Issues with X chromosome inactivation as a reason for female predominance in ME/CFS

[Utsikt]

Split from United Kingdom: ME Research UK (MERUK) News

From MERUK at the link above:

A closer look at the X chromosome​

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.

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 immune system, such as systemic lupus erythematosus. There is also reason to suspect that dysregulation of XCI could affect the function of the mitochondria, the powerhouses of the cell.

Objectives​

Dr Manousaki’s research will test the idea that, in ME/CFS, XCI is not being maintained correctly. This could lead to abnormal levels of certain X-linked genes, disrupting immune balance and energy production in cells.

This mechanism could therefore explain the higher prevalence of ME/CFS in females than in males. Dr Manousaki plans to investigate this using super-resolution microscopy and gene expression analysis.

She will first assess whether XCI is dysregulated in women with ME/CFS, specifically looking at genetic factors which regulate XCI and may therefore have value as a diagnostic biomarker.

She will also investigate whether cells from men and women with ME/CFS struggle to generate and use energy efficiently, analysing mitochondrial structure and its interactions with associated endoplasmic reticulum contact sites which have been implicated in other diseases such as Alzheimer’s and Parkinson’s diseases.

Finally, linking these two areas, Dr Manousaki will test whether XCI disruption can directly cause mitochondrial dysfunction, linking the genetic findings with cellular energy problems and exploring whether these effects differ between men and women.

 

[Hutan]

Background reading

The Role of Genetic Sex and Mitochondria in Response to COVID-19 Infection, 2020
Looks like the sex chromosomes are very important for immunity. (I'm looking forward to the DecodeME results for these chromosomes.) I guess there might be something protective on the Y chromosome.

the human chromosome X consists of over 150 million DNA base pairs and contains more than 800 protein-coding genes, which include the highest number of the innate and adaptive immunity-related genes of the whole human genome, and several hundred non-coding genes.

The Y chromosome regulates many different immune-response functions, immune cell numbers, and immune cell phenotypes through the regulation of transcriptionally inert (heterochromatin) and active (euchromatin) status of X chromosome and autosomes.

Studies showed that Y chromosome can regulate the heterochromatin/euchromatin status of the autosomes and X chromosomes and, thus, affects silencing/expression of various genes, including the immune response genes, and regulate the tissue-/cell-specific alternative gene splicing

Although the mechanism by which the Y chromosome influences heterochromatin/euchromatin content and thus the transcription of the other genes is largely unknown, one of the hypotheses postulates that the Y chromosome sequesters heterochromatinization factors and another that it affects the architecture of cell nucleus, which makes specific genes inaccessible to the transcription factors

Mosaicism in females - some cells express one X chromosome, other cells can express the other X chromosome

Because in the female cells, the inactivation of one of the X chromosomes is random, the female body may contain different alleles of the same gene.

 

[Jonathan Edwards]

I don't understand the motive for this study. MECFS is almost certainly more common in women because they are women and have no Y chromosome. Not because they are rare cases where the normal female state has gone wrong. No man has MECFS because of X chromosomes going wrong, so it seems unlikely to be why women do.

 

[SNT Gatchaman]

No man has MECFS because of X chromosomes going wrong, so it seems unlikely to be why women do.

My experience is that the key to these diseases is finding the way in which the normal rules are broken, not in finding what is following the normal rules. We have done those diseases.

The normal rule here is that the "spare" X chromosome in females is silenced by XIST to compensate for dosage. In males, apart from normal spermatogenesis, this can occur in cancer cells Somatic XIST activation and features of X chromosome inactivation in male human cancers (2022, Cell Systems)

So could the rule be broken? Males and females both have X chromosomes and XIST is derived from the XIC (X-chromosome inactivation centre). What if XIST is inappropriately affecting the "good" X chromosome in females or the solitary X chromosome in males and reducing some gene product that's needed — rather than the normal rule of not over-producing some gene product that isn't wanted?

And then the rules might be further bent if there is any possibility it's able to adversely affect an autosome (with more chance in females because XIST is always active). This paper looks to suggest that possibility (in mice).

XIST directly regulates X-linked and autosomal genes in naive human pluripotent cells (2024, Cell, PMC)

We found that XIST spreads across the X chromosome and induces dampening of X-linked gene expression in naive hPSCs. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences in autosomes. […] Together, our study identifies XIST as the regulator of X chromosome dampening, uncovers an evolutionarily conserved trans-acting role of XIST/Xist, and reveals a correlation between XIST/Xist dispersal and autosomal targeting.