title: Alu-miRNA interactions modulate transcript isoform diversity in stress response and reveal signatures of positive selection.
abstract: Primate-specific Alus harbor different regulatory features, including miRNA targets. In this study, we provide evidence for miRNA-mediated modulation of transcript isoform levels during heat-shock response through exaptation of Alu-miRNA sites in mature mRNA. We performed genome-wide expression profiling coupled with functional validation of miRNA target sites within exonized Alus, and analyzed conservation of these targets across primates. We observed that two miRNAs (miR-15a-3p and miR-302d-3p) elevated in stress response, target RAD1, GTSE1, NR2C1, FKBP9 and UBE2I exclusively within Alu. These genes map onto the p53 regulatory network. Ectopic overexpression of miR-15a-3p downregulates GTSE1 and RAD1 at the protein level and enhances cell survival. This Alu-mediated fine-tuning seems to be unique to humans as evident from the absence of orthologous sites in other primate lineages. We further analyzed signatures of selection on Alu-miRNA targets in the genome, using 1000 Genomes Phase-I data. We found that 198 out of 3177 Alu-exonized genes exhibit signatures of selection within Alu-miRNA sites, with 60 of them containing SNPs supported by multiple evidences (global-FST > 0.3, pair-wise-FST > 0.5, Fay-Wu's H < -20, iHS > 2.0, high ΔDAF) and implicated in p53 network. We propose that by affecting multiple genes, Alu-miRNA interactions have the potential to facilitate population-level adaptations in response to environmental challenges.
authors: CSIR Ayurgenomics Unit - TRISUTRA, CSIR- Institute of Genomics and Integrative Biology (IGIB), Sukhdev Vihar, Mathura Road, New Delhi-110025, INDIA.
authors: Rajesh
authors: R
authors: Pandey
authors: Genomics and Molecular Medicine Unit, CSIR- IGIB, Sukhdev Vihar, Mathura Road, New Delhi-110025, INDIA.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, INDIA.
authors: Aniket
authors: A
authors: Bhattacharya
authors: Genomics and Molecular Medicine Unit, CSIR- IGIB, Sukhdev Vihar, Mathura Road, New Delhi-110025, INDIA.
authors: Vivek
authors: V
authors: Bhardwaj
authors: Persistent LABS, Persistent Systems Ltd., Pune-411004, Maharashtra, INDIA.
authors: Vineet
authors: V
authors: Jha
authors: GN Ramachandran Knowledge Centre for Genome Informatics, CSIR-IGIB, Sukhdev Vihar, Mathura Road, New Delhi-110025, INDIA.
authors: Amit K
authors: AK
authors: Mandal
authors: CSIR Ayurgenomics Unit - TRISUTRA, CSIR- Institute of Genomics and Integrative Biology (IGIB), Sukhdev Vihar, Mathura Road, New Delhi-110025, INDIA.|Genomics and Molecular Medicine Unit, CSIR- IGIB, Sukhdev Vihar, Mathura Road, New Delhi-110025, INDIA.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, INDIA.|GN Ramachandran Knowledge Centre for Genome Informatics, CSIR-IGIB, Sukhdev Vihar, Mathura Road, New Delhi-110025, INDIA.
authors: Mitali
authors: M
authors: Mukerji
mesh_terms: D020087:Alu Elements; D002470:Cell Survival; D005092:Exonucleases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006367:HeLa Cells; D018869:Heat-Shock Response / Q000235:genetics*; D006358:Hot Temperature; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D012641:Selection, Genetic; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics*; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: C122078:FKBP9 protein, human; C115080:GTSE1 protein, human; C505361:MIRN15 microRNA, human; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; C539822:NR2C1 protein, human; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D044763:Ubiquitin-Conjugating Enzymes; D005092:Exonucleases; C113574:Rad1 protein, human; D022021:Tacrolimus Binding Proteins; D000098843:Ubiquitin-Conjugating Enzyme UBC9