Regulation of gene dosage on the mouse X chromosome

Introduction

Differences in gene dosage can be as powerful as to drive species evolution (e.g., whole-genome duplications) and as harmful as to lead to human diseases (e.g., aneuploidies or haploinsufficiencies). Regulating the effects of gene-dosage differences is thus extremely critical, and this is paradigmatically illustrated by what happens to the X chromosome in mammals.

X-Chromosome Inactivation

In XX individuals, one of the X chromosomes is transcriptionally silenced as a result of a developmental and epigenetic process called X-chromosome inactivation (XCI), which is presumed to have evolved to compensate for X-linked gene dosage between XX and XY individuals. Since its ‘discovery’ in 1961 by Mary Lyon, we have learned much about XCI developmental dynamics and molecular underpinnings. However, very little is understood about the developmental and molecular reasons at the basis of its evolution.

Project Objectives

REGULADOSIX aims to gain a functional and mechanistic understanding of the need for X-linked dosage compensation in mammals. We will:

1. Determine the developmental and molecular consequences in the absence of XCI in mouse embryogenesis.
2. Functionally identify genes on the X chromosome that are dosage-sensitive, as well as their functions, which would have dictated the emergence of XCI in mammalian evolution.

Methodology

Building on my previous expertise, I propose a multidisciplinary approach at the intersection between development and genetic engineering. This includes:

• Cutting-edge genomic technologies (epigenetic screens, functional transcriptomics, and proteomics).
• Novel approaches that we will develop to tune levels of expression in mouse embryonic stem cells and in mouse models.

Expected Outcomes

Besides bringing new insights into the need for dosage compensation between the mammalian sexes, REGULADOSIX will contribute to a quantitative understanding of gene expression and pave the way to establishing fundamental principles of gene dosage regulation in development and disease.