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REGULADOSIX

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Regulation of gene dosage on the mouse X chromosome

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... ver más

31/12/2029

CNRS

2M€

Presupuesto del proyecto: 2M€

Líder del proyecto

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

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Financiación concedida El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2024-09-18

ERC-2024-STG: ERC STARTING GRANTS Scope:Objectives

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2 Participantes

CNRS

1.95M€ | Lider

UNIVERSITE TOULOUSE III - Pa...

N.D. | Participante

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Duración del proyecto: 63 meses Fecha Inicio: 2024-09-18
Fecha Fin: 2029-12-31

Líder del proyecto

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 2M€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto 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. 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 X-linked gene dosage between XX and XY individuals. Since its ‘discovery’ in 1961 by Mary Lyon, we have learnt 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. REGULADOSIX aims to gain a functional and mechanistic understanding of the need of X-linked dosage compensation in mammals – we will (i) determine the developmental and molecular consequences in the absence of XCI in mouse embryogenesis, and (ii) 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. Building on my previous expertise, I propose a multidisciplinary approach at the intersection between development and genetic engineering, which includes cutting-edge genomic technologies (epigenetic screens, functional transcriptomics and proteomics) and novel approaches that we will develop to tune levels of expression in mouse embryonic stem cells and in mouse models. 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.

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