A carregar...
Publicação
Assessing the Impact of XIST and X Chromosome Dysregulation in Systemic Lupus Erythematosus
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 3.15 MB | Adobe PDF |
Autores
Orientador(es)
Resumo(s)
O lúpus eritematoso sistémico (LES) é uma doença autoimune complexa que afeta predominantemente mulheres, caracterizada pela desregulação do sistema imunitário, o que, por sua vez, resulta em inflamação generalizada e danos nos tecidos. A razão para a maior incidência da doença em mulheres tem sido amplamente atribuída a diferenças de expressão dos genes do cromossoma X e há regulação do processo de inativação do mesmo. Este processo é controlado principalmente pela expressão do gene XIST durante a fase embrionária do desenvolvimento. O nosso estudo investiga o papel do XIST, e de outros genes do cromossoma X, através da análise computacional dos perfis transcriptómicos de 27 tipos de células de doentes com LES e saudáveis. Assim, demonstramos que o XIST é sub-expresso em praticamente todas as células imunes observadas, simultaneamente, e XIST e a sobre-expressão de genes do cromossoma X que normalmente se encontrariam inativos. Esta sub-expressão do XIST correlaciona-se com a expressão elevada de genes associados ao LES em células imunes fundamentais, nomeadamente monócitos, células T helper-1 (Th1), e células dendríticas mieloides (mDC). Análises de correlação suplementares também sugerem que a ação regulatória do XIST poderá estender se a outros cromossomas. Adicionalmente, através da integração dos diferentes perfis transcriptómicos num único modelo de caracterização, revelamos que a expressão de genes do cromossoma X, e a interação entre os mesmos, em diferentes células imunes é suficiente para distinguir doentes com LES e indivíduos saudáveis. A aplicação deste modelo revelou novos potenciais marcadores da doença, incluindo alguns específicos a determinados tipos celulares, como o XIST, o que pode ajudara compreender melhor o viés feminino no LES. Assim, realçamos a importância dos genes do cromossoma X na manifestação feminina do lúpus, destacando o XIST como um regulador dos genes associados ao LES em células imunes específicas.
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder that predominantly affects women, marked by the dysregulation of the immune system, leading to widespread inflammation and tissue damage. The female bias in SLE incidence has been largely attributed to differences in the expression of X chromosome genes and the regulation of the X chromosome inactivation (XCI). The XCI process is mainly controlled by the expression of the long non-coding RNA XIST during the embryonic stages of development. Our study investigates the role of XIST, and other X chromosome genes, through transcriptome profiles of 27 immune cells from SLE patients and healthy controls. Using computational approaches, we revealed that XIST down-regulation is present in nearly all observed immune cells, along with the up-regulation of typically inactive X-linked genes. Notably, this XIST down-regulation correlates with the increased expression of SLE-associated genes in key immune cells, such as monocytes, T-helper 1 cells (Th1) and myeloid dendritic cells (mDC). Further correlation analyses between XIST and other genes suggest that XIST may influence gene expression beyond the X chromosome. Additionally, through integration of the different transcriptome profiles, we were able to demonstrate that the expression of X chromosome genes and their interactions across different immune cells can distinguish between SLE patients and healthy individuals. Our model exposed new possible disease markers, some of them cell-specific, such as XIST, that can help better understand the female bias in SLE. Overall, we underscore the importance of X-linked genes in the female presentation of the disease, focusing on XIST as a regulator of SLE-associated genes in specific immune cells.
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder that predominantly affects women, marked by the dysregulation of the immune system, leading to widespread inflammation and tissue damage. The female bias in SLE incidence has been largely attributed to differences in the expression of X chromosome genes and the regulation of the X chromosome inactivation (XCI). The XCI process is mainly controlled by the expression of the long non-coding RNA XIST during the embryonic stages of development. Our study investigates the role of XIST, and other X chromosome genes, through transcriptome profiles of 27 immune cells from SLE patients and healthy controls. Using computational approaches, we revealed that XIST down-regulation is present in nearly all observed immune cells, along with the up-regulation of typically inactive X-linked genes. Notably, this XIST down-regulation correlates with the increased expression of SLE-associated genes in key immune cells, such as monocytes, T-helper 1 cells (Th1) and myeloid dendritic cells (mDC). Further correlation analyses between XIST and other genes suggest that XIST may influence gene expression beyond the X chromosome. Additionally, through integration of the different transcriptome profiles, we were able to demonstrate that the expression of X chromosome genes and their interactions across different immune cells can distinguish between SLE patients and healthy individuals. Our model exposed new possible disease markers, some of them cell-specific, such as XIST, that can help better understand the female bias in SLE. Overall, we underscore the importance of X-linked genes in the female presentation of the disease, focusing on XIST as a regulator of SLE-associated genes in specific immune cells.
Descrição
Palavras-chave
Systemic Lupus Erythematosus Autoimmune Disease X Chromosome XIST Multi-Omics Integration