GSE112801
Transfer RNA fragments and microRNAs co-predict circadian-dependent recovery from ischemic stroke [small RNA]
Ischemic stroke incidence increases with extending life expectancy, and inflammation exacerbates symptoms severity, but finding the underlying controllers and predicting recovery prospects are challenging. Here, we report whole blood RNA-sequencing of 2 days post-stroke patients and matched controls (38/10), which revealed multiple co-modified cholinergic-targeting small tRNA fragments (tRFs), mainly methionine and alanine tRNA-derived and microRNAs (miRs). Weighted gene correlation network analysis segregated stroke-modified tRFs and miRs into inter-related modules, linking pro-inflammatory interleukin-8 with 3-months cognitive recovery. However, interrupting the cholinergic blockade of inflammation in stroke model mice by microRNA-132-targeted oligonucleotide or recombinant acetylcholinesterase failed to improve recovery. Since patients whose stroke occurred between 6AM-12PM showed better recovery prospects (183/484 patients, p<0.03), we separately sought tRFs- and miRs-based recovery-predicting ROC curves in morning and non-morning patients. Combining tRF-16-MBQ4NKD with miR-1249-3p, -547-3p and -3913-5p strongly predicted non-morning patients' recovery (AUC 0.969, p< 0.002, 95% confidence interval 0.895-1), whereas tRF-22-WEKSPM852 and miR-1307-3p, -6881-3p and -132-5p co-predicted morning patients' recovery (AUC 0.93, p<0.004, 95% confidence interval 0.788-1). Implicating JAK-STAT inflammation control, improving morning patients showed increases of the circadian-regulated SOCS3 and its stabilizer PIM1, with decreases of the SOCS3-targeting miR-326 and -532-3p. Our findings highlight circadian-controlled cholinergic-targeted tRFs and miRs as co-regulators of post-stroke recovery, enable predicting long-term cognitive recovery by day 2 post-stroke and indicate novel therapeutic targets. Overall design: Small RNA sequencing of ischemic stroke patients two days post stroke and age matched controls