Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Genome organization within the nucleus is crucial for cell viability and gene expression. Proteins that control nuclear organization have been identified, but this process has not been well characterized so far. Importantly, nuclear organization has been shown to be disrupted in diseases classified as laminopathies, as well as in some neurodegenerative diseases. We hypothesize that Lamin A is one of the key players responsible for maintaining nuclear organization and normal cell function. Our goal is to characterize the molecular mechanism through which Lamin A interacts with DNA, by defining the domains within Lamin A that are sufficient for this effect. We also want to use next generation sequencing methods to determine the effects of Lamin A on genome organization, as well the changes in gene expression. For these purposes, we have developed an assay for specifically isolating the effects of Lamin A on the genome. We propose to take advantage of the unique architecture of mouse rod photoreceptor nuclei. Rods are devoid of any other tethering proteins, allowing a very clean read-out of Lamin A activity. We expect to characterize new determinants of chromatin organization and disentangle their roles in higher order chromatin organization and gene expression, which is vital for finding a solution for the treatment of some of the most deadly neurodegenerative disorders and syndromes, as well as ageing. We expect to find a critical region of Lamin A that is important in reorganizing the genome and with this knowledge we will contribute to finding a cure for laminopathic and neurodegenerative diseases connected with chromatin disorganization.