Enhanced transcriptomic resilience following increased alternative splicing and differential isoform production between air pollution conurbations
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Adversehealth outcomes caused by ambient particulate matter (PM) pollution occur in a 16progressive process, with neutrophils eliciting inflammation or pathogenesis. We investigated the 17toxico-transcriptomic mechanisms of PM in real-life settings by comparing healthy residents living 18in Beijing and Chengde, the opposing ends of a well-recognised air pollution (AP) corridor in China. 19Beijing recruits (BRs) uniquelyexpressed ~12,000 alternativesplicing (AS)-derived transcripts, 20largely elevating the proportion of transcripts significantly correlated with PM concentration. BRs 21expressed PM-associated isoforms (PMAIs) of PFKFB3and LDHA,encoding enzymes responsible 22for stimulatingand maintaining glycolysis. PMAIsof PFKFB3featured different COOH-terminals, 23targeting PFKFB3 to different sub-cellular functional compartments and stimulating glycolysis. 24PMAIs of LDHAhavelonger 3’UTRs relative to those expressed in Chengderecruits (CRs),allowing 25glycolysis maintenance by enhancing LDHAmRNA stability and translational efficiency. PMAIs 26weredirectly regulated by different HIF-1Aand HIF-1Bisoforms. BRs expressed more non-func-27tional Fasisoforms and a resultant reduction of intact Fasproportion is expectedto inhibit the trans-28mission of apoptotic signals and prolong neutrophil lifespan. BRs expressed both membrane-bound 29and soluble IL-6Risoforms insteadof only one in CRs. The presence of both IL-6Risoforms sug-30gested a higher migration capacity of neutrophils in BRs. PMAIs of HIF-1Aand PFKFB3were down-31regulated inChronic Obstructive Pulmonary Disease patients compared with BRs, implying HIF-1 32mediated defective glycolysis may mediate neutrophil dysfunction. PMAIs could explain large var-33iances of different phenotypes, highlighting their potential application as biomarkers and therapeu-34tic targets in PM-induced diseases, which remain poorly elucidated.
Article accepted for publication in Atmosphere
Cardiff Metropolitan University (Grant ID: Cardiff Metropolian (Internal))
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