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.