Daniel He, David Wu, Soren Muller, Lin Wang, Parna Saha, Sajad Hamid Ahanger, Siyuan John Liu, Miao Cui, Sung Jun Hong, Miten Jain, Hugh E Olson, Mark Akeson, Joseph F Costello, Aaron Diaz, Daniel A Lim
Proceedings of the National Academy of Sciences of the United States of America 2021 Mar 30Among the large, diverse set of mammalian long noncoding RNAs (lncRNAs), long noncoding primary microRNAs (lnc-pri-miRNAs) are those that host miRNAs. Whether lnc-pri-miRNA loci have important biological function independent of their cognate miRNAs is poorly understood. From a genome-scale lncRNA screen, lnc-pri-miRNA loci were enriched for function in cell proliferation, and in glioblastoma (i.e., GBM) cells with DGCR8 or DROSHA knockdown, lnc-pri-miRNA screen hits still regulated cell growth. To molecularly dissect the function of a lnc-pri-miRNA locus, we studied LOC646329 (also known as MIR29HG), which hosts the miR-29a/b1 cluster. In GBM cells, LOC646329 knockdown reduced miR-29a/b1 levels, and these cells exhibited decreased growth. However, genetic deletion of the miR-29a/b1 cluster (LOC646329-miR29Δ) did not decrease cell growth, while knockdown of LOC646329-miR29Δ transcripts reduced cell proliferation. The miR-29a/b1-independent activity of LOC646329 corresponded to enhancer-like activation of a neighboring oncogene (MKLN1), regulating cell propagation. The LOC646329 locus interacts with the MKLN1 promoter, and antisense oligonucleotide knockdown of the lncRNA disrupts these interactions and reduces the enhancer-like activity. More broadly, analysis of genome-wide data from multiple human cell types showed that lnc-pri-miRNA loci are significantly enriched for DNA looping interactions with gene promoters as well as genomic and epigenetic characteristics of transcriptional enhancers. Functional studies of additional lnc-pri-miRNA loci demonstrated cognate miRNA-independent enhancer-like activity. Together, these data demonstrate that lnc-pri-miRNA loci can regulate cell biology via both miRNA-dependent and miRNA-independent mechanisms.
Daniel He, David Wu, Soren Muller, Lin Wang, Parna Saha, Sajad Hamid Ahanger, Siyuan John Liu, Miao Cui, Sung Jun Hong, Miten Jain, Hugh E Olson, Mark Akeson, Joseph F Costello, Aaron Diaz, Daniel A Lim. miRNA-independent function of long noncoding pri-miRNA loci. Proceedings of the National Academy of Sciences of the United States of America. 2021 Mar 30;118(13)
PMID: 33758101
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