Kocabas A, Duarte T, Kumar S, Hynes MA.
Widespread Differential Expression of Coding Region and 3' UTR Sequences in Neurons and Other Tissues.
Neuron. 2015 Dec 16;88(6):1149-56.
PubMed.
The study by Kocabas et al., revealing “Widespread differential expression of coding region (CDS) and 3'UTR sequences in neurons ...” for many genes is both surprising and highly interesting. According to current thinking, the 3'UTR and CDS of a gene are expected to show relatively similar abundance, as they are different regions of the same mRNA. However, the authors present convincing in situ hybridization and other evidence that this expectation in many cases may well be incorrect. The study reveals several surprising results, including: 1) that there are different levels of 3'UTR to CDS for some, but not all genes; 2) that these occur in patterns that are developmentally and spatially regulated and conserved across different biological samples; and 3) that there is a correlation between the 3'UTR-to-CDS ratio and protein level. This phenomenon is widespread among genes, including several genes that are commonly used as “control” genes (β-actin and GAPDH). But the unbalance is not random, in that certain gene ontology categories are more likely to be associated with the 3'UTR disconnect than others.
The functional implications of these new findings are not yet clear. The data could indicate that post-translational degradation or pre-translational association with ribosomes of some mRNA species involves previously unrecognized cleavage of the UTR and CDS. Alternatively, the correlation between protein and UTR-to-CDS ratio may indicate that this unbalance reflects a novel mechanism of gene regulation, perhaps one designed to coordinate rapid alterations in expression of related genes by separating the CDS from the regulatory influence of the 3'UTR in multiple sensitive genes of a functional network. If further work supports the conclusion that this differential expression reflects regulatory mechanisms, then, as the authors note, probe sets for all regions of the mRNA will need to be included in microarrays. And then it will be of great interest to determine which gene categories and networks are subject to such regulation and whether neurons vulnerable to neurodegenerative disorders are particularly susceptible (or resistant) to this type of differential expression.
This report of differential expression of exon-coding sequences (CDS) and 3′ UTR sequences in neurons and other cellular sources provides interesting information regarding potential regulation of cell-specific expression of individual transcripts and their encoded proteins during development and in adulthood. The work has strong implications for molecular mechanisms underlying neurodegenerative disorders. Interestingly, defined neuronal populations were found to have varying ratios of cognate 3′ UTR and CDS sequences, as some genes displayed a high 3′ UTR:CDS ratio while others revealed a low 3′ UTR:CDS ratio. A functional consequence of a differential 3′ UTR:CDS ratio was demonstrated in two genes whereby a high ratio correlated strongly with low protein expression. The discrepant levels of cognate 3′ UTR and CDS sequences is somewhat surprising, as the generally accepted dogma is that these elements were more or less equivalent until translation or degradation. The authors are commended for looking at neurons in different brain regions during development and adulthood as well as other tissue sources, such as the kidney.
Discrete expression of tyrosine hydroxylase (TH) 3′ UTR:CDS ratio and protein in embryonic midbrain neurons provided convincing proof of concept that a ratio >3 predicted low or no protein expression. Extrapolating this finding of cell-specific 3′ UTR:CDS ratios to AD pathogenesis, it will be interesting to evaluate cognate 3′ UTR:CDS sequences in neurons that are selectively vulnerable to neurodegeneration during the progression of AD. For example, cholinergic markers such as choline acetyltransferase and neurotrophin receptors such as TrkA and p75NTR in cholinergic basal forebrain (CBF) neurons in AD, mild cognitive impairment (MCI), and age-matched nondemented controls would be ideal to evaluate potential pathogenic shifts in 3′ UTR:CDS ratios. Parallel studies would be of high interest in animal models of AD pathology where basal forebrain cholinergic neurons (BFCNs) lose their phenotype, including the Ts65Dn mouse model of AD and Down’s syndrome.
In sum, the data present by Kocabas et al. has broad relevance for AD research. Re-evaluation of high-throughput (e.g., RNA-seq and/or microarray) data as well as prospective studies with built-in cognate 3′ UTR and CDS measurements is warranted to parse out potential large-scale expression discrepancies between 3′ UTR and CDS sequences. A caveat would be that data must arise from individual populations, e.g., from neurons extracted via laser-capture microdissection rather than regional or global tissue dissections to avoid contaminating signals from different neuronal, glial, and vascular cell populations, among others. Unfortunately, calculating the 3′ UTR:CDS ratio from data repositories using admixed cell types in postmortem AD tissues or AD animal models will not likely lead to interpretable results based upon the analyses of Kocabas et al., because the 3′ UTR:CDS ratio is likely cell-type specific throughout development and adulthood.
Comments
University of Kentucky
University of Kentucky
The study by Kocabas et al., revealing “Widespread differential expression of coding region (CDS) and 3'UTR sequences in neurons ...” for many genes is both surprising and highly interesting. According to current thinking, the 3'UTR and CDS of a gene are expected to show relatively similar abundance, as they are different regions of the same mRNA. However, the authors present convincing in situ hybridization and other evidence that this expectation in many cases may well be incorrect. The study reveals several surprising results, including: 1) that there are different levels of 3'UTR to CDS for some, but not all genes; 2) that these occur in patterns that are developmentally and spatially regulated and conserved across different biological samples; and 3) that there is a correlation between the 3'UTR-to-CDS ratio and protein level. This phenomenon is widespread among genes, including several genes that are commonly used as “control” genes (β-actin and GAPDH). But the unbalance is not random, in that certain gene ontology categories are more likely to be associated with the 3'UTR disconnect than others.
The functional implications of these new findings are not yet clear. The data could indicate that post-translational degradation or pre-translational association with ribosomes of some mRNA species involves previously unrecognized cleavage of the UTR and CDS. Alternatively, the correlation between protein and UTR-to-CDS ratio may indicate that this unbalance reflects a novel mechanism of gene regulation, perhaps one designed to coordinate rapid alterations in expression of related genes by separating the CDS from the regulatory influence of the 3'UTR in multiple sensitive genes of a functional network. If further work supports the conclusion that this differential expression reflects regulatory mechanisms, then, as the authors note, probe sets for all regions of the mRNA will need to be included in microarrays. And then it will be of great interest to determine which gene categories and networks are subject to such regulation and whether neurons vulnerable to neurodegenerative disorders are particularly susceptible (or resistant) to this type of differential expression.
View all comments by Susan KranerNathan Kline Institute/NYU Langone School of Medicine
This report of differential expression of exon-coding sequences (CDS) and 3′ UTR sequences in neurons and other cellular sources provides interesting information regarding potential regulation of cell-specific expression of individual transcripts and their encoded proteins during development and in adulthood. The work has strong implications for molecular mechanisms underlying neurodegenerative disorders. Interestingly, defined neuronal populations were found to have varying ratios of cognate 3′ UTR and CDS sequences, as some genes displayed a high 3′ UTR:CDS ratio while others revealed a low 3′ UTR:CDS ratio. A functional consequence of a differential 3′ UTR:CDS ratio was demonstrated in two genes whereby a high ratio correlated strongly with low protein expression. The discrepant levels of cognate 3′ UTR and CDS sequences is somewhat surprising, as the generally accepted dogma is that these elements were more or less equivalent until translation or degradation. The authors are commended for looking at neurons in different brain regions during development and adulthood as well as other tissue sources, such as the kidney.
Discrete expression of tyrosine hydroxylase (TH) 3′ UTR:CDS ratio and protein in embryonic midbrain neurons provided convincing proof of concept that a ratio >3 predicted low or no protein expression. Extrapolating this finding of cell-specific 3′ UTR:CDS ratios to AD pathogenesis, it will be interesting to evaluate cognate 3′ UTR:CDS sequences in neurons that are selectively vulnerable to neurodegeneration during the progression of AD. For example, cholinergic markers such as choline acetyltransferase and neurotrophin receptors such as TrkA and p75NTR in cholinergic basal forebrain (CBF) neurons in AD, mild cognitive impairment (MCI), and age-matched nondemented controls would be ideal to evaluate potential pathogenic shifts in 3′ UTR:CDS ratios. Parallel studies would be of high interest in animal models of AD pathology where basal forebrain cholinergic neurons (BFCNs) lose their phenotype, including the Ts65Dn mouse model of AD and Down’s syndrome.
In sum, the data present by Kocabas et al. has broad relevance for AD research. Re-evaluation of high-throughput (e.g., RNA-seq and/or microarray) data as well as prospective studies with built-in cognate 3′ UTR and CDS measurements is warranted to parse out potential large-scale expression discrepancies between 3′ UTR and CDS sequences. A caveat would be that data must arise from individual populations, e.g., from neurons extracted via laser-capture microdissection rather than regional or global tissue dissections to avoid contaminating signals from different neuronal, glial, and vascular cell populations, among others. Unfortunately, calculating the 3′ UTR:CDS ratio from data repositories using admixed cell types in postmortem AD tissues or AD animal models will not likely lead to interpretable results based upon the analyses of Kocabas et al., because the 3′ UTR:CDS ratio is likely cell-type specific throughout development and adulthood.
View all comments by Stephen D. GinsbergMake a Comment
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