Uncovering the missing X factors to understand sex bias in cardiovascular disease

Informations projet

EscapeX

N° de convention de subvention: 101078764

DOI

10.3030/101078764

Date de signature de la CE 22 Octobre 2023

Date de début 1 Janvier 2024

Date de fin 31 Decembre 2028

Financé au titre de

• European Research Council (ERC)

Coût total

€ 1 491 750,00

Contribution de l’UE

€ 1 491 750,00

Coordonné par

TECHNISCHE UNIVERSITAET MUENCHEN
Germany

Periodic Reporting for period 1 - EscapeX (Uncovering the missing X factors to understand sex bias in cardiovascular disease)

Période du rapport: 2024-01-01 au 2026-06-30

Résumé du contexte et des objectifs généraux du projet

Cardiac remodeling in response to chronic stress is a key process in the development of chronic non-ischemic heart failure and contributes substantially to the global disease burden. This process often involves cardiac hypertrophy, in which the heart muscle becomes abnormally thickened due to long-term increased workload, such as in conditions like high blood pressure, aortic stenosis, or aging. Notably, cardiac hypertrophy and the progression to heart failure show important differences between women and men, indicating that biological sex influences disease development, progression, and clinical outcomes. While sex hormones contribute to these differences, genetic factors linked to the X chromosome are increasingly recognized as additional contributors. Women carry two X chromosomes, whereas men carry one, and to ensure balanced gene expression between sexes, one X chromosome is normally silenced in female cells through a process known as X-chromosome inactivation. However, some genes escape this silencing and remain active on the otherwise inactive X chromosome. The resulting higher expression of these genes in female cells may contribute to sex-specific differences in cellular function and disease mechanisms, but their role in cardiac hypertrophy and heart failure remains largely unknown. EscapeX aims to determine how X-chromosome escape changes during chronic cardiac stress and investigate whether altered gene dosage influences disease progression. The project is expected to provide new mechanistic insight into sex differences in cardiac remodeling and heart failure and identify potential targets for future therapeutic strategies.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

EscapeX established the experimental and analytical framework required to investigate X-chromosome regulation in cardiac remodeling during chronic heart failure. Experimental models of cardiac remodeling were implemented and combined with transcriptomic and allele-resolved genomic approaches to study changes in X-linked gene expression during disease progression. Cell-type-resolved strategies were established to investigate X-chromosome escape across major cardiac cell populations, complemented by single-cell approaches. Computational pipelines for allele-specific analysis were also developed and applied across mouse and human datasets. These studies have enabled the identification and prioritisation of X-linked genes for functional follow-up. Together, these achievements provide the foundation for the next phase of EscapeX, which will determine how altered X-linked gene dosage contributes to sex-specific mechanisms of chronic heart failure.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

EscapeX is extending current knowledge of X-chromosome regulation by investigating escape from X-chromosome inactivation during chronic heart failure at tissue and cell-type resolution. The project has established approaches to resolve X-linked gene activity across individual cardiac cell populations rather than relying solely on whole-organ measurements. A major advance is the integration of allele-specific genomics with single-cell technologies, linking X-chromosome activity with cellular identity. Candidate X-linked genes for functional investigation have also been identified, alongside approaches for translation to human cardiac tissue. Together, these studies advance the mechanistic understanding of how X-chromosome regulation may contribute to disease development and progression. Further functional studies will experimentally alter the dosage of selected escape genes to determine their contribution to cardiac disease progression and potential as therapeutic targets.