Genomic imprinting is an epigenetic phenomenon in mammals, where mono-allelic expression of genes during development depends strictly on the parental origin of the gene. Imprinted genes play key roles in development, growth and behavior, and their epigenetic perturbation causes complex congenital diseases in humans. Importantly, most of the known imprinted genes are clustered in large chromosomal domains. Nevertheless, it has remained unclear which domain-wide regulatory and organizational features differentiate the parental chromosomes, and how they intersect to achieve mono-allelic imprinted gene expression. Based on our recent work, we hypothesize that imprinted long non-coding RNAs (lncRNAs) are essential for this process. In the IMP-domain project we will address this outstanding question using genome-wide and domain-specific approaches at two imprinted gene domains in mouse cells: the Dlk1-Dio3 and Kcnq1 domains. Using WT and CRISPR-engineered hybrid mouse pluripotent and differentiated cells, we will explore the regulatory and structural roles of specific nuclear lncRNAs that accumulate in cis. We will investigate the function of these lncRNAs within the context of ‘Topologically Associating Domains’ (TADs) and relative to global levels of chromatin organization like DNA replication timing and sub-nuclear localization. Our consortium previously showed that all these aspects of chromosome organization are related to noticeable allele-specific differences at the Dlk1-Dio3 domain. We will also uniquely explore whether specific structural features within the lncRNAs are essential for their domain-wide cis-effects, possibly through interacting proteins or higher-order folding of the RNA itself. Our dedicated structural investigation will guide the design of structure-based mutations in the lncRNAs, and our mouse pluripotent and differentiated cell models will allow us to test the functional effects of these mutations in physio-pathologically-relevant contexts, with unprecedented molecular precision. IMP-domain brings together three partner teams with complementary expertise in epigenetics and genomic imprinting, chromatin structure and epigenomics, and the biophysics of lncRNA structure. We expect this multidisciplinary project to provide mechanistic insights of broad relevance and to enhance our understanding of imprinted gene expression in development and disease.
Monsieur Robert FEIL (Centre national de la recherche scientifique)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
IGMM Centre national de la recherche scientifique
EMBL EUROPEAN MOLECULAR BIOLOGY LABORATORY
I2BC Centre national de la recherche scientifique
Help of the ANR 539,661 euros
Beginning and duration of the scientific project: September 2022 - 48 Months