Abstract
The abundance of mRNA is mainly determined by the rates of RNA transcription and decay. Here, we present a method for unbiased estimation of differential mRNA decay rate from RNA-sequencing data by modeling the kinetics of mRNA metabolism. We show that in all primary human tissues tested, and particularly in the central nervous system, many pathways are regulated at the mRNA stability level. We present a parsimonious regulatory model consisting of two RNA-binding proteins and four microRNAs that modulate the mRNA stability landscape of the brain, which suggests a new link between RBFOX proteins and Alzheimer’s disease. We show that downregulation of RBFOX1 leads to destabilization of mRNAs encoding for synaptic transmission proteins, which may contribute to the loss of synaptic function in Alzheimer’s disease. RBFOX1 downregulation is more likely to occur in older and female individuals, consistent with the association of Alzheimer’s disease with age and gender.
Highlights
This concept has been recently suggested to capture the differential mRNA decay rate in a wide set of contexts[5], where the change in mRNA half-life is estimated as the difference of the logarithm of fold-change of exonic reads and the logarithm of fold-change of intronic reads (Δexon–Δintron)
We show that a substantial portion of the brain mRNA stability profile can be explained by the functions of two RNA-binding protein families and four miRNAs
By considering a simple model of RNA metabolism (Fig. 1a) and solving the kinetic equations of this model (Methods and Supplementary Fig. 1), we found that Δexon–Δintron is affected by a “bias term” that depends on the maximum capacity of the pre-mRNA processing machinery, which is limited in the cell[9], as well as the change in transcription rate (Fig. 1b)
Summary
This concept has been recently suggested to capture the differential mRNA decay rate in a wide set of contexts[5], where the change in mRNA half-life is estimated as the difference of the logarithm of fold-change of exonic reads and the logarithm of fold-change of intronic reads (Δexon–Δintron). Our results indicate that mRNA stability plays an integral role in shaping the transcriptomes of all tested tissues, those of the central nervous system. We show that a substantial portion of the brain mRNA stability profile can be explained by the functions of two RNA-binding protein families (the RBFOX and ZFP36 families) and four miRNAs (miR-124, miR-29, miR-9, and miR-128). The RBFOX targets are enriched for mRNAs that encode synaptic transmission proteins, and are destabilized in the brains of individuals with Alzheimer’s disease (AD). We show that knockdown of RBFOX1 can partially recreate the AD stability profile, and its expression rescues the normal transcriptome, suggesting a link between dysregulation of RBFOX1 and AD
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