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

Karam Aboudehen, Shayan Farahani, Mohammed Kanchwala, Siu Chiu Chan, Svetlana Avdulov, Alan Mickelson, Dayeon Lee, Micah D. Gearhart, Vishal Patel, Chao Xing, Peter Igarashi

Research output: Contribution to journalArticle

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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, PKD1 and PKD2. 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 Pkd1 and Pkd2 mutant mice). We identified a kidney-specific, evolutionarily conserved lncRNA called Hoxb3os that was down-regulated in cystic kidneys from Pkd1 and Pkd2 mutant mice. The human ortholog HOXB3-AS1 was down-regulated in cystic kidneys from ADPKD patients. Hoxb3os 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 Hoxb3os, we utilized CRISPR/Cas9 to knock out its expression in mIMCD3 cells. Deletion of Hoxb3os 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, Hoxb3os mutant cells displayed increased mitochondrial respiration. The Hoxb3os mutant phenotype was partially rescued upon re-expression of Hoxb3os in knockout cells. These findings identify Hoxb3os as a novel lncRNA that is down-regulated in ADPKD and regulates mTOR signaling and mitochondrial respiration.

Original languageEnglish (US)
Pages (from-to)9388-9398
Number of pages11
JournalJournal of Biological Chemistry
Volume293
Issue number24
DOIs
StatePublished - Jan 1 2018

Fingerprint

Long Noncoding RNA
Autosomal Dominant Polycystic Kidney
Cystic Kidney Diseases
Kidney
Respiration
Clustered Regularly Interspaced Short Palindromic Repeats
Ribosomal Protein S6
70-kDa Ribosomal Protein S6 Kinases
Cyst Fluid
Protein Biosynthesis
Epigenomics
Open Reading Frames
Phosphorylation
Cysts
Epithelium
Nucleotides
RNA
Phenotype
Mutation
Genes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Aboudehen, K., Farahani, S., Kanchwala, M., Chan, S. C., Avdulov, S., Mickelson, A., ... Igarashi, P. (2018). Long noncoding RNA Hoxb3os is dysregulated in autosomal dominant polycystic kidney disease and regulates mTOR signaling. Journal of Biological Chemistry, 293(24), 9388-9398. https://doi.org/10.1074/jbc.RA118.001723

Long noncoding RNA Hoxb3os is dysregulated in autosomal dominant polycystic kidney disease and regulates mTOR signaling. / Aboudehen, Karam; Farahani, Shayan; Kanchwala, Mohammed; Chan, Siu Chiu; Avdulov, Svetlana; Mickelson, Alan; Lee, Dayeon; Gearhart, Micah D.; Patel, Vishal; Xing, Chao; Igarashi, Peter.

In: Journal of Biological Chemistry, Vol. 293, No. 24, 01.01.2018, p. 9388-9398.

Research output: Contribution to journalArticle

Aboudehen, K, Farahani, S, Kanchwala, M, Chan, SC, Avdulov, S, Mickelson, A, Lee, D, Gearhart, MD, Patel, V, Xing, C & Igarashi, P 2018, 'Long noncoding RNA Hoxb3os is dysregulated in autosomal dominant polycystic kidney disease and regulates mTOR signaling', Journal of Biological Chemistry, vol. 293, no. 24, pp. 9388-9398. https://doi.org/10.1074/jbc.RA118.001723
Aboudehen, Karam ; Farahani, Shayan ; Kanchwala, Mohammed ; Chan, Siu Chiu ; Avdulov, Svetlana ; Mickelson, Alan ; Lee, Dayeon ; Gearhart, Micah D. ; Patel, Vishal ; Xing, Chao ; Igarashi, Peter. / Long noncoding RNA Hoxb3os is dysregulated in autosomal dominant polycystic kidney disease and regulates mTOR signaling. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 24. pp. 9388-9398.
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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, PKD1 and PKD2. 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 Pkd1 and Pkd2 mutant mice). We identified a kidney-specific, evolutionarily conserved lncRNA called Hoxb3os that was down-regulated in cystic kidneys from Pkd1 and Pkd2 mutant mice. The human ortholog HOXB3-AS1 was down-regulated in cystic kidneys from ADPKD patients. Hoxb3os 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 Hoxb3os, we utilized CRISPR/Cas9 to knock out its expression in mIMCD3 cells. Deletion of Hoxb3os 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, Hoxb3os mutant cells displayed increased mitochondrial respiration. The Hoxb3os mutant phenotype was partially rescued upon re-expression of Hoxb3os in knockout cells. These findings identify Hoxb3os as a novel lncRNA that is down-regulated in ADPKD and regulates mTOR signaling and mitochondrial respiration.",
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