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Editor | Xi It is well known that women have one more X chromosome than men.
In order to balance the X chromosome gene expression levels in both sexes, female mammals have evolved a unique epigenetic system to inactivate one of the X chromosomes: this inactivation process occurs during early embryonic development and consists of a long non-coding RNA (lncRNA).
) XIST recruits various proteins in an orderly manner to cover and inhibit the gene expression of the entire X chromosome.
Research in recent decades has focused on how XIST initiates and regulates X chromosome inactivation in embryonic stem cells.
However, how XIST maintains X chromosome inactivation in somatic cells after development is poorly understood, and even the entire field tends to think of XIST.
It is not important in the maintenance of subsequent X chromosome inactivation.
The immune response of women is often stronger than that of men.
When encountering pathogens, women will produce more immune B cells and the antibodies they produce to resist the invasion.
However, excessive immune responses will also make them attack their own tissues, making women more susceptible to autoimmune diseases.
80% of patients with lupus erythematosus (an autoimmune disease) are women.
The risk of lupus in men with Klinefelter syndrome (XXY, an extra X chromosome) is 14 times that of normal men, suggesting that the X chromosome may be involved in the immune response.
This may be caused by the overexpression of immune-related genes on the X chromosome that escaped from X inactivation and eventually induced autoimmune diseases.
However, it is unclear whether X chromosome inactivation is involved in the regulation of gender differences in the immune system.
On March 17, 2021, the team of Professor Howard Chang from Stanford University published a paper on Cell B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells.
This article reports for the first time the important role and regulatory mechanism of XIST in maintaining X chromosome inactivation in adult immune B cells.
This discovery overturns the previous understanding of the role of XIST in X inactivation in adult somatic cells, broadens the cell-specific functions of lncRNA-protein complexes, and reveals the important impact of X inactivation on gender differences in immune responses.
In order to study the role of XIST in X chromosome inactivation in adult cells, the authors selected the lymphatic B cell line GM12878 as a model, used CRISPRi to knock down XIST expression, and detected X chromosome inactivation by RNA-seq.
The authors found that after the loss of XIST, genes on the partially inactivated X chromosome were reactivated, and these genes contained important immune regulatory genes (such as TLR7).
Further epigenetic analysis revealed that the promoters of these XIST-dependent genes exhibit DNA demethylation, and XIST promotes the deacetylation of H3K27ac to maintain the X-inactive state of these genes.
The author found that XIST can bind different proteins in different cell types through XIST RNA-guided proteomics.
And through CRISPRi directed screening to identify the important role of the B cell-specific XIST binding protein TRIM28, it was found that TRIM28 can inhibit the expression of part of the X chromosome gene by regulating the retention of Pol II in the promoter.
By analyzing the single-cell transcriptomes of female patients with autoimmune diseases and COVID-19 infections, the authors found that XIST-dependent gene expression was excessive in CD11c + atypical B cells (ABCs), thus deducing that XIST dysregulation in these cells cannot ensure X Chromosome inactivation.
ABC is a special type of B-cell subtype, which is relatively rare under normal circumstances.
However, it can be found in patients with certain infectious diseases such as malaria, HIV and the recent COVID-19, or in women with autoimmune diseases (lupus erythematosus, Rheumatoid arthritis and Sjogren’s syndrome, etc.
) patients have a large increase.
Interestingly, ABC is abnormally amplified in aging female mice, but this phenomenon does not appear in male mice.
The formation of ABC depends on the activation of the TLR7 signaling pathway, and TLR7 is an XIST-dependent gene on the X chromosome, suggesting that XIST and the inactivation of the X chromosome regulated by XIST may affect the formation of ABC.
To explore this idea, the authors extracted B cells from the peripheral blood of normal women, knocked out XIST using CRISPR technology, and added TLR7 agonists in vitro to promote B cell differentiation.
After the level of XIST decreased, the authors found that ABC, especially ABC with IgG type antibodies The increase indicates that XIST can regulate and limit the formation of ABC.
In summary, this article opens up the research direction in the field of X chromosome inactivation, from previous studies on X inactivation in embryonic stem cells to the study of how XIST maintains X inactivation in adult somatic cells, providing potential for women with multiple autoimmune diseases Molecular mechanism.
In addition, gender differences are also reflected in neurological, metabolic, and cardiovascular diseases.
This discovery provides new ideas for people to study gender differences in these diseases.
The corresponding author of the article is Professor Howard Chang of Stanford University, and the first author is Yu Bingfei, a postdoctoral fellow of the research group.
Original link: Platemaker: Instructions for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article, and personal forwarding and sharing are welcome.
Reprinting is prohibited without permission, the author has all legal rights, and offenders must be investigated.
In order to balance the X chromosome gene expression levels in both sexes, female mammals have evolved a unique epigenetic system to inactivate one of the X chromosomes: this inactivation process occurs during early embryonic development and consists of a long non-coding RNA (lncRNA).
) XIST recruits various proteins in an orderly manner to cover and inhibit the gene expression of the entire X chromosome.
Research in recent decades has focused on how XIST initiates and regulates X chromosome inactivation in embryonic stem cells.
However, how XIST maintains X chromosome inactivation in somatic cells after development is poorly understood, and even the entire field tends to think of XIST.
It is not important in the maintenance of subsequent X chromosome inactivation.
The immune response of women is often stronger than that of men.
When encountering pathogens, women will produce more immune B cells and the antibodies they produce to resist the invasion.
However, excessive immune responses will also make them attack their own tissues, making women more susceptible to autoimmune diseases.
80% of patients with lupus erythematosus (an autoimmune disease) are women.
The risk of lupus in men with Klinefelter syndrome (XXY, an extra X chromosome) is 14 times that of normal men, suggesting that the X chromosome may be involved in the immune response.
This may be caused by the overexpression of immune-related genes on the X chromosome that escaped from X inactivation and eventually induced autoimmune diseases.
However, it is unclear whether X chromosome inactivation is involved in the regulation of gender differences in the immune system.
On March 17, 2021, the team of Professor Howard Chang from Stanford University published a paper on Cell B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells.
This article reports for the first time the important role and regulatory mechanism of XIST in maintaining X chromosome inactivation in adult immune B cells.
This discovery overturns the previous understanding of the role of XIST in X inactivation in adult somatic cells, broadens the cell-specific functions of lncRNA-protein complexes, and reveals the important impact of X inactivation on gender differences in immune responses.
In order to study the role of XIST in X chromosome inactivation in adult cells, the authors selected the lymphatic B cell line GM12878 as a model, used CRISPRi to knock down XIST expression, and detected X chromosome inactivation by RNA-seq.
The authors found that after the loss of XIST, genes on the partially inactivated X chromosome were reactivated, and these genes contained important immune regulatory genes (such as TLR7).
Further epigenetic analysis revealed that the promoters of these XIST-dependent genes exhibit DNA demethylation, and XIST promotes the deacetylation of H3K27ac to maintain the X-inactive state of these genes.
The author found that XIST can bind different proteins in different cell types through XIST RNA-guided proteomics.
And through CRISPRi directed screening to identify the important role of the B cell-specific XIST binding protein TRIM28, it was found that TRIM28 can inhibit the expression of part of the X chromosome gene by regulating the retention of Pol II in the promoter.
By analyzing the single-cell transcriptomes of female patients with autoimmune diseases and COVID-19 infections, the authors found that XIST-dependent gene expression was excessive in CD11c + atypical B cells (ABCs), thus deducing that XIST dysregulation in these cells cannot ensure X Chromosome inactivation.
ABC is a special type of B-cell subtype, which is relatively rare under normal circumstances.
However, it can be found in patients with certain infectious diseases such as malaria, HIV and the recent COVID-19, or in women with autoimmune diseases (lupus erythematosus, Rheumatoid arthritis and Sjogren’s syndrome, etc.
) patients have a large increase.
Interestingly, ABC is abnormally amplified in aging female mice, but this phenomenon does not appear in male mice.
The formation of ABC depends on the activation of the TLR7 signaling pathway, and TLR7 is an XIST-dependent gene on the X chromosome, suggesting that XIST and the inactivation of the X chromosome regulated by XIST may affect the formation of ABC.
To explore this idea, the authors extracted B cells from the peripheral blood of normal women, knocked out XIST using CRISPR technology, and added TLR7 agonists in vitro to promote B cell differentiation.
After the level of XIST decreased, the authors found that ABC, especially ABC with IgG type antibodies The increase indicates that XIST can regulate and limit the formation of ABC.
In summary, this article opens up the research direction in the field of X chromosome inactivation, from previous studies on X inactivation in embryonic stem cells to the study of how XIST maintains X inactivation in adult somatic cells, providing potential for women with multiple autoimmune diseases Molecular mechanism.
In addition, gender differences are also reflected in neurological, metabolic, and cardiovascular diseases.
This discovery provides new ideas for people to study gender differences in these diseases.
The corresponding author of the article is Professor Howard Chang of Stanford University, and the first author is Yu Bingfei, a postdoctoral fellow of the research group.
Original link: Platemaker: Instructions for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article, and personal forwarding and sharing are welcome.
Reprinting is prohibited without permission, the author has all legal rights, and offenders must be investigated.
