Profiling of miRNAs and target genes related to cystogenesis in ADPKD mouse models

Woo, Yu Mi; Kim, Do Yeon; Koo, Nam Jin; Kim, Yong Min; Lee, Sun Young; Ko, Je Yeong; Shin, Yubin; Kim, Bo Hye; Mun, Hyowon; Choi, Seonju; Lee, Eun Ji; Shin, Jeong Oh; Park, Eun Young; Bok, Jinwoong; Park, Jong Hoon

doi:10.1038/s41598-017-14083-8

Cited by 35 publications

(37 citation statements)

References 50 publications

(51 reference statements)

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“…In our previous study, the total RNA of kidney tissues from 3 Pkd2 f/f control mice and 3 Pkd2 f/f :HoxB7-Cre mice was analyzed by miRNA sequencing (14). The data revealed different expressional patterns of the miRNAs in Pkd2 f/f and Pkd2 f/f :HoxB7-Cre mice.…”

Section: Resultsmentioning

confidence: 99%

Regulation of KLF12 by microRNA‐20b and microRNA‐106a in cystogenesis

Shin

Kim

et al. 2018

FASEB j.

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Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders. ADPKD is caused by mutations in the gene encoding either polycystic kidney disease 1 ( PKD1) or polycystic kidney disease 2 ( PKD2). Patients with ADPKD show progressive growth of cystic fluid-filled renal cysts. Here, we used Pkd2 control mice and Pkd2:HoxB7-Cre experimental mice, which are bred to have a conditional deletion of Pkd2 in the collecting ducts, and analyzed the expression pattern of microRNAs (miRNAs) of kidney tissues from Pkd2 and Pkd2:HoxB7-Cre mice. Decreased expression of miR-20b-5p and miR-106a-5p in Pkd2:HoxB7-Cre mice compared to that in Pkd2 mice was observed. These miRNAs target Klf12 (Krüppel-like factor 12), which has low expression in kidney tissues of Pkd2 mice; however, its expression is enhanced in Pkd2:HoxB7-Cre mice over time. Moreover, miR-20b-5p and miR-106a-5p directly target Klf12 mRNA by binding to the 3'-UTR of Klf12. In addition, human and mouse cell lines exhibit similar patterns. These findings were also consistent with the data from Pkd2 knockout mouse embryonic fibroblasts. Furthermore, direct and indirect knockdown of Klf12 slows cyst growth and cell proliferation in mouse inner medullary collecting duct cells. Taken together, we suggest that the induction of miR-20b-5p or miR-106a-5p or the down-regulation of KLF12 could be used as potential novel therapies for inhibiting cyst growth in patients with ADPKD.-Shin, Y., Kim, D. Y., Ko, J. Y., Woo, Y. M., Park, J. H. Regulation of KLF12 by microRNA-20b and microRNA-106a in cystogenesis.

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Section: Resultsmentioning

confidence: 99%

Regulation of KLF12 by microRNA‐20b and microRNA‐106a in cystogenesis

Shin

Kim

et al. 2018

FASEB j.

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“…In our previous study, we performed integrative analysis of miR-and RNA-seq using 2 ADPKD mouse models to identify miR-mediated regulatory systems and networks during cystogenesis (31). miR and mRNA differences between Pkd1-and Pkd2-deficient mouse models were partially shared, but not all were the same.…”

Section: Discussionmentioning

confidence: 99%

“…To generate Pkd1 conditional KO mouse models, we used the Pkd1 flox mouse model in combination with the HoxB7-Cre or Aqp2-Cre mice (31). The floxed Pkd1 was obtained from Dr. Stefan Somlo (Yale University, New Haven, CT, USA).…”

Section: Animal Modelsmentioning

confidence: 99%

“…Orange dotted line: cutoff level. D) Snapshot illustrating highly enriched methylation at miR-192 and -194-2 loci in ADPKD compared with non-ADPKD.observed phenotypic changes resulting from the collecting-duct-specific inactivation of Pkd1 at postnatal day (P) 1, P3, and P7 in Pkd1 f/f :HoxB7-Cre mice(31). These mice began to form several cysts at P3, and numerous cysts were observed by P5.To investigate the time point of expressional changes of miR-192 and -194 and their connection to the severity of cyst development in vivo, miR-192 and -194 expression levels were measured at various postnatal time points in kidney tissues from Pkd1 f/f :HoxB7-Cre mice.…”

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confidence: 99%

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Impact of miR‐192 and miR‐194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease

et al. 2018

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Altered miRNA (miR) expression occurs in various diseases. However, the therapeutic effect of miRNAs in autosomal dominant polycystic kidney disease (ADPKD) is unclear. Genome‐wide analyses of miRNA expression and DNA methylation status were conducted to identify crucial miRNAs in end‐stage ADPKD. miR‐192 and ‐194 levels were down‐regulated with hypermethylation at these loci, mainly in the intermediate and late stages, not in the early stage, of cystogenesis, suggesting their potential impact on cyst expansion. Cyst expansion has been strongly associated with endothelial‐mesenchymal transition (EMT). Zinc finger E‐box‐binding homeobox‐2 and cadherin‐2, which are involved in EMT, were directly regulated by miR‐192 and ‐194. The therapeutic effect of miR‐192 and ‐194 in vivo and in vitro were assessed. Restoring these miRs by injection of precursors influenced the reduced size of cysts in Pkd1 conditional knockout mice. miR‐192 and ‐194 may act as potential therapeutic targets to control the expansion and progression of cysts in patients with ADPKD.—Kim, D. Y., Woo, Y. M., Lee, S., Oh, S., Shin, Y., Shin, J.‐O., Park, E. Y., Ko, J. Y., Lee, E. J., Bok, J., Yoo, K. H., Park, J. H. Impact of miR‐192 and miR‐194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease. FASEB J. 33, 2870–2884 (2019). http://www.fasebj.org

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“…According to the original authors (Woo et al, 2017), the experiments on mice sourced by Stefan Somlo were carried out in compliance with the Animal Care and Use Committee (IACUC) rules at Sookmyung Women's University. Therefore, we believe that correct ethics were followed during the experiment.…”

Section: Model Organismsmentioning

confidence: 99%

A new member in the Argonaute crew: the mt-miRNAs

Pozzi¹,

Dowling²

2020

Preprint

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1Mutations within the mitochondrial genome have been linked to many diverse phenotypes. 2 Moreover, the effects of these mutations have been shown to differ across sexes and environments. 3 The mechanisms that explain the manifold array of mitochondrial genotypic effects on organismal 4 function, and their context-dependency, have however remained a mystery. Here, we present 5 evidence that mitochondria are involved in nuclear gene regulation via RNA interference; 6 transcribing mitochondrial (mt-)miRNAs that may repress the transcription of nuclear genes that 7 previously had no known involvement in mitochondrial function. Our findings uncover a new 8 mechanism by which mitochondria may shape the expression of animal life-histories and health 9 components; implying that the influence of the mitochondria in regulating organismal function 10 extends well beyond the process of energy production. 11 Introduction 12 Interest in mitochondrial biology is on the rise, with a growing number of studies 13 highlighting the complex role of the mitochondria in cell regulation (Picard, Wallace, and Burelle 14 2016; Sloan et al. 2018; Sprenger and Langer 2019). Among these, numerous studies have found 15 that sequence variation in the mitochondrial DNA (mtDNA) can affect the expression of a range 16 of life-history and health related traits, from fertility, to longevity and thermal tolerance (Lajbner 17 et al. 2018; Camus et al. 2017; Rand, Fry, and Sheldahl 2006; Song and Lewis 2008; Yee, Sutton, 18 and Dowling 2013; James and Ballard 2003). Furthermore, while it is well known that the mtDNA 19 can harbour loss-of-function mutations conferring mitochondrial disease in humans (Wallace 20 2018), emerging studies implicate mtDNA mutations in a range of other late-onset diseases not 21 previously linked to mitochondrial function (Hudson et al. 2014). For example, Hopkins et al. 22 (2017) recently reported an association between the frequency and type of mtDNA mutations and aggressiveness of prostate cancer. Furthermore, the phenotypic effects of these mtDNA mutations 1 appear to be routinely moderated by the nuclear genetic background alongside which the mtDNA 2 mutations are co-expressed (Hill et al. 2018), suggesting a broad role for intergenomic regulation 3 ("mitonuclear communication") involving exchange of proteins, metabolites and genetic products 4 between genomes (Wu et al. 2019; Moriyama, Koshiba, and Ichinohe 2019; Zhu, Ingelmo, and 5 Rand 2014). The mechanistic basis of the molecular interactions that underpin mitonuclear 6 regulation of cellular and organismal function, however, remains elusive. 7 In 2019, Kopinski et al. provided new insights into how the mitochondria communicate 8 with the nucleus, reporting a key role for mitochondrial metabolites and subcellular redox levels. 9The authors found that variation in the level of intracellular mtDNA heteroplasmy (i.e. the 10 frequency of normal to mutant mtDNA molecules) modulates mitochondrial metabolites, 11 influencing the abundance of substrate necessary for...

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Profiling of miRNAs and target genes related to cystogenesis in ADPKD mouse models

Cited by 35 publications

References 50 publications

Regulation of KLF12 by microRNA‐20b and microRNA‐106a in cystogenesis

Regulation of KLF12 by microRNA‐20b and microRNA‐106a in cystogenesis

Impact of miR‐192 and miR‐194 on cyst enlargement through EMT in autosomal dominant polycystic kidney disease

A new member in the Argonaute crew: the mt-miRNAs

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