Investigating long noncoding RNAs using animal models

Feyder, Michael; Goff, Loyal A.

doi:10.1172/jci84422

Cited by 30 publications

(18 citation statements)

References 131 publications

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“…ASOs and RNAi as described above) has been used as an alternative strategy to investigate their functions in vivo. However, this knockdown method may not be sufficient to eliminate lncRNAs compared with a knockout approach, and the introduction of exogenous molecules may be toxic to organisms and induce off-target effects [174]. Therefore, lncRNA knockout mouse models are more reliable and necessary for revealing their functions, whereas no such models have been used in the studies of HCC so far.…”

Section: Discussionmentioning

confidence: 99%

The role of long noncoding RNAs in hepatocellular carcinoma

et al. 2020

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Hepatocellular carcinoma (HCC) is the most frequent subtype of primary liver cancer and one of the leading causes of cancer-related death worldwide. However, the molecular mechanisms underlying HCC pathogenesis have not been fully understood. Emerging evidences have recently suggested the crucial role of long noncoding RNAs (lncRNAs) in the tumorigenesis and progression of HCC. Various HCC-related lncRNAs have been shown to possess aberrant expression and participate in cancerous phenotypes (e.g. persistent proliferation, evading apoptosis, accelerated vessel formation and gain of invasive capability) through their binding with DNA, RNA or proteins, or encoding small peptides. Thus, a deeper understanding of lncRNA dysregulation would provide new insights into HCC pathogenesis and novel tools for the early diagnosis and treatment of HCC. In this review, we summarize the dysregulation of lncRNAs expression in HCC and their tumor suppressive or oncogenic roles during HCC tumorigenesis. Moreover, we discuss the diagnostic and therapeutic potentials of lncRNAs in HCC.

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Section: Discussionmentioning

confidence: 99%

The role of long noncoding RNAs in hepatocellular carcinoma

et al. 2020

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“…However, lncRNA loci potentially contain multiple modes that can exert function, including DNA regulatory elements (including the promoter), the act of transcription, and the lncRNA. Therefore, attributing an RNA-based role to a lncRNA locus requires the development of multiple genetic models to determine the activities and contributions of potential regulatory modalities 20,21,59 .…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, deletions of entire lncRNA loci have uncovered a number of in vivo phenotypes 9–13 ; however, this approach alone is confounded because in addition to the lncRNA transcript, lncRNA loci can also exert function through DNA regulatory elements 14–16 , the promoter region 17 , as well as by the act of transcription 18,19 . Thus, attributing RNA-based role(s) to lncRNA loci requires testing whether other regulatory modes potentially present at the locus have molecular activity that could contribute to phenotypic effects 11,20,21 .…”

Section: Introductionmentioning

confidence: 99%

The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis

Lewandowski

Lee

Hwang

et al. 2019

Preprint

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39RNA has been classically known to play central roles in biology, including maintaining telomeres 1 , 40 protein synthesis 2 , and in sex chromosome compensation in certain species 3,4 . At the center of 41 these important biological systems are noncoding RNAs. While thousands of long noncoding 42 RNAs (lncRNAs) have been identified in mammalian genomes 5-8 , attributing RNA-based roles to 43 lncRNA loci requires an assessment of whether the observed effect could be due to DNA 44 regulatory elements, the act of transcription, or the lncRNA transcript. Here, we use the 45 syntenically conserved lncRNA locus, Functional intergenic repeating RNA element (Firre), that 46 is located on the X chromosome as a model to discriminate between DNA-and RNA-mediated 47 effects in vivo. To this end, we generated genetically defined loss-of-function, gain-of-function, 48 and rescue mouse models for Firre and provide genetic evidence that the Firre locus produces a 49 trans-acting RNA. We report that: (i) Firre mutant mice have cell-specific defects during 50 hematopoiesis and changes in gene expression that can be rescued by induction of Firre RNA 51 from a transgene in the Firre knockout background, (ii) mice overexpressing Firre from a 52 transgene exhibit increased levels of pro-inflammatory cytokines and impaired survival upon 53 exposure to lipopolysaccharide, and (iii) deletion of the Firre locus did not result in changes in 54 local gene expression on the X chromosome in 9 different biological contexts, suggesting that 55 Firre does not function by cis-acting RNA or DNA elements. Together, our results provide genetic 56 evidence that the Firre locus produces a trans-acting lncRNA that has physiological roles in 57 hematopoiesis and immune function.58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 102 of pro-inflammatory cytokines and impaired survival upon exposure to lipopolysaccharide (LPS).103 Finally, the Firre locus does not contain cis-acting RNA or DNA elements (including the promoter) 104 that regulate neighboring gene expression on the X chromosome (9 biological contexts 105 examined), suggesting that Firre does not function in cis. Collectively, our study provides evidence 106 4 for a trans-acting RNA-based role for the Firre locus that has physiological importance for 107 hematopoiesis and immune function. 108 109 110 111 RESULTS 112The Firre locus produces an abundant lncRNA. We first sought to investigate the gene 113 expression properties for Firre RNA in vivo. To determine potential spatial and temporal aspects 114 of Firre RNA expression during development, we performed in situ hybridization in wildtype (WT) 115 mouse embryos (E8.0 -E12.5). Notably, we detected Firre RNA in many embryonic tissues, 116 including the forebrain, midbrain, pre-somitic mesoderm, lung, forelimb, hindlimb, liver, and heart 117 ( Fig. 1A). Since noncoding RNAs have been described to be generally expressed at lower levels 118 compared to protein-coding genes 39-42 , we determined the relative abundance of Firre RNA in 119 vivo. We per...

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“…Still, it is not known whether noncentromeric lncRNAs exist to interact with proteins involved in kinetochore assembly. Additionally, in vivo functional analysis is in general lacking for most lncRNAs studied so far despite a wealth of knowledge accumulated from using in vitro cell culture; to date there have been only a few lncRNA genetically studied using knockout (KO) animals 22,23 .…”

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confidence: 99%

Long noncoding RNA SAM promotes myoblast proliferation through stabilizing Sugt1 and facilitating kinetochore assembly

Yuan

Chen

et al. 2020

Nat Commun

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The functional study of lncRNAs in skeletal muscle satellite cells (SCs) remains at the infancy stage. Here we identify SAM (Sugt1 asssociated muscle) lncRNA that is enriched in the proliferating myoblasts. Global deletion of SAM has no overt effect on mice but impairs adult muscle regeneration following acute damage; it also exacerbates the chronic injury-induced dystrophic phenotype in mdx mice. Consistently, inducible deletion of SAM in SCs leads to deficiency in muscle regeneration. Further examination reveals that SAM loss results in a cellautonomous defect in the proliferative expansion of myoblasts. Mechanistically, we find SAM interacts and stabilizes Sugt1, a co-chaperon protein key to kinetochore assembly during cell division. Loss of SAM or Sugt1 both disrupts kinetochore assembly in mitotic cells due to the mislocalization of two components: Dsn1 and Hec1. Altogether, our findings identify SAM as a regulator of SC proliferation through facilitating Sugt1 mediated kinetochore assembly during cell division.

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Investigating long noncoding RNAs using animal models

Cited by 30 publications

References 131 publications

The role of long noncoding RNAs in hepatocellular carcinoma

The role of long noncoding RNAs in hepatocellular carcinoma

The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis

Long noncoding RNA SAM promotes myoblast proliferation through stabilizing Sugt1 and facilitating kinetochore assembly

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