Targeting Xist with compounds that disrupt RNA structure and X inactivation

Aguilar, Rodrigo; Spencer, Kerrie B; Kesner, Barry; Rizvi, Noreen F.; Badmalia, Maulik D.; Mrozowich, Tyler; Mortison, Jonathan D.; Rivera, Carlos; Smith, G. F.; Burchard, Julja; Dandliker, Peter J.; Patel, Trushar R.; Nickbarg, Elliott; Lee, Jeannie T.

doi:10.1038/s41586-022-04537-z

Cited by 85 publications

(62 citation statements)

References 28 publications

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“…Virus-vector-based technologies, which have been available for practical use in the last few years as COVID-19 vaccines [ 142 ], should be considered for lncRNA therapy in the future. In recent years, a small molecule-based inhibitor for Xist lncRNA has been developed [ 143 ]; therefore, the application of such a method may also be considered for other lncRNAs. The third issue is the complexity of the pathogenic factors of muscle atrophy [ 15 ], and lncRNAs, which function across the entire spectrum of muscle atrophy caused by cancer cachexia, disuse, fasting, and aging, have not yet been elucidated.…”

Section: Therapeutic Potential and Limitations Of Lncrnas For Skeleta...mentioning

confidence: 99%

The Functional Role of Long Non-Coding RNA in Myogenesis and Skeletal Muscle Atrophy

Hitachi

Honda

Tsuchida

2022

Cells

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Skeletal muscle is a pivotal organ in humans that maintains locomotion and homeostasis. Muscle atrophy caused by sarcopenia and cachexia, which results in reduced muscle mass and impaired skeletal muscle function, is a serious health condition that decreases life longevity in humans. Recent studies have revealed the molecular mechanisms by which long non-coding RNAs (lncRNAs) regulate skeletal muscle mass and function through transcriptional regulation, fiber-type switching, and skeletal muscle cell proliferation. In addition, lncRNAs function as natural inhibitors of microRNAs and induce muscle hypertrophy or atrophy. Intriguingly, muscle atrophy modifies the expression of thousands of lncRNAs. Therefore, although their exact functions have not yet been fully elucidated, various novel lncRNAs associated with muscle atrophy have been identified. Here, we comprehensively review recent knowledge on the regulatory roles of lncRNAs in skeletal muscle atrophy. In addition, we discuss the issues and possibilities of targeting lncRNAs as a treatment for skeletal muscle atrophy and muscle wasting disorders in humans.

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Section: Therapeutic Potential and Limitations Of Lncrnas For Skeleta...mentioning

confidence: 99%

The Functional Role of Long Non-Coding RNA in Myogenesis and Skeletal Muscle Atrophy

Hitachi

Honda

Tsuchida

2022

Cells

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“…Inactivation of XIST in nuclear donor cells or its attenuation in SCNT embryos improved blastocyst rates and cloning efficiency in mice and pigs ( Matoba et al, 2011 ; Zeng et al, 2016 ; Ruan et al, 2018 ; Yang et al, 2019 ). A recent study demonstrated that the small molecule X1 can target a specific motif of Xist and blocks initiation of XCI ( Aguilar et al, 2022 ). This may represent a new alternative for preventing early inaction of X chromosome in SCNT embryos, however, more studies are needed to evaluate efficiency and toxicity in pig embryos.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of Chromatin and Epigenetic Reprogramming in Porcine SCNT Embryos—Progresses and Perspectives

Glanzner

Macedo

Gutierrez

et al. 2022

Front. Cell Dev. Biol.

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Over the last 25 years, cloned animals have been produced by transferring somatic cell nuclei into enucleated oocytes (SCNT) in more than 20 mammalian species. Among domestic animals, pigs are likely the leading species in the number of clones produced by SCNT. The greater interest in pig cloning has two main reasons, its relevance for food production and as its use as a suitable model in biomedical applications. Recognized progress in animal cloning has been attained over time, but the overall efficiency of SCNT in pigs remains very low, based on the rate of healthy, live born piglets following embryo transfer. Accumulating evidence from studies in mice and other species indicate that new strategies for promoting chromatin and epigenetic reprogramming may represent the beginning of a new era for pig cloning.

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“…IPPase is an essential component not only for cells to synthesize RNA but also for in vitro transcription (IVT) reactions. IVTs are expensive reactions that can produce large amounts of RNA, which is needed for almost all in vitro RNA biological experiments, including RNA structure-function characterization studies and the development of RNA-based therapies (8). IPPase drastically improves the yield of RNA through two different mechanisms (9).…”

Section: Introductionmentioning

confidence: 99%

Purification and Characterization of Inorganic Pyrophosphatase for in vitro RNA Transcription

Tersteeg

Mrozowich

Henrickson

et al. 2022

Preprint

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Inorganic pyrophosphatase (iPPase) is an enzyme that cleaves pyrophosphate into two phosphate molecules. This enzyme is an essential component of in vitro transcription (IVT) reactions for RNA preparation as it prevents pyrophosphate from precipitating with magnesium, ultimately increasing the rate of the IVT reaction. Large-scale RNA production is often required for biochemical and biophysical characterization studies of RNA, therefore requiring large amounts of IVT reagents. Commercially purchased iPPase is often the most expensive component of any IVT reaction. In this paper, we demonstrate that iPPase can be produced in large quantities and of high quality using a reasonably generic laboratory facility and that laboratory-purified iPPase is as effective as commercially available iPPase. Furthermore, using size-exclusion chromatography coupled with multi-angle light scattering and dynamic light scattering (SEC-MALS-DLS), analytical ultracentrifugation (AUC), and small-angle X-ray scattering (SAXS), we demonstrate that yeast iPPase can form tetramers and hexamers in solution as well as the enzymatically active dimer. Our work provides a robust protocol for labs involved with RNA in vitro transcription to efficiently produce active iPPase, significantly reducing the financial strain of large-scale RNA production.

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Targeting Xist with compounds that disrupt RNA structure and X inactivation

Cited by 85 publications

References 28 publications

The Functional Role of Long Non-Coding RNA in Myogenesis and Skeletal Muscle Atrophy

The Functional Role of Long Non-Coding RNA in Myogenesis and Skeletal Muscle Atrophy

Enhancement of Chromatin and Epigenetic Reprogramming in Porcine SCNT Embryos—Progresses and Perspectives

Purification and Characterization of Inorganic Pyrophosphatase for in vitro RNA Transcription

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