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RNA-mediated gene regulation is less evolvable than transcriptional regulation.

ABSTRACT: Much of gene regulation is carried out by proteins that bind DNA or RNA molecules at specific sequences. One class of such proteins is transcription factors, which bind short DNA sequences to regulate transcription. Another class is RNA binding proteins, which bind short RNA sequences to regulate RNA maturation, transport, and stability. Here, we study the robustness and evolvability of these regulatory mechanisms. To this end, we use experimental binding data from 172 human and fruit fly transcription factors and RNA binding proteins as well as human polymorphism data to study the evolution of binding sites in vivo. We find little difference between the robustness of regulatory protein-RNA interactions and transcription factor-DNA interactions to DNA mutations. In contrast, we find that RNA-mediated regulation is less evolvable than transcriptional regulation, because mutations are less likely to create interactions of an RNA molecule with a new RNA binding protein than they are to create interactions of a gene regulatory region with a new transcription factor. Our observations are consistent with the high level of conservation observed for interactions between RNA binding proteins and their target molecules as well as the evolutionary plasticity of regulatory regions bound by transcription factors. They may help explain why transcriptional regulation is implicated in many more evolutionary adaptations and innovations than RNA-mediated gene regulation.

SUBMITTER: Payne JL

PROVIDER: S-EPMC5899451 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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RNA-mediated gene regulation is less evolvable than transcriptional regulation.

Payne Joshua L JL Khalid Fahad F Wagner Andreas A

Proceedings of the National Academy of Sciences of the United States of America 20180326 15

Much of gene regulation is carried out by proteins that bind DNA or RNA molecules at specific sequences. One class of such proteins is transcription factors, which bind short DNA sequences to regulate transcription. Another class is RNA binding proteins, which bind short RNA sequences to regulate RNA maturation, transport, and stability. Here, we study the robustness and evolvability of these regulatory mechanisms. To this end, we use experimental binding data from 172 human and fruit fly transc ...[more]

PMID: 29581298

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Project description:BackgroundRheumatoid arthritis (RA) is an autoimmune disease characterised by systemic inflammation of joints. The observed complexity of RA pathogenesis and studies that have been carried out so far indicate that RA pathogenesis is regulated at multiple levels. Given the role of RNA editing in autoimmune disease, we hypothesised that RNA editing could contribute to RA pathogenesis by regulating gene expression through post-transcriptional mechanisms.MethodsWe identified RNA editing events in synovial tissues from early and established RA compared with normal subjects from an available transcriptome data set using REDItools. To investigate the potential effect of these RNA editing events on gene expression, we carried out an analysis of differential exon usage in the vicinity of the differentially edited sites using DEXSeq. We then used STRING to identify putative interactions between differentially edited genes identified from REDItools analysis. We also investigated the possible effects of these RNA editing events on miRNA-target mRNA interactions as predicted by miRanda.ResultsOur analysis revealed that there is extensive RNA editing in RA, with 304 and 273 differentially edited events in early RA and established RA, respectively. Of these, 25 sites were within 11 genes in early RA, and 34 sites were within 7 genes in established RA. DEXSeq analysis revealed that RNA editing correlated with differential exon usage in 4 differentially edited genes that have previously also been associated with RA in some measure: ATM, ZEB1, ANXA4, and TIMP3. DEXSeq analysis also revealed enrichment of some non-functional isoforms of these genes, perhaps at the expense of their full-length counterparts. Network analysis using STRING showed that several edited genes were part of the p53 protein-protein interaction network. We also identified several putative miRNA binding sites in the differentially edited genes that were lost upon editing.ConclusionsOur results suggested that the expression of genes involved in DNA repair and cell cycle, including ATM and ZEB1 which are well-known functional regulators of the DNA damage response pathway, could be regulated by RNA editing in RA synovia. This may contribute to an impaired DNA damage response in synovial tissues.

Dataset Information

RNA-mediated gene regulation is less evolvable than transcriptional regulation.

Publications

RNA-mediated gene regulation is less evolvable than transcriptional regulation.

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