Haematopoietic stem cell-derived immune cells have reduced X chromosome inactivation skewing in systemic lupus erythematosus 2024 Roberts et al

Andy

Andy

Senior Member (Voting rights)

Abstract​

Objectives​

Systemic lupus erythematosus (SLE) shows a marked female bias in prevalence. X chromosome inactivation (XCI) is the mechanism which randomly silences one X chromosome to equalise gene expression between 46, XX females and 46, XY males. Though XCI is expected to result in a random pattern of mosaicism across tissues, some females display a significantly skewed ratio in immune cells, termed XCI-skew. We tested whether XCI was abnormal in females with SLE and hence contributes to sexual dimorphism.

Methods​

We assayed XCI in whole blood DNA in 181 female SLE cases, 796 female healthy controls and 10 twin pairs discordant for SLE. Using regression modelling and intra-twin comparisons, we assessed the effect of SLE on XCI and combined clinical, cellular and genetic data via a polygenic score to explore underlying mechanisms.

Results​

Accommodating the powerful confounder of age, XCI-skew was reduced in females with SLE compared with controls (p=1.3×10−5), with the greatest effect seen in those with more severe disease. Applying an XCI threshold of >80%, we observed XCI-skew in 6.6% of SLE cases compared with 22% of controls. This difference was not explained by differential white cell counts, medication or genetic susceptibility to SLE. Instead, XCI-skew correlated with a biomarker for type I interferon-regulated gene expression.

Conclusions​

These results refute current views on XCI-skew in autoimmunity and suggest, in lupus, XCI patterns of immune cells reflect the impact of disease state, specifically interferon signalling, on the haematopoietic stem cells from which they derive.

Open access
 
This looks interesting but the story is obviously complicated. We have been discussing reduced X inactivation being relevant to lupus and maybe ME/CFS. This paper is about reduced skewing of X inactivation, which would be something quite different but might contribute to the same story. Reduced skewing is the norm in young people so it is a bit hard to see what it might mean having just read the intro.
 
We previously had some information about someone working on X inactivation in the context of ME/CFS in Edinburgh I seem to remember? At the time I was unclear why that would be useful but I can see now why it might well be.

Can anyone remember who that was?
 
Jonathan Edwards said:
We previously had some information about someone working on X inactivation in the context of ME/CFS in Edinburgh I seem to remember? At the time I was unclear why that would be useful but I can see now why it might well be.

Can anyone remember who that was?
Click to expand...
This?
Sasha

Post in thread 'Is the key pathology of ME/CFS in bone marrow?'

Just picked up the latest copy of MERUK's Breakthrough magazine and there's what seems a very relevant study by a Dr Manousaki starting up:

Chromosomes carry our genetic information and, typically, females have two X chromosomes while males have one X and one Y chromosome. In females, one of the X chromosomes is inactivated in each cell in order to avoid a double-dose of X-linked genes.​
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X chromosome inactivation (XCI) therefore needs to be maintained throughout life, and disruption of this can lead to developmental problems and diseases, including those affecting the...​
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Briefly discussed here:
 
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