Unravelling the complex biology of sex-bias in autoimmune disease

The autoimmune disease, Systemic Lupus Erythematosus (SLE), exhibits an extreme sex-bias (female 9:1 male).

Genes that escape the process of X-inactivation (XCI) are present in a higher dose in female cells and have been implicated in altered T-cell function in SLE.

However, our knowledge of XCI dynamics in immune cell biology remains rudimentary.I hypothesize that dysregulation of XCI is a key pathogenic mechanism in SLE.

Here, I will (AIM 1A & 1B) reveal the dynamics of X-inactivation and sex-biased gene expression during normal human T-cell differentiation and further use this data to (AIM 2) reveal the contribution of XCI dysregulation in primary immune cells from SLE patients.I will combine ‘X’-ome genotyping and whole transcript single-cell RNA-Seq to generate the most complete map of human T-cell XCI to date.

I will combine FISH, IHC and RAP-Seq, to investigate the recent discovery of direct regulation of autosomal immune genes by the non-coding RNA, XIST.

Subsequently, I will use the data above as a reference to identify SLE-specific XCI dysregulation in primary T-cell from patients and use gene editing to validate the functional relevance of the observed changes.My approach holds promise for delivering novel insights into the process of XCI in human immune cell biology and its contribution to autoimmunity in females.