴, Kate Delfosse⁵, Milad Mokhtaridoost⁵, Cassandra J Wong⁶, Anne-Claude Gingras⁷, Brian Ciruna⁸, Marc R Fabian⁹, Benjamin J Blencowe¹⁰, Philipp G Maass¹¹

Affiliations

¹ Genetics and Genome Biology Program, SickKids Research Institute, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
² Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
³ Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
⁴ Life Sciences Department, Barcelona Supercomputing Center, 08034 Barcelona, Catalonia, Spain.
⁵ Genetics and Genome Biology Program, SickKids Research Institute, Toronto, ON M5G 0A4, Canada.
⁶ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health, Toronto, ON M5G 1X5, Canada.
⁷ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health, Toronto, ON M5G 1X5, Canada.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Developmental and Stem Cell Biology Program, SickKids Research Institute, Toronto, ON M5G 0A4, Canada.
⁹ Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
¹⁰ Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
¹¹ Genetics and Genome Biology Program, SickKids Research Institute, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: philipp.maass@sickkids.ca.

PMID: 41075247
DOI: 10.1016/j.celrep.2025.116417

Abstract

The functions of most long non-coding RNAs (lncRNAs) are not known. Here, we define a group of "tRNA-overlapping lncRNA" (tROL) genes that are upregulated during in vitro cartilage development. Deletions of tROLs result in changes in the expression of codon-biased genes, where downregulated genes are enriched in codons corresponding to tRNAs overlapping disrupted tROLs. tROL loci are located in gene-dense regions and interact extensively between chromosomes, and tROL whole-gene deletions result in the upregulation of significantly overlapping subsets of genes in the vicinity of tROL loci. Inhibiting the lncRNA transcription and degrading the lncRNA transcripts of a tROL gene downregulates tRNA expression. Taken together, the results suggest that tROL loci coalesce and are dependent on each other's transcription to repress genes in spatial proximity and to activate tRNA expression. Our investigation thus provides insight into a previously uncharacterized role for tROLs as a regulatory bridge between the non-coding and coding genomes.

Keywords: CP: Molecular biology; LINC00324; chondrogenesis; gene regulation; genome organization; inter-chromosomal contact; lncRNA; tRNA; tROL.

MeSH terms

Animals
Codon* / genetics
Genetic Loci*
Mice
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
RNA, Transfer* / genetics
RNA, Transfer* / metabolism

Substances

RNA, Transfer
RNA, Long Noncoding
Codon