期刊
NUCLEIC ACIDS RESEARCH
卷 41, 期 2, 页码 1164-1177出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gks1098
关键词
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资金
- Clayton Foundation for Research
- National Institutes of Health (NIH) [HL095382]
- NIH [HL095382]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL095382] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX002221] Funding Source: NIH RePORTER
RNA interference mediated through antisense transcripts is a fundamentally important mechanism regulating gene expression that remains incompletely understood. Here, we have used next-generation sequencing to determine from mouse CD4+ T cells the functional implications of antisense transcripts binding to argonaute (AGO) proteins that mediate RNA interference and post-transcriptional gene silencing. This effort identified 90 new microRNAs (miRNAs) and six endogenous hairpin RNA-derived small interfering RNAs (siRNAs) mapping to distinct introns. Unexpectedly, 69 miRNAs were expressed as non-canonical isomiRs as the dominant AGO-binding transcript, with extensive 3' terminal nucleotide modifications. Furthermore, differential expression analysis between AGO1- and AGO2-bound miRNAs suggested preferential binding of isomiRs ending with 3' adenine residues to AGO1 and 3' uridine residues to AGO2. Analysis of the putative targets of all miRNAs suggested a striking preference for regulating transcription and transcription factors with additional evidence of a functional division of labor between AGO proteins in this regard. We further provide evidence that multiple mitochondrial genomic loci serve as the source of endogenous cis-natural antisense transcripts. These findings imply diversity in AGO protein function based on differential miRNA binding and indicate that RNA interference-based gene regulation is more complex than previously recognized.
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