Descrizione del progetto
L’inattivazione del cromosoma X nelle risposte immunitarie
Le donne sono portatrici di due copie di tutti i geni legati al cromosoma X. Per questo, subiscono l’inattivazione casuale del cromosoma X (XCI) durante la formazione dell’embrione per garantire un’espressione identica nei due sessi. Sono però presenti determinati geni che sfuggono all’inattivazione oppure tessuti in cui viene alterata. Il risultato è l’inattivazione di cromosomi X materni rispetto a quelli paterni in base a rapporti diversi. Il progetto XX-Health, finanziato dal Consiglio europeo della ricerca, si prefigge di esaminare il ruolo dell’inattivazione casuale del cromosoma X nelle risposte immunitarie nelle donne rispetto agli uomini. I ricercatori intendono studiare le cellule T provenienti da donne con XCI alterata o uniparentale per stabilirne la rilevanza funzionale nella biologia di queste cellule. I risultati del progetto favoriranno la comprensione dell’impatto di XCI nello stato di salute e malattia.
Obiettivo
Females have a higher risk for autoimmune disease and lower risk of mortality from infectious disease than males, reflecting a more robust immune response in females against both self-antigens (autoimmunity) and non-self-antigens (infections). Genes that escape the process of X-inactivation (XCI) are present in a higher dose in female cells and many play key roles in T-cell biology. XX-Health will reveal the role of escape genes in mediating sex-differences in T-cell response.
Different cells in a tissue can inactivate the maternal (Xm) or paternal X-chromosome (Xp) (mosaicism). In addition, different ratios of Xm and Xp may become silenced in cells of a given tissue resulting in skewed X-inactivation (sXCI), rendering functional dissection of XCI very challenging. Rare females (~1:300) inactivate the same parental X-chromosome in all cells (cXCI), removing the confounding effect of mosaicism, and offering a powerful genetic system in which to dissect XCI in T-cell biology.
We will develop a novel methodology, TriX-Seq, allowing high-resolution screening of sXCI and cXCI in a large (N~8,000) unselected cohort of females. Using T-cells isolated from identified cXCI females, we will (i) generate a unique multi-omic map of XCI during human T-cell differentiation at a resolution well beyond the state-of-the-art and (ii), directly test the function of alleles specifically expressed from the inactive X-chromosome (Xi) in T-cell biology. With sXCI data in hand, we will also reveal the associations, if any, of sXCI with disease risk and use the unique availability of parental and grand-parental DNA to assess the genetic origin of cXCI.
Sex-bias in COVID-19 mortality has highlighted the importance of sex as a contributor to disease risk. The technical and conceptual advances delivered by XX-Health will make a seminal contribution to our understanding of this poorly understood component of human health.
Campo scientifico
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
ERC - Support for frontier research (ERC)Istituzione ospitante
581 83 Linkoping
Svezia