Extensive Changes in Transcription Dynamics Reflected on Alternative Splicing Events in Systemic Lupus Erythematosus Patients

Papanikolaou, Sofia; Βertsias, George; Nikolaou, Christoforos

doi:10.3390/genes12081260

Cited by 6 publications

(4 citation statements)

References 36 publications

(51 reference statements)

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“…Research on alternative splicing attracted more and more attention [59][60][61] . People reported increased alternative splicing events for IRF5 which was associated with the incidence and severity of lupus 62 .…”

Section: Discussionmentioning

confidence: 99%

High throughput sequencing revealed enhanced cell cycle signaling in SLE patients

Yang

Wang

Liu

et al. 2023

Sci Rep

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The multi-system involvement and high heterogeneity of systemic lupus erythematosus (SLE) pose great challenges to its diagnosis and treatment. The purpose of the current study is to identify genes and pathways involved in the pathogenesis of SLE. High throughput sequencing was performed on the PBMCs from SLE patients. We conducted differential gene analysis, gene ontology (GO) analysis, kyoto encyclopedia of genes and genomes (KEGG) analysis, and quantitative real-time PCR (qRT-PCR) verification. Protein–protein interaction (PPI) analysis, alternative splicing analysis, and disease correlation analysis were conducted on some key pathogenic genes as well. Furthermore, si-CDC6 was used for transfection and cell proliferation was monitored using a cell counting kit-8 (CCK-8) assay. We identified 2495 differential genes (1494 upregulated and 1001 downregulated) in SLE patients compared with healthy controls. The significantly upregulated genes were enriched in the biological process-related GO terms of the cell cycle, response to stress, and chromosome organization. KEGG enrichment analysis revealed 7 significantly upregulated pathways including SLE, alcoholism, viral carcinogenesis, cell cycle, proteasome, malaria, and transcriptional misregulation in cancer. We successfully verified some differential genes on the SLE pathway and the cell cycle pathway. CDC6, a key gene in the cell cycle pathway, had remarkably higher MXE alternative splicing events in SLE patients than that in controls, which may explain its significant upregulation in SLE patients. We found that CDC6 participates in the pathogenesis of many proliferation-related diseases and its levels are positively correlated with the severity of SLE. Knockdown of CDC6 suppressed the proliferation of Hela cells and PBMCs from SLE patients in vitro. We identified SLE-related genes and their alternative splicing events. The cell cycle pathway and the cell cycle-related biological processes are over-activated in SLE patients. We revealed a higher incidence of MXE events of CDC6, which may lead to its high expression in SLE patients. Upregulated cell cycle signaling and CDC6 may be related to the hyperproliferation and pathogenesis of SLE.

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Section: Discussionmentioning

confidence: 99%

High throughput sequencing revealed enhanced cell cycle signaling in SLE patients

Yang

Wang

Liu

et al. 2023

Sci Rep

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“…Alternative splicing represents a vital component of the gene regulation process through the reduction of mRNA translation or the production of non-functional or malfunctional proteins. Previous studies have shown that SLE-related genes are subject to alternative splicing ( 28 , 29 ). Therefore, we sought to identify whether alternative splicing events might affect hematopoiesis in patients with SLE.…”

Section: Resultsmentioning

confidence: 99%

Single-cell transcriptomic analysis of hematopoietic progenitor cells from patients with systemic lupus erythematosus reveals interferon-inducible reprogramming in early progenitors

Filia,

Mitroulis,

Loukogiannaki

et al. 2024

Front. Immunol.

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IntroductionImmune cells that contribute to the pathogenesis of systemic lupus erythematosus (SLE) derive from adult hematopoietic stem and progenitor cells (HSPCs) within the bone marrow (BM). For this reason, we reasoned that fundamental abnormalities in SLE can be traced to a BM-derived HSPC inflammatory signature.MethodsBM samples from four SLE patients, six healthy controls, and two umbilical cord blood (CB) samples were used. CD34+ cells were isolated from BM and CB samples, and single-cell RNA-sequencing was performed.ResultsA total of 426 cells and 24,473 genes were used in the analysis. Clustering analysis resulted in seven distinct clusters of cell types. Mutually exclusive markers, which were characteristic of each cell type, were identified. We identified three HSPC subpopulations, one of which consisted of proliferating cells (MKI67 expressing cells), one T-like, one B-like, and two myeloid-like progenitor subpopulations. Differential expression analysis revealed i) cell cycle-associated signatures, in healthy BM of HSPC clusters 3 and 4 when compared with CB, and ii) interferon (IFN) signatures in SLE BM of HSPC clusters 3 and 4 and myeloid-like progenitor cluster 5 when compared with healthy controls. The IFN signature in SLE appeared to be deregulated following TF regulatory network analysis and differential alternative splicing analysis between SLE and healthy controls in HSPC subpopulations.DiscussionThis study revealed both quantitative—as evidenced by decreased numbers of non-proliferating early progenitors—and qualitative differences—characterized by an IFN signature in SLE, which is known to drive loss of function and depletion of HSPCs. Chronic IFN exposure affects early hematopoietic progenitors in SLE, which may account for the immune aberrancies and the cytopenias in SLE.

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“…SLE and many other autoimmune diseases, such as scleroderma, multiple sclerosis and myasthenia gravis, are reported to have abnormalities in splicing resulting in increased or aberrant alternative splicing 29 . Specifically, it has been recognized that splicing factor perturbation has a broad impact in SLE 30 , especially in T cells 31 , 32 .…”

Section: Introductionmentioning

confidence: 99%

Abnormalities in intron retention characterize patients with systemic lupus erythematosus

Sun

Liu

et al. 2023

Sci Rep

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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.

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Extensive Changes in Transcription Dynamics Reflected on Alternative Splicing Events in Systemic Lupus Erythematosus Patients

Cited by 6 publications

References 36 publications

High throughput sequencing revealed enhanced cell cycle signaling in SLE patients

High throughput sequencing revealed enhanced cell cycle signaling in SLE patients

Single-cell transcriptomic analysis of hematopoietic progenitor cells from patients with systemic lupus erythematosus reveals interferon-inducible reprogramming in early progenitors

Abnormalities in intron retention characterize patients with systemic lupus erythematosus

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