Preferential Isoform Usage and Isoform Switching in Systemic Lupus Erythematosus Patients with Distinct Autoantibody Profile
RNA sequencing has advanced our understanding of molecular heterogeneity in systemic lupus erythematosus (SLE), yet most studies have focused on differential gene expression (DGE), which overlooks transcript-level complexity. Alternative splicing and polyadenylation generate multiple isoforms from a single gene, and their dysregulation may contribute to autoimmune pathogenesis, including through…
Recent advancements in RNA sequencing have illuminated the complex molecular nuances of systemic lupus erythematosus (SLE); yet, many previous investigations have primarily concentrated on differential gene expression, which fails to capture the intricacies of the transcriptome. Isoforms, formed through alternative splicing and polyadenylation from a single gene, can contribute to autoimmune pathology via their production of non-canonical variants with potential autoantigenic characteristics.
To delve into this underexplored facet, researchers examined differential isoform usage (DIU) and major isoform switching (MIS) in SLE categories categorized by autoantibody signatures: anti-dsDNA+, anti-ENA+, and anti-dsDNA+ENA+. Subgroup-specific DIU and MIS events were identified to be enriched in RNA-binding and transcription-related operations.
In the anti-dsDNA+ cohort, the T-cell receptor adaptor GRAP2 exhibited isoform switching, coupled with a surge in a non-coding retained-intron transcript. Anti-ENA+ patients showcased IGHM transitioning from a membrane-bound to a secretory form, aligning with an antibody-secreting cell profile; NACA, a recognized IgE autoantigen, experienced isoform switching; and BRI3, implicated in TNF-α-induced cell death, migrated towards its protein-coding transcript.
In the anti-dsDNA+ENA+ cohort, TNFAIP2, a TNF-α induced gene, displayed isoform redistribution, accompanied by the loss of a uORF-containing transcript. These insights underscore isoform regulation as a unique, subgroup-specific, and functionally significant dimension of transcriptomic dysregulation in SLE.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
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