"Alternative pre-mRNA splicing is more a rule than an exception because it is estimated to affect the expression of nearly 65%of human genes. The importance of alternative splicing (AS) is confirmed by findings that mutations that affect it are frequent in human hereditary disease and because AS factors can be misregulated in cancer. It is now well established that splicing can be cotranscriptional and that AS regulation not only depends on the interaction of splicing factors with their target sequences in the pre-mRNA, but is also coupled to RNA polymerase II (Pol II) transcription, similar to what happens with other pre-mRNA processing reactions. A unique feature of this polymerase is the presence of a highly repetitive carboxy terminal domain (CTD), which is subject to multiple regulatory post-translational modifications. The ways in which transcription, and more precisely CTD phosphorylation events, regulate AS involve both the association of splicing factors to the transcribing polymerase (recruitment coupling) and modulation of Pol II elongation rates (kinetic coupling). Moreover, it has been recently shown that chromatin template modifications, through Pol II elongation inhibition, can influence AS. But the mechanisms involved in alternative splicing regulation, especially those acting through coupling with transcription, have not been deeply studied in in vivo models. Much of our knowledge comes from in vitro approaches, where conditions can be precisely controlled at the expense of losing several levels of regulation present in intact cells. In this project, we plan to address two major questions: 1) how hyperphosphorylation of Pol II induces a decrease in Pol II elongation rate and 2) how AS changes caused through modifications in Pol II activity and chromatin structure are regulated during the cell cycle. To tackle these questions, we will take advantage of recent findings obtained by both the Kornblihtt and the Valcárcel labs."