RANdOM · Systematic search of RegulAtory elements coNtrOlling autosomal Monoallelic expression

Systematic search of RegulAtory elements coNtrOlling autosomal Monoallelic expression

The establishment and maintenance of the epigenetic states that define cell identity are fundamental processes in metazoan biology. By crystallizing gene expression regulatory states in cell populations, permanently or transiently, these mechanisms set the foundations of embryonic development, cell differentiation, and tissue homeostasis. Among the diverse epigenetic phenomena, perhaps one of the most intriguing is the process of gene expression regulation that results in biases of allelic expression, sometimes with the complete silencing of one of the alleles (monoallelic expression). This is because the silencing of one of the two copies of a gene in a diploid genome potentially abolishes the benefits of a redundant genome. Monoallelic expression is also intriguing because it reveals the asymmetric regulation of two genetic entities (the two alleles of the same gene) that are otherwise identical. This project aims at better understand the mitotically stable random monoallelic expression (RME) and random imbalanced expression (RIE) that is observed on a fraction of the autosomal genes. Although it is estimated that only 1-10% of the autosomes show such an expression pattern, the widespread of functional classes observed among the affected genes underlies diverse pathways and emphasizes the potential for disease consequent from the perturbation of RME and RIE regulation. Indeed, great focus has been given to the role of allelic-specific cis-regulatory genetic effects on disease, but these studies are insensitive to the random allelic effects of epigenetic nature, either because these are canceled out (e.g., RNA-Seq studies in bulk tissues), the technology is not (yet) sensitive enough to reliably call mitotically-stable epigenetic allelic biases (single-cell RNA-Seq), or are not high-throughput (e.g., FISH) and thus lack power. As a consequence, the impact of allelic imbalances of epigenetic nature on disease remains uncertain. The overall objective of this action is to identify mechanisms of regulation of mitotically stable allelic imbalances in murine cells. Additionally, we will characterize the dynamics of allele-specific expression along the cell cycle progression and characterize for the first time the highly stable monoallelic expression states in hematopoietic stem cells in the mouse model, in vivo. These studies will consolidate the base knowledge in the field and set the ground for the introduction of the clonal parameter on studies of functional genetics.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз