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Thesis defense: Lies Chikhaoui

When Oct 21, 2022
from 02:00 to 05:00
Where Amphi G1, ISFA
Contact Name
Attendees Dr. Ouria Dkhissi-Benyahya, Chargée de recherche HDR, Université Lyon 1
Dr. Virginie Faure, Maîtresse de conférences HDR, Université Grenoble-Alpes
Dr. Benjamin Audit, Directeur de recherche, ENS Lyon
Dr. Sandrine Hughes, Chargée de recherche, ENS Lyon;
Dr. Joel Richter, Professeur, University of Massachusetts;
Dr. Marie Sémon, Professeure des universités, ENS Lyon;
Dr. Yutaka Suzuki, Professeur, University of Tokyo;
Dr. Kiran Padmanabhan, Chargé de recherche HDR, ENS Lyon.
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On October 21st, Lies Chikhaoui of the team of Kiran Padmanabhan will support his thesis entitled:


"Oxford Nanopore sequencing reveals a pervasive role for the mammalian circadian clock in shaping the tissue transcriptome"



In mammals, robust circadian clocks determine the rhythmicity of many biological phenomena and coordinate gene expression programs in a tissue-specific manner. Transcriptome analyses using conventional technologies, such as microarray and Illumina-seq, have revealed rhythms in approximately 10-15% of the genes expressed in the mice liver. Direct RNA sequencing with Oxford Nanopore technology allows the detection of different gene isoforms and thus the study of alternative splicing/promoters, the precise measurement of poly(A) tail length, and the identification and quantification of epi-transcriptomic modifications, thus generating a comprehensive view of the transcriptome.

Using a proteomics approach, we identify alternative splicing factors that are mis- regulated in the livers of mice with impaired circadian rhythms but also a component of the core spliceosome complex that oscillates over time.
To measure the potential consequences of such observations on general splicing in the tissue, we performed long-read sequencing with Promethion at an unprecedented level, generating over 100 million reads from livers of wild-type mice over 24 hours as well as from Per1-/-;Per2-/- mice lacking circadian rhythms.

Results of the analysis reveal new cyclic transcripts, as well as isoforms with different dynamics (or even antiphase) although generated by the same gene, suggesting a circadian activity of alternative splicing. Furthermore, we identified about 2000 deregulated alternative splicing events in Per knockout mice and observed isoform switches that could impact metabolism. Consistent with proteomics results, mis-regulated splicing events were enriched for targets of a factor identified in mass spectrometry. In addition, we found time-dependent polyA tail length dynamics as well as a global change in PerKO mice. Altogether, our results provide evidence that the circadian clock modulates post-transcriptional modifications in order to shape the tissue transcriptome.