Lackey and colleagues reported a newly discovered alternative polyadenylation event that influences alpha-1 antitrypsin (AAT) expression, as published in PLOS Genetics. They demonstrated how post-transcriptional regulation affects disease phenotype and can be used as a potential target for RNA therapeutics.
AAT deficiency (AATD) can often lead to panlobular emphysema and liver cirrhosis. This is because the AAT protein modulates inflammatory responses by inhibiting neutrophil elastase.
“Although the role of the [AAT] protein in disease etiology is well established, the SERPINA1 mRNA, and in particular its multiple alternative splicing transcriptional isoforms is exceptional and still poorly understood,” Lackey et al wrote. “To date, the role of the 3′ UTR [untranslated region] of the SERPINA1 mRNA in [AAT] expression has yet to be investigated.”
Studies have shown that SERPINA1 mRNA expression can vary significantly between patients with AATD. However, phenotype variability cannot be accounted for by genetic variation alone. “We characterize a distal polyadenylation site in the SERPINA1 mRNA that is differentially used in the lungs of [chronic obstructive pulmonary disease] individuals,” the researchers wrote.
“By combining quantitative 3′ end sequencing, large scale transcriptomic profiling of individuals, quantitative nanoluciferase reporter assays, RNA chemical structure probing, and single-cell RNA sequencing, we characterize the role of SERPINA1 [Alternative Poly-Adenylation] in controlling [AAT] translation.”
Read more about AATD etiology
They carried out their investigation by visualizing the median expression of SERPINA1 mRNA across patients sequenced in the Gene Tissue Expression Atlas. They then identified 6 tissues (blood, liver, small intestine, lung, spleen, and kidney) where the median expression was sufficient enough to obtain estimates of individual exon specific expression.
Lackey and colleagues discovered that SERPINA1 3’ UTR had a long and short isoform. They also concluded that quaking homolog suppresses AAT protein expression via long 3’ UTRs from SERPINA1 isoforms. “The molecular response in the lung at the level of RNA binding proteins favors the short 3′ UTR of the SERPINA1 mRNA, increasing the translation and expression of the [AAT] protein,” they wrote.
The clinical implication of this study is that by understanding in greater detail the mechanisms that affect AAT expression, medical researchers might be able to develop better therapeutics that target AATD.
Lackey L, Coria A, Ghosh AJ, et al. Alternative poly-adenylation modulates α1-antitrypsin expression in chronic obstructive pulmonary disease. PLOS Genet. Published online November 16, 2021. doi:10.1371/journal.pgen.1009912