Abnormalities in intron retention characterize patients with systemic lupus erythematosus

Abstract

Regulation of intron retention (IR), a form of alternative splicing, is a newly recognized checkpoint in gene expression. Since there are numerous abnormalities in gene expression in the prototypic autoimmune disease systemic lupus erythematosus (SLE), we sought to determine whether IR was intact in patients with this disease. We, therefore, studied global gene expression and IR patterns of lymphocytes in SLE patients. We analyzed RNA-seq data from peripheral blood T cell samples from 14 patients suffering from systemic lupus erythematosus (SLE) and 4 healthy controls and a second, independent data set of RNA-seq data from B cells from16 SLE patients and 4 healthy controls. We identified intron retention levels from 26,372 well annotated genes as well as differential gene expression and tested for differences between cases and controls using unbiased hierarchical clustering and principal component analysis. We followed with gene-disease enrichment analysis and gene-ontology enrichment analysis. Finally, we then tested for significant differences in intron retention between cases and controls both globally and with respect to specific genes. Overall decreased IR was found in T cells from one cohort and B cells from another cohort of patients with SLE and was associated with increased expression of numerous genes, including those encoding spliceosome components. Different introns within the same gene displayed both up- and down-regulated retention profiles indicating a complex regulatory mechanism. These results indicate that decreased IR in immune cells is characteristic of patients with active SLE and may contribute to the abnormal expression of specific genes in this autoimmune disease.

Extensive Alternative Splicing Patterns in Systemic Lupus Erythematosus Highlight Sexual Differences

“…We observed a small-yet significant-inverse association between intron-retention-affected genes and their corresponding mRNA expression, specifically in SLE disease. Intron retention abnormalities have previously been described in active-SLE-patient-derived blood immune cells and is associated with the disrupted expression of the underlying genes [20,21]. This is also in line with the study of Ni et al [70], where most of the genes upregulated in CD4+ T-cells during activation had a reduction in intron retention due to enhanced mRNA stability [70].…”

“…In agreement with the small number of shared genes, we found distinct molecular Intron retention represented the most prevalent class of AS among both SLE patients and healthy individuals (52.3% and 50.1% of sex-biased AS events, respectively) (Figure 1A,B). This predominance of intron retention events comes as a corroboration of recent data reported by us [21] and others [20] in the context of SLE. We observed a remarkable inverse relationship of intron retention events across the sex and disease state subgroups.…”

“…In addition, we and others have characterized genetic variants that regulate the splicing behavior (so-called splicing quantitative trait loci) of genes connected to lupus, including IRF7, IRF5, TCF7 and WDFY4 [18,19]. Further analysis revealed that splicing perturbation in SLE is driven primarily by abnormalities in intron retention, which is a process where introns are retained in the final transcript [20,21]. Collectively, these findings highlight an important, previously overlooked layer of molecular variation associated with SLE disease.…”

PRMT1-SFPQ regulates intron retention to control matrix gene expression during craniofacial development

“…The IR changes were further exemplified by the elevation of intronic expression in Pex12, Nkx3-2, Nkiras1, 1810026B05Rik, and the reduction of intronic expression in Tbx1 (Figure -1D-F). To analyze the intronic expression comprehensively at a gene-specific level, we employed IRI (intron reads index) analysis, which is an algorithm that quantifies the ratio of normalized read counts between intronic and exonic regions (Ni et al 2016;Sun et al 2023;Tian et al 2020). Subsequent analysis for retained introns demonstrated that Prmt1 deficiency-induced change in intron retention altered an array of biology pathways.…”

Unleashing the potential of catalytic RNAs to combat mis-spliced transcripts

“…Recent evolution of the deep tech and artificial intelligence have enormously improved the outcome for the precise and accurate detection of intronic sequences among transcripts to assist in the diagnosis of intronic abnormalities and aberrant splicing events (Zheng et al, 2020). For instance, Sun et al (2023) employ the Intron Retention Index (IRI), an IRtools that provides IR analysis reads from RNA sequences collected from patients with systemic lupus erythematosus (SLE). The study reported dysregulation in IR as a hallmark of SLE disorder, which can be incorporate to enhance the accuracy of the IR detection.…”