Nuclear Ago in splicing and repair

On Monday the  28th 2016 at 2.00 pm A Harel-Bellan, CNRS Director of Research at th Service de Biologie Intégrative et de Génétique Moléculaire of the Commissariat à l’énergie atomique in Saclay (France) will give a seminar entitled Nuclear Ago in splicing and repair in the Unit of Immunology and General Pathology (9, via A Ferrata). All members of the Department and other interested participants are invited to attend.

Abstract. Nearly 95% of genes are alternatively spliced (variant exons being included or not in the final product) and disruptions of this process cause a variety of diseases such as immunological, neurological disorders or cancers.Splicing is initiated co-transcriptionally, and chromatin-borne information, such as elevated H3K9 methylation or HP1 recruitment, participates in the regulation of alternative splicing, at least in part by slowing down elongating RNA polymerase II (RNAPII). We discovered a link between alternative splicing and RNA interference (RNAi), a machinery that regulates gene expression at the translational level. Altogether, our data indicate that Argonaute (AGO) proteins, key components of RNAi, are recruited to chromatin of variant exons, and that nuclear RNAi is required for alternative splicing, H3K9me3 and HP1 targeting at variant exons. In addition, our results on the model gene CD44 suggest that antisense long intragenic non-coding RNAs (aslncRNA) are involved in the regulation of alternative splicing. Based on our data, as well as on a variety of published observations, we propose a model in which head to head collisions between sense- and antisense-going RNAPII slow down sense RNAPII molecules, thereby triggering alternative splicing. Argonaute proteins, recruited to antisense transcripts through short complementary RNA sequences, would help resolving the collisions.

Reference. Ameyar-Zazoua M et al. Argonaute proteins couple chromatin silencing to alternative splicing. Nat Struct Mol Biol 19:998 (2012). The original paper describing the discovery of the link between RNA splicing and the RNA interference pathway.

Biography.  Annick Harel-Bellan is currently a research director at the CNRS. She obtained a PhD in Immunology from the “Université Paris 7” (1986) in the lab of Jean Dausset (Hôpital Saint-Louis, Paris France). She spent a few months at EMBL (Heidelberg, Germany, lab of Kathryn Howell and Daniel Louvard, 1981), and two years in the lab of Bill Farrar (NCI, Frederick, MD, USA, 1986-1988). She is currently in the SBIGEM at the CEA Saclay. Since 1988, Annick-Harel-Bellan is interested in deciphering the mechanisms involved in controlling cell fate, focusing on epigenetic (chromatin modifications and miRNAs) aspects of this control, and  thus linking epigenetics and cancer, notably by demonstrating the role of chromatin modification in the mechanism of action of the tumour suppressor Rb or of miRNAs in the balance between cell differentiation and proliferation.   During the course of these studies, she designed a strategy to inhibit small RNAs that is widely used, based on chemically modified antisense oligonucleotides (LNAs). She is also interested in nuclear RNA interference.  More recently she started to be interested in applying mathematical modelling to biological questions, focussing on the mode of action of miRNAs or on the dynamic of cancer cell populations.