miRNA-independent function of long noncoding pri-miRNA loci | Zendy

Daniel He | Zendy; David Wu | Zendy; Sören Müller | Zendy; Lin Wang | Zendy; Parna Saha | Zendy; Sajad Hamid Ahanger | Zendy; Siyuan Liu | Zendy; Miao Cui | Zendy; Sung Jun Hong | Zendy; Miten Jain | Zendy; Hugh E. Olson | Zendy; Mark Akeson | Zendy; J Costello | Zendy; Aaron A. Diaz | Zendy; Daniel A. Lim | Zendy

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miRNA-independent function of long noncoding pri-miRNA loci

Author(s) -

Daniel He,

David Wu,

Sören Müller,

Lin Wang,

Parna Saha,

Sajad Hamid Ahanger,

Siyuan Liu,

Miao Cui,

Sung Jun Hong,

Miten Jain,

Hugh E. Olson,

Mark Akeson,

J Costello,

Aaron A. Diaz,

Daniel A. Lim

Publication year - 2021

Publication title -

proceedings of the national academy of sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.011

H-Index - 771

eISSN - 1091-6490

pISSN - 0027-8424

DOI - 10.1073/pnas.2017562118

Subject(s) - drosha , biology , gene knockdown , microrna , enhancer , genetics , epigenetics , computational biology , gene , rna interference , gene expression , rna

Among 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.

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