Abstract
BackgroundSurveillance of integrity of the basic elements of the cell including DNA, RNA, and proteins is a critical element of cellular physiology. Mechanisms of surveillance of DNA and protein integrity are well understood. Surveillance of structural RNAs making up the vast majority of RNA in a cell is less well understood. Here, we sought to explore integrity of processing of structural RNAs in relapsing remitting multiple sclerosis (RRMS) and other inflammatory diseases.ResultsWe employed mononuclear cells obtained from subjects with RRMS and cell lines. We used quantitative-PCR and whole genome RNA sequencing to define defects in structural RNA surveillance and siRNAs to deplete target proteins. We report profound defects in surveillance of structural RNAs in RRMS exemplified by elevated levels of poly(A) + Y1-RNA, poly(A) + 18S rRNA and 28S rRNAs, elevated levels of misprocessed 18S and 28S rRNAs and levels of the U-class of small nuclear RNAs. Multiple sclerosis is also associated with genome-wide defects in mRNA splicing. Ro60 and La proteins, which exist in ribonucleoprotein particles and play different roles in quality control of structural RNAs, are also deficient in RRMS. In cell lines, silencing of the genes encoding Ro60 and La proteins gives rise to these same defects in surveillance of structural RNAs.ConclusionsOur results establish that profound defects in structural RNA surveillance exist in RRMS and establish a causal link between Ro60 and La proteins and integrity of structural RNAs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0629-x) contains supplementary material, which is available to authorized users.
Highlights
Surveillance of integrity of the basic elements of the cell including DNA, RNA, and proteins is a critical element of cellular physiology
We found that levels of total Y RNAs were not markedly different between CTRL and relapsing remitting multiple sclerosis (RRMS) subjects (Figure 1A)
Levels of polyadenylated Y1 RNA, but not other Y RNAs, were increased by about 20-fold in RRMS relative to CTRL (Figure 1B). This elevation of polyadenylated Y1 RNA was not seen in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), neuromyelitis optica (NMO), or Parkinson’s disease (PD) (Additional file 1: Table S1 for a description of subjects) (Figure 1C)
Summary
Surveillance of integrity of the basic elements of the cell including DNA, RNA, and proteins is a critical element of cellular physiology. Mechanisms of surveillance of DNA and protein integrity are well understood. We sought to explore integrity of processing of structural RNAs in relapsing remitting multiple sclerosis (RRMS) and other inflammatory diseases. Involvement of innate and adaptive arms of the immune system is detected in inflammatory demyelinating lesions implicating these in pathogenesis. Both genetic and environmental factors are implicated in the origins of RRMS [1,2,3,4,5,6,7,8]. Y RNAs are approximately 100 nucleotides in length and are Spurlock et al Genome Biology (2015) 16:58 neuron 1), give rise to specific neurodegenerative disorders rather than global defects [22,23,24,25,26]
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