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Regulation and reprogramming of alternative splicing in cellular transformation

Periodic Reporting for period 1 - SPLICANCER (Regulation and reprogramming of alternative splicing in cellular transformation)

Okres sprawozdawczy: 2017-07-01 do 2019-06-30

The human genome contains all the information that a human cell requires to survive and develop healthy and functionally. This information is present in the genome as subunits called genes, which are read by the cell thanks to specialized biological machineries. Genes are first transcribed in the cell nucleus as messenger RNAs (mRNA), which are then exported to the cytoplasm where they are finally translated into proteins. This linear sequence of events is complicated by additional regulatory steps that occur during the process. Indeed, genes are first transcribed as immature precursor mRNAs (pre-mRNAs) that contain both coding (exons) and non-coding segments (introns). In following steps, then, introns are removed and exons are joined together by a process called “splicing” to ultimately obtain a mature mRNA. During splicing, some exons (alternative exons) can be occasionally included from pre-mRNAs, thus generating different mature mRNAs and, as a consequence, different protein isoforms. This process is known as alternative splicing (AS) and it amplifies the protein-coding capacity of the human genome by generating multiple protein isoforms, each with different functions, from a single gene. Alterations during the process of AS can be detrimental for cells, leading to diseases including cancer. Indeed, the identification of mutations in genes coding for AS regulators in tumors highlighted the effects of AS dysfunction in cancer progression.
The aim of this project was to study the physiological mechanism behind alternative splicing of myosin VI in order to understand its de-regulation in tumors and cancer progression.
Myosin VI is an acting-binding and motor protein and its pre-mRNA undergoes AS generating two different Myosin VI isoforms. Importantly, AS of myosin VI is de-regulated in cancer. Based on this background we analyzed myosin VI AS as a model system to unravel de-regulation of AS during cancer progression.
The first part of the project was focused on the identification of proteins that can bind the myosin VI pre-mRNA and, consequently, regulate the AS of myosin VI in physiological conditions. We employed different approaches, and identified proteins that regulate the AS of myosin VI.
The second part of the project, instead, was focused on the identification of signaling pathways that influence the AS of myosin VI in physiological conditions. We identified such pathway, and we are currently analyzing additional splicing-regulated targets and their possible implications in the de-regulation of AS in cancer.
The results achieved with this project were presented to the scientific community, the educational community and the civil society. We share scientific information with the society by participating in the PubScience initiative organized in Milan, Italy.
No website has been developed for the project.
The data and results generated in this project will increase the current knowledge regarding the regulation of AS and its implications in cancer development and progression. The scientific community will have access to our data, which may be used in order to initiate new projects or complement our research. For example, new projects with the aim to understand how our findings impact tumor biology, cancer spreading and metastasis.

This project will also impact the state-of-the art of the techniques applied by scientist working in the RNA field, thanks to the development of a new in vivo technology for the identification of proteins that bind mRNAs in a physiological context.