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Researchers have recently discovered that reactivation of one copy of the X chromosome in women at least partly explains their predisposition to autoimmune diseases. Naturally deactivated from the start of embryonic development, this copy can be reactivated at a certain stage of aging. This would thus “wake up” genes supposed to be permanently inactive, including some regulating immune cells.
In mammals, biological sex is determined by the presence in each cell of two X chromosomes for females and X and Y chromosomes for males. The Y chromosome contains only a few active genes. It is therefore entirely possible to live without it. On the other hand, no cell, whether male or female, can survive without at least one copy of the X chromosome, which contains several hundred active genes.
However, having two X chromosomes logically implies the production of twice as many proteins specific to this chromosome, which would be fatal for the cells. As a result, each female cell at the beginning of embryogenesis is programmed to deactivate the activity of one of the copies of these two X chromosomes. This inactivation is then maintained in all future daughter cells during fetal development and postnatal. In this way, female cells produce the same amount of specific proteins as male cells, which only have one X chromosome.
However, researchers from Paris Cité University and Paul Sabatier University (in Toulouse) reveal that in women, the copy of the X chromosome that is supposed to be deactivated begins to reactivate as they age. This reactivation would be partly involved in their predisposition to autoimmune diseases. Indeed, the X chromosome has a very large number of genes involved in immune functions, including TLR7, TASL and CXCR3 or CD40LG, which tend to be overexpressed in autoimmune diseases.
On the other hand, studies have shown that men with Klinefelter syndrome (who have an extra X chromosome) have an equivalent risk to women of developing relatively rare immune disorders, such as systemic lupus erythematosus (SLE), Sjögren syndrome (affecting connective tissue) or systemic sclerosis.
However, the exact mechanisms governing these marked sexual dimorphisms in immune functions are not fully understood. The French researchers therefore explored the phenomenon further in their new study, recently published in the journal Science Advances.
A reactivation linked to aging
At the beginning of embryogenesis, the inactivation of the copy of the X chromosome is carried out through a molecule called “Xist”. The Xist gene is present on all X chromosomes, even in males, but it is only activated when they have a matching pair. In women, the gene (a long non-coding RNA strand) attaches to one of the copies of the X chromosome to stop its activity completely (or close to it).
While in most cells the repressed state of one of the copies of the X chromosome is maintained, studies have previously shown that this state has certain specificities at the level of immune cells. Indeed, the TLR7, TASL and CXCR3 genes would tend to escape deactivation by Xist and would be substantially transcribed in immune cells, even in the physiological state. This transcription is more pronounced in people suffering from an autoimmune disease.
To further explore the process, researchers in the new study genetically modified female mice so that the expression of the silencing gene Xist was disrupted. This means that the procedure does not completely prevent chromosome inactivation (as this would be fatal for mice), but only decreases it.
See as well
At first, everything seemed normal and the mice showed no signs of pathology or physiological decline. However, inflammatory symptoms similar to those of lupus began to appear as they aged. In particular, they produced anti-nucleic acid autoantibodies, an age-related overproduction of B lymphocytes as well as an increased proliferation of monocytes or macrophages and dendritic cells.
(A) Map of the X chromosome showing genes known to constitutively escape silencing by Xist (yellow), genes with immune function and a tendency to escape silencing by Xist (orange), others genes with immune function (black) and “cleaning” genes (gray). Bottom, change between median RNA levels measured by RT-qPCR in Xist-impaired (KO) versus WT (unaltered Xist) mice for each gene, in the indicated cell type, or in a pup of 3 months (left), i.e. in 1 year old mice (right). (B) RNA levels of Tlr7, Cxcr3, Tasl, Tlr8, and Tlr13 as measured by RT-qPCR in cell types showing detectable expression. Each triangle represents RNA levels in a mouse. © Christophe Huret et al.
By analyzing the mice’s immune cells, the researchers found that genes at copies of the While overexpression of this gene is suspected to protect women against many infectious diseases, it may also make them more prone to autoimmune diseases.
According to experts, these findings would apply to all mammals and explain both why women are more vulnerable than men to autoimmune diseases and why these diseases (such as rheumatoid arthritis) tend to appear as we age. They are getting old. Understanding this correlation could potentially help identify better therapeutic targets and strategies.
