The DEXI gene, encoding the dexamethasone-induced protein (DEXI), has emerged as a significant player in the context of autoimmune diseases, particularly in the realm of type 1 diabetes and multiple sclerosis. It is also implicated in the regulation of immune responses and has been associated with the progression of certain cancers. The functional role of DEXI has been the subject of intense investigation, with studies aiming to elucidate its precise mechanisms of action and its potential as a therapeutic target.

DEXI has been identified as a candidate gene for type 1 diabetes, as it modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signaling pathway [3]. This suggests that DEXI may play a role in the pathogenesis of type 1 diabetes by influencing the immune response within the beta cells of the pancreas. Furthermore, the CLEC16A gene, located in the same chromosomal region as DEXI, has been shown to be the primary gene influencing diabetes risk, while DEXI itself is unlikely to contribute to the pathogenesis of type 1 diabetes [4]. However, recent research indicates that intronic variants in CLEC16A can affect the expression of DEXI, highlighting the complex interplay between genes in this region and their potential roles in disease susceptibility [6].

In the context of multiple sclerosis, DEXI has been identified as a susceptibility gene. Large-scale genome-wide association studies have revealed that genetic variants in the CLEC16A gene are associated with increased risk of developing MS and other autoimmune disorders [1]. Additionally, several autoimmune-associated genetic variants in CLEC16A introns act as expression quantitative trait loci for the DEXI gene, adding DEXI to the growing list of MS susceptibility genes [1]. The molecular and functional characterization of DEXI in autoimmunity is an area of active research, with the goal of translating this knowledge into clinical applications.

In bladder cancer, DEXI has been identified as a target of the microRNA miR-3960. miR-3960 levels in bladder cancer tissue have been found to be positively correlated with patient survival time. Dexi knockout in a mouse bladder carcinoma cell line inhibited cell proliferation and promoted cisplatin- and gemcitabine-induced apoptosis [2]. This suggests that DEXI may play a role in bladder cancer progression and that miR-3960-mediated inhibition of DEXI could be a potential therapeutic strategy against the disease.

Furthermore, DEXI has been implicated in the regulation of HLA class II gene expression during Epstein-Barr Virus (EBV) infection of B-lymphocytes. EBNA2, a viral-encoded transcriptional regulatory factor, has been shown to down-regulate HLA class II transcription through the down-regulation of CIITA, the major transcriptional activator of HLA class II gene transcription. EBNA2 causes an increase in DEXI transcription and a graded change in histone modifications near the DEXI locus, suggesting that DEXI may play a role in the immune response to viral infections [5].

In summary, DEXI is a gene that has been implicated in the pathogenesis of several diseases, including type 1 diabetes and multiple sclerosis. Its role in the regulation of immune responses and its potential as a therapeutic target in various diseases are areas of ongoing research. Further studies are needed to fully understand the molecular and functional mechanisms of DEXI and its implications for disease treatment and prevention.

References:

1. Eriksson, Anna M, Emini, Nora, Harbo, Hanne F, Berge, Tone. 2025. Is DEXI a Multiple Sclerosis Susceptibility Gene? In International journal of molecular sciences, 26, . doi:10.3390/ijms26031175. https://pubmed.ncbi.nlm.nih.gov/39940946/

2. Li, Wenqing, Wang, Zihao, Jiang, Ziming, Wang, Ming, Qin, Zhihai. 2023. MiR-3960 inhibits bladder cancer progression via targeting of DEXI. In Biochemical and biophysical research communications, 668, 8-18. doi:10.1016/j.bbrc.2023.05.055. https://pubmed.ncbi.nlm.nih.gov/37230046/

3. Dos Santos, Reinaldo S, Marroqui, Laura, Velayos, Teresa, Castaño, Luis, Santin, Izortze. 2018. DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway. In Diabetologia, 62, 459-472. doi:10.1007/s00125-018-4782-0. https://pubmed.ncbi.nlm.nih.gov/30478640/

4. Gingerich, Morgan A, Sidarala, Vaibhav, Soleimanpour, Scott A. 2019. Clarifying the function of genes at the chromosome 16p13 locus in type 1 diabetes: CLEC16A and DEXI. In Genes and immunity, 21, 79-82. doi:10.1038/s41435-019-0087-7. https://pubmed.ncbi.nlm.nih.gov/31570815/

5. Su, Chenhe, Lu, Fang, Soldan, Samantha S, Kossenkov, Andrew V, Lieberman, Paul M. 2021. EBNA2 driven enhancer switching at the CIITA-DEXI locus suppresses HLA class II gene expression during EBV infection of B-lymphocytes. In PLoS pathogens, 17, e1009834. doi:10.1371/journal.ppat.1009834. https://pubmed.ncbi.nlm.nih.gov/34352044/

6. Davison, Lucy J, Wallace, Chris, Cooper, Jason D, Tennstedt, Stefanie, Wallace, Chris. 2011. Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene. In Human molecular genetics, 21, 322-33. doi:10.1093/hmg/ddr468. https://pubmed.ncbi.nlm.nih.gov/21989056/