SP140 regulates the expression of immune-related genes associated with multiple sclerosis and other autoimmune diseases by NF-κB inhibition

Abstract

SP140 locus has been associated with multiple sclerosis (MS) as well as other autoimmune diseases by genome-wide association studies (GWAS). The causal variant of these associations (rs28445040-T) alters the splicing of the SP140 gene transcripts reducing the protein expression. We aimed to understand why the reduction of SP140 expression produced by the risk variant can increase the susceptibility to MS. To this end, we determined by RNA sequencing (RNA-seq) analysis the differentially expressed genes after SP140 silencing in lymphoblastoid cell lines (LCLs). We analyzed these genes by gene ontology (GO), comparative transcriptome profiles, enrichment of transcription factors (TFs) in the promoters of these genes and colocalization with GWAS risk variants. We also monitored the activity of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in SP140-silenced cells by luciferase reporter system. We identified 100 genes that were up-regulated and 22 genes down-regulated in SP140-silenced LCLs. GO analysis revealed that genes affected by SP140 were involved in regulation of cytokine production, inflammatory response and cell-cell adhesion. We observed enrichment of NF-κB TF in the promoter of up-regulated genes and NF-κB-increased activity in SP140-silenced cell lines. We showed enrichment of genes regulated by SP140 in GWAS-detected risk loci for MS (14.63 folds), Crohn's disease (4.82 folds) and inflammatory bowel disease (4.47 folds), not observed in other unrelated immune diseases. Our findings showed that SP140 is an important repressor of genes implicated in inflammation, suggesting that decreased expression of SP140, promoted by the rs28445040-T risk variant, may lead to up-regulation of these genes by means of NF-κB inhibition in B cells.

Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons

“…Another major question is whether or how the repression of type I IFNs by SP140 is specific for bacterial infections and, if not, whether the presence of SP140 impairs anti-viral immunity. Lastly, polymorphisms in human SP140 are associated with chronic lymphocytic leukemia (CLL), Crohn’s disease and multiple sclerosis (MS) (Franke et al, 2010; Jostins et al, 2012; Karaky et al, 2018; Matesanz et al, 2015; Slager et al, 2013). Studies using siRNA and shRNA-mediated knockdown have also implicated SP140 in the repression of lineage-inappropriate genes in macrophages (Mehta et al, 2017).…”

Host Gene Expression of Macrophages in Response to Feline Coronavirus Infection

“…On the other hand, some upregulated transcripts included the protein tyrosine phosphatase, which is involved in attenuating T-cell activation [ 59 ] or nuclear body protein SP140. The latter has been shown to act as important repressor of genes involved in the regulation of cytokine production, inflammatory response, and cell-cell adhesion [ 60 ].…”

Splice-site variant in ACSL5: a marker promoting opposing effect on cell viability and protein expression

“…A detrimental alternative splicing that involves exon 7 skipping in the SP140 transcripts has also been reported [34, 35]. The genetic variant that promotes this alternative splicing is associated with multiple sclerosis, Crohn’s disease, and chronic lymphocytic leukemia.…”