Most studies of gene expression variation, including my own, measure expression as a steady level. However, a gene's expression level is the result of two dynamic processes: mRNA transcription and mRNA decay. We've talked a bit on this blog about studies that have investigated mechanisms of mRNA transcription (like DNaseI seq and ChIP seq), but we've so far ignored mRNA decay. So I'm going to summarize this paper:
The authors in this study measured relative mRNA decay rate in 70 human cell lines by treating the cells with a chemical that halts transcription and measuring expression level at a number of time points after the treatment.
First, they did a number of gene by gene comparisons using data pooled from all individuals. They classified genes into fast-decaying and slow-decaying categories and found that genes in these categories are associated with a number of things that they'd expect (gene length, cis-reg elements, etc). More interestingly, the authors also looked for associations between a gene's rate of decay and expression level.They expected that genes with transcripts that decay quickly will tend to have low expression and genes with slow-decaying transcripts will have high expression and they found that this is, indeed, the general pattern. However they also found a number of genes with the opposite pattern: fast-decay time and high expression.
Next, they looked at between-individual variation in decay rate and how that relates to expression variation. They tested for associations between a gene's decay rate and nearby SNPs and found a handful of significant associations. These 'rdQTLs' ('rate of decay QTLs') overlap with a significant number of the eQTLs they were also able to find with this data set. In 55% of the cases where a gene has an rdQTL and an eQTL, the allele that's associated with faster decay is also associated with lower expression and vice versa. This makes sense: if allele causes a gene to decay faster it should lower expression. However, 45% of the time the relationship was reversed, which seems pretty strange to me.
Overall, what I think is really interesting about this paper is that it gets at some of the mechanisms which contribute to expression level variation. I tend to treat expression level as a fairly abstract trait, so it's useful to remember that it's the result of multiple processes, which can interact in complex and sometimes strange ways.
Next, they looked at between-individual variation in decay rate and how that relates to expression variation. They tested for associations between a gene's decay rate and nearby SNPs and found a handful of significant associations. These 'rdQTLs' ('rate of decay QTLs') overlap with a significant number of the eQTLs they were also able to find with this data set. In 55% of the cases where a gene has an rdQTL and an eQTL, the allele that's associated with faster decay is also associated with lower expression and vice versa. This makes sense: if allele causes a gene to decay faster it should lower expression. However, 45% of the time the relationship was reversed, which seems pretty strange to me.
Overall, what I think is really interesting about this paper is that it gets at some of the mechanisms which contribute to expression level variation. I tend to treat expression level as a fairly abstract trait, so it's useful to remember that it's the result of multiple processes, which can interact in complex and sometimes strange ways.
I have 2 questions. First, do they suggest what causes exactly the rdQTLs? Is there a certain sequence on mRNA or something that causes those RNAs to decay faster, or vice versa?
ReplyDeleteSecond, what genes showed high decay and high expression? I'd expect things that have to do with pathways that are only intermittently activated, but need to be activated A LOT would fit there. For example, insulin or other glucose metabolism genes may be highly expressed only after a meal when glucose is abundant.
Yay, I can answer these!
Delete1) I glossed over this but they to find some associations between decay rate and certain gene features. For example, both transcript length and 3'UTR length are associated with decay rate (genes with longer transcripts and longer 3'UTR decay faster). They suggest that this could be because long 3'UTRs have more RNA-decay regulatory elements.
Previous research has also found some cis-regulatory elements (miRNA binding sites and 'AU-rich elements') that can speed RNA decay and, in this study, fast-decaying genes were more likely to have these kinds of elements.
2) Yeah you're totally right. From the paper: "One example is the BTG1 gene, which is involved i
regulating the glucocorticoid receptor autoregulatory pathway [35], and has both a significantly increased decay rate and a high expression level (Figure S5). Interestingly, seven of the top nine genes with discordant patterns (both the expression levels and
decay rates of these nine genes are within the top 5% of thegenome-wide distributions of gene expression and decay rate respectively; Figure 3C; see Methods) have been experimentally shown to be involved in auto-regulatory or regulatory feedback pathways (Table 1) [61–69]. More broadly, the top 49 genes with discordant patterns (constituting the top 10% of both the genome wide distributions of gene expression levels and decay rate Figure 3C) are enriched for genes with functions related to signaling pathways, stress response, and immune function.