Argonaute proteins and their small RNA cofactors short interfering RNAs (siRNAs) are mainly known to inhibit gene expression by a variety of mechanisms, which include inhibition of mRNA translation, mRNA or pre-mRNA degradation, and inhibition of transcription by promoting heterochromatin assembly. Surprisingly, nuclear Argonaute proteins also localize on active euchromatic regions of metazoan genomes, including humans, and their functions on these active loci still remain largely unknown.
I will present the results of our work on the C. elegans nuclear Argonaute protein CSR-1. CSR-1 localizes to the nucleus and is exclusively loaded with endogenous siRNAs (endo-siRNAs), called 22G-RNAs, which are antisense to more than 4,000 active protein-coding transcripts expressed in the germline. Inactivation of the CSR-1 pathway components leads to specific germline defects and embryonic lethality. Despite these observations, the role of CSR-1 in gene regulation is unclear. We adapted the Global Run-On sequencing (GRO-seq) method for use in C. elegans to investigate a possible function of CSR-1-bound 22G-RNAs in controlling transcription genome wide. We discovered that CSR-1 globally promotes transcription of its target genes. Moreover, we demonstrated that CSR-1 interacts with RNA polymerase II (Pol II) through nascent RNAs in a siRNA-dependent manner. Finally, our analyses revealed that CSR-1 restricts the activity of Pol II to active genomic regions to avoid ectopic initiation of transcription of silent chromatin domains. Remarkably, the distinction between silent and active chromatin domains is lost in CSR-1 mutant embryos. Based on these observations, we propose a model whereby CSR-1-bound 22G-RNAs produced from the active locations of the genome reinforce germline transcription and help to propagate the distinction between active and silent chromatin domains across generations.
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