Long noncoding RNA Hoxb3os is dysregulated in autosomal dominant polycystic kidney disease and regulates mTOR signaling

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating disease that is characterized by the accumulation of numerous fluid-filled cysts in the kidney. ADPKD is primarily caused by mutations in two genes, and Long noncoding RNAs (lncRNA), defined by a length >200 nucleotides and absence of a long ORF, have recently emerged as epigenetic regulators of development and disease; however, their involvement in PKD has not been explored previously. Here, we performed deep RNA-Seq to identify lncRNAs that are dysregulated in two orthologous mouse models of ADPKD (kidney-specific and mutant mice). We identified a kidney-specific, evolutionarily conserved lncRNA called that was down-regulated in cystic kidneys from and mutant mice. The human ortholog was down-regulated in cystic kidneys from ADPKD patients. was highly expressed in renal tubules in adult WT mice, whereas its expression was lost in the cyst epithelium of mutant mice. To investigate the function of, we utilized CRISPR/Cas9 to knock out its expression in mIMCD3 cells. Deletion of resulted in increased phosphorylation of mTOR and its downstream targets, including p70 S6 kinase, ribosomal protein S6, and the translation repressor 4E-BP1. Consistent with activation of mTORC1 signaling, mutant cells displayed increased mitochondrial respiration. The mutant phenotype was partially rescued upon re-expression of in knockout cells. These findings identify as a novel lncRNA that is down-regulated in ADPKD and regulates mTOR signaling and mitochondrial respiration.

Interstitial microRNA miR-214 attenuates inflammation and polycystic kidney disease progression

“…Thus, the Pkd2-KO model can be considered an early postnatal ADPKD model (24). Analysis of these previous data sets revealed that both miR-214 and Dnm3os are upregulated in Pkd1-KO and Pkd2-KO mouse models ( Figure 1A) (14,19). Therefore, we decided to examine miR-214 more closely in the context of ADPKD.…”

“…miR-214, an evolutionarily conserved miRNA, is derived from a long noncoding RNA (lncRNA) called dynamin 3 opposite strand (DNM3OS) (18). We have previously performed global transcriptomic analysis to identify differentially expressed miRNAs and lncRNAs across various PKD mouse models (14,19). Analysis of these data sets revealed that both miR-214 and its host lncRNA Dnm3os are upregulated in multiple PKD models.…”

Reverse-genetics studies of lncRNAs—what we have learnt and paths forward

“…On the other end of the spectrum, deletion of a 1.1-Mbp region on the human chromosome 6 containing a cluster of vlincRNAs in a fibrosarcoma cell line also using CRISPR/Cas9 has implicated one of them, vlinc273 or ASAR6-141, in control of replication timing of that chromosome [118]. In fact, lncRNA knockouts using genome-editing techniques in cultured cell models implicated lncRNAs in metabolism control [119,120], cell growth [119,[121][122][123], metastasis [124], and migration and invasion of human cancer cells [119,122,123,125].…”

Long noncoding RNAs in renal diseases

“…One microarray study characterized thousands of lncRNAs in patients with IgA-negative MsPGN (mesangial proliferative glomerulonephritis) [83]. LncRNA Hoxb3os, which regulates mTOR signaling, was found to be deregulated in polycystic kidney disease [84]. The lncRNA NEAT1 (Nuclear Enriched Abundant Transcript 1) was characterized as a novel inflammatory mediator in human lupus.…”