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Komen","doi-asserted-by":"publisher","award":["CCR19609287"],"award-info":[{"award-number":["CCR19609287"]}],"id":[{"id":"10.13039\/100009634","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>MicroRNA (miRNA) is not a single sequence, but a series of multiple variants (also termed isomiRs) with sequence and expression heterogeneity. Whether and how these isoforms contribute to functional variation and complexity at the systems and network levels remain largely unknown. To explore this question systematically, we comprehensively analyzed the expression of small RNAs and their target sites to interrogate functional variations between novel isomiRs and their canonical miRNA sequences. Our analyses of the pan-cancer landscape of miRNA expression indicate that multiple isomiRs generated from the same miRNA locus often exhibit remarkable variation in their sequence, expression and function. We interrogated abundant and differentially expressed 5\u2032 isomiRs with novel seed sequences via seed shifting and identified many potential novel targets of these 5\u2032 isomiRs that would expand interaction capabilities between small RNAs and mRNAs, rewiring regulatory networks and increasing signaling circuit complexity. Further analyses revealed that some miRNA loci might generate diverse dominant isomiRs that often involved isomiRs with varied seeds and arm-switching, suggesting a selective advantage of multiple isomiRs in regulating gene expression. Finally, experimental validation indicated that isomiRs with shifted seed sequences could regulate novel target mRNAs and therefore contribute to regulatory network rewiring. Our analysis uncovers a widespread expansion of isomiR and mRNA interaction networks compared with those seen in canonical small RNA analysis; this expansion suggests global gene regulation network perturbations by alternative small RNA variants or isoforms. Taken together, the variations in isomiRs that occur during miRNA processing and maturation are likely to play a far more complex and plastic role in gene regulation than previously anticipated.<\/jats:p>","DOI":"10.1093\/bib\/bbab091","type":"journal-article","created":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T12:13:33Z","timestamp":1614773613000},"source":"Crossref","is-referenced-by-count":10,"title":["mi-IsoNet: systems-scale microRNA landscape reveals rampant isoform-mediated gain of target interaction diversity and signaling specificity"],"prefix":"10.1093","volume":"22","author":[{"given":"Li","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongsheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kara M","family":"Cirillo","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A","family":"Marick","sequence":"additional","affiliation":[{"name":"Department of Oncology, Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Oncology, Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Oncology, Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gordon B","family":"Mills","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental and Cancer Biology, School of Medicine, Oregon Health & Science University, Portland, OR 97201, USA"},{"name":"Precision Oncology, Knight Cancer Institute, Portland, OR 97201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nidhi","family":"Sahni","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA"},{"name":"Program in Quantitative and Computational Biosciences (QCB), Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S Stephen","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Oncology, Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA"},{"name":"Oden Institute for Computational Engineering and Sciences (ICES), The University of Texas at Austin, Austin, TX 78712, USA"},{"name":"Interdisciplinary Life Sciences Graduate 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