Systematic discovery of previously unknown genes involved in Beckwith–Wiedemann and Silver–Russell syndromes

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2021

We inherit two copies of each genes, one from the mother, the other from the father. Our cells usually use both copies equally but some of these do not behave in this way: they are “imprinted genes”. These genes exist as pairs, but only one copy is active while the other is switched-off. The choice of which copy should be ignored depends on whether it comes from the mother or the father. How do our cells ‘know’ which parent gave us a given imprinted gene? This is controlled by a chemical tag added on top of the genes by our parents before they are passed on to us. This gene marking is called “epigenetic” because it carries information on top of the gene, exactly like a label. This biological phenomenon is important as imprinted genes are critical for healthy development of the foetus. There are some rare diseases caused by abnormalities in the control of the chemical label on imprinted genes. For example, babies born with the Beckwith–Wiedemann syndrome (WBS) or the Silver–Russel syndrome (SRS) do not have the correct label at one key gene so consequently, some of their organs are too big or too small, respectively. These syndromes are very difficult to diagnose and cure because we do not know much about how imprinted genes are correctly controlled. To improve disease diagnosis and treatments, scientists need to identify the molecules that correctly attach and read the tags on top of the genes. This project will interrogate more than 3,000 genes that scientists have not yet studied. As one of them was recently identified by our group and by another laboratory, we suspect that some of these genes are involved in such syndromes. We will discover new genes using a powerful technology (CRISPR) that will enable us to test all genes in parallel and ask which ones play a role in controlling the genes in WBS and SRS. Our objective is to identify new molecules whose role is to ensure that epigenetic labels are correctly laid down and the molecules involved in reading them.