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XCYCLE

Financiado

Toward a comprehensive analysis of the dynamics and mechanisms of X chromosome i...

Toward a comprehensive analysis of the dynamics and mechanisms of X chromosome inactivation in Humans The X chromosome is subjected to a formidable degree of concerted gene regulation, with appropriate dosage of X-linked expression in female mammals being ensured by the stable yet reversible inactivation of one of the two copies.... ver más

30/11/2026

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

Ver 2 Participantes

Financiación concedida El organismo H2020 notifico la concesión del proyecto el día 2021-10-20

ERC-2020-ADG: ERC ADVANCED GRANT

I+D

Cerrada hace 4 años

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2 Participantes

CNRS

2.50M€ | Lider

INFRICO

904.98K€ | Participante

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Duración del proyecto: 61 meses Fecha Inicio: 2021-10-20
Fecha Fin: 2026-11-30

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€

Descripción del proyecto The X chromosome is subjected to a formidable degree of concerted gene regulation, with appropriate dosage of X-linked expression in female mammals being ensured by the stable yet reversible inactivation of one of the two copies. The process of X chromosome inactivation (XCI) is critical for female development and linked to sex-specific traits and susceptibilities to various diseases. Well characterized in rodents, there is remarkably little knowledge of how XCI is articulated and controlled in humans, despite its major implication for human health. Here we propose to model in vitro the whole XCI cycle in humans to gain novel and high resolution insights into the key steps of the process and to identify critical actors and mechanisms We will exploit human embryonic stem cells and recent culture methods to mimic the early stage of development as well as more advanced organogenesis. This will allow us to investigate the four phases of XCI: (i) the steps that precede XCI (ii) its initiation, (iii) its maintenance in tissues including the hematopoietic system and intestinal organoids and (iv) its reversion in the germline. We will implement a combination of exploratory and mechanistic approaches integrating single cell analyses, CRISPR/Cas9 genome editing and genetic screens to build a comprehensive spatiotemporal map of X-chromosome activity across the human life cycle, to screen for regulators of each phase and to assess the importance of XCI and appropriate X-linked gene dosage to tissue development and homeostasis. Using an innovative set of approaches, we hope to challenge the general principles of XCI that were formerly defined in model organisms and to unravel human-specific features of XCI that could serve as new research paradigms in developmental epigenetics. The molecular and cellular understanding of human XCI that this project should provide is a fundamental pre-requisite to further understand the principles of human development and sex-specific diseases.

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