Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism.
Bibliographical noteFunding Information:
We thank Cédric Notredame, Anthony Mathelier, Oriol Fornes Crespo, Philip Richmond, Jean-Christophe Andrau, Diego Garrido Martin, Dimitri D. Pervouchine, Roderic Guigo, Charles Plessy, and Chung Hon for their help in analyzing the data and for insightful suggestions. We also thank Takahiro Arakawa for the preparation and provision of cell culture samples. We are indebted to the researchers around the globe who generated experimental data and made them freely available. C.-H.L. is grateful to Marc Piechaczyk and Edouard Bertrand for their continued support. The work was supported by funding from CNRS (International Associated Laboratory “miREGEN”), INSERM-ITMO Cancer project “LIONS” BIO2015-04, Plan d’Investissement d’Avenir #ANR-11-BINF-0002 Institut de Biologie Computationnelle (young investigator grant to C-H.L.) and GEM Flagship project funded from Labex NUMEV (ANR-10-LABX-0020). M.G. was supported by a Conventions Industrielles de Formation par la Recherche (CIFRE) PhD fellowship from SANOFI R&D. FANTOM5 was made possible by the following grants: Research Grant for RIKEN Omics Science Center from MEXT to Y.H.; Grant of the Innovative Cell Biology by Innovative Technology (Cell Innovation Program) from the MEXT to Y.H.; Research Grant from MEXT to the RIKEN Center for Life Science Technologies; Research Grant to RIKEN Preventive Medicine and Diagnosis Innovation Program from MEXT to Y.H. This work was further supported by a Research Grant from MEXT to the RIKEN Center for Integrative Medical Sciences.
© 2021, The Author(s).
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)