Descripción del proyecto
Inactivación del cromosoma X en las respuestas inmunitarias
Las hembras portan dos copias de todos los genes ligados al cromosoma X, por lo que sufren una inactivación aleatoria del cromosoma X (XCI) al principio de la embriogénesis para garantizar una expresión igual en los dos sexos. Existen determinados genes que eluden el XCI, o tejidos en que el XCI está sesgado, con diferentes proporciones de cromosomas X maternos en comparación con los paternos que se inactivan. El objetivo del equipo del proyecto XX-Health, financiado por el Consejo Europeo de Investigación, es estudiar el papel del XCI en la respuesta inmunitaria de las hembras en comparación con los machos. Los investigadores planean analizar los linfocitos T de hembras con XCI sesgado o uniparental y determinar la importancia funcional del XCI en la biología de los linfocitos T. Los resultados del proyecto ayudarán a comprender la repercusión del XCI en la salud y la enfermedad.
Objetivo
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.
Ámbito científico
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
ERC - Support for frontier research (ERC)Institución de acogida
581 83 Linkoping
Suecia