Project description
X chromosome inactivation in immune responses
Females carry two copies of all X-linked genes, and thus they undergo random X chromosome inactivation (XCI) early during embryogenesis to ensure equal expression in the two sexes. There are certain genes that escape XCI, or tissues where XCI is skewed, with different ratios of maternal versus paternal X chromosomes being inactivated. Funded by the European Research Council, the XX-Health project aims to investigate the role of XCI in immune responses in females compared to males. Researchers plan to analyse T cells from females with skewed or uniparental XCI and determine the functional significance of XCI in T cell biology. Project results will help comprehend the impact of XCI in health and disease.
Objective
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.
Fields of science
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
ERC - Support for frontier research (ERC)Host institution
581 83 Linkoping
Sweden