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4 novembre

Germano Cecere Transcriptional and epigenetic regulation by short RNAs

14h à 15h30

Le séminaire de Germano Cecere (Columbia University Medical Center, New York) aura lieu dans la salle Favard, IBENS 46 rue d’Ulm 75005 Paris


RNA interference (RNAi) is largely known as a negative regulator of gene expression. The mechanisms by which RNAi negatively regulate gene expression include Argonaute proteins and their small RNA cofactors short interfering RNAs (siRNAs) inhibiting mRNA translation, mRNA or pre-mRNA degradation, and RNA transcription. Interestingly, the association of nuclear Argonaute proteins with transcriptionally active gene loci has been described in animals, including humans, raising the interesting possibility that RNAi-mediated mechanism could regulate active genes.
I will present the results of my work on the C. elegans nuclear Argonaute protein CSR-1. CSR-1 is exclusively loaded with endogenous siRNAs (endo-siRNAs) antisense to thousands of active germline transcripts. CSR-1 associates with chromatin, and inactivation of the components of the CSR-1 pathway leads to sterility, embryonic lethality, and chromosome organization defects. To investigate the nuclear role of CSR-1, I adapted the Global Run-On sequencing (GRO-seq) method, which measures nascent RNA polymerase II (Pol II) transcripts in a genome-wide fashion, for use in C. elegans. Surprisingly, I discovered that CSR-1 and its associated endo-siRNAs globally promote sense-oriented Pol II transcription of germline genes. Moreover, CSR-1 directly interacts with nascent RNA target transcripts and the Pol II machinery in siRNA-dependent manner. Loss of CSR-1 function results in global increase in antisense transcription and ectopic transcription of silent chromatin domains, which affects centromere formation and chromatin organization. Together, these results suggest that the CSR-1 pathway has a role in maintaining the genome-wide distribution of Pol II and thus propagating the distinction between active and silent chromatin domains. I propose a model where CSR-1 endo-siRNAs may constitute an RNA-based system for propagating the memory of actively transcribed genomic chromatin regions across generations.