Long-range function of secreted small nucleolar RNAs that direct 2′-O-methylation

Rimer, Jamie M.; Lee, Jiyeon; Holley, Christopher L.; Crowder, Robert J.; Chen, Delphine L.; Hanson, Phyllis I.; Ory, Daniel S.; Schaffer, Jean E.

doi:10.1074/jbc.ra118.003410

Cited by 54 publications

(51 citation statements)

References 48 publications

(60 reference statements)

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“…Efforts to characterize tissue-specific noncoding transcripts have recently resumed with the advent of RNA sequencing (RNA-seq), which greatly advanced the discovery of novel and previously undetected miRNA (24,25). However, no prior study encompasses a spectrum of mammalian tissues from both female and male individuals, nor includes the other noncoding RNA types that have recently been identified to carry out tissue-and cell type-specific functions (26,27).…”

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confidence: 99%

A mouse tissue atlas of small noncoding RNA

Isakova

Fehlmann

Keller

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Small noncoding RNAs (ncRNAs) play a vital role in a broad range of biological processes both in health and disease. A comprehensive quantitative reference of small ncRNA expression would significantly advance our understanding of ncRNA roles in shaping tissue functions. Here, we systematically profiled the levels of five ncRNA classes (microRNA [miRNA], small nucleolar RNA [snoRNA], small nuclear RNA [snRNA], small Cajal body-specific RNA [scaRNA], and transfer RNA [tRNA] fragments) across 11 mouse tissues by deep sequencing. Using 14 biological replicates spanning both sexes, we identified that ∼30% of small ncRNAs are distributed across the body in a tissue-specific manner with some also being sexually dimorphic. We found that some miRNAs are subject to “arm switching” between healthy tissues and that tRNA fragments are retained within tissues in both a gene- and a tissue-specific manner. Out of 11 profiled tissues, we confirmed that brain contains the largest number of unique small ncRNA transcripts, some of which were previously annotated while others are identified in this study. Furthermore, by combining these findings with single-cell chromatin accessibility (scATAC-seq) data, we were able to connect identified brain-specific ncRNAs with their cell types of origin. These results yield the most comprehensive characterization of specific and ubiquitous small RNAs in individual murine tissues to date, and we expect that these data will be a resource for the further identification of ncRNAs involved in tissue function in health and dysfunction in disease.

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confidence: 99%

A mouse tissue atlas of small noncoding RNA

Isakova

Fehlmann

Keller

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…[1,10] These are the representative pathologies of HD, thus extending the survival of HD mice. The positive effect ofheterochronic parabiosis originates from the shared blood circulation, [25,26] just like the other neurodegenerative diseases ameliorated by heterochronic parabiosis. [9,27,28]It is worth noting that the R6/2 mice die typically at around 3-4 months of ageaccompanied by trimming and muscle loss [10,11] and highly vulnerable to stress.…”

Section: Discussionmentioning

confidence: 99%

Identifying Exosomes as a Messenger Unit During Heterochronic Parabiosis for Amelioration of Huntington’s Disease

Lee

Kim

2020

Preprint

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Abstract Background:Huntington’s disease (HD) starts its pathology long before clinical manifestation, however, there is no therapy to cure it completely and only a few studies have been reported for delaying the progression of HD. We demonstrated the blood sharing effect by heterochronic parabiosis in HD and explored the underlying mechanism for transferring positive factors in the young blood serum.A shared blood circulation by heterochronic parabiosis has improved behavioral performance and HD pathology through mediation of mitochondria dysfunction and cell death. Furthermore, the messenger unit for the effective components in young blood is identified for the first time to the best of our knowledge.Methods:R6/2 mice were surgically connected with young wild-type mice (n=13), old wild-type mice (n=8), or R6/2 mice (n=6) to examine the effect of heterochronic parabiosis.Parabionts composed of 5- to 6-week-old transgenic and wild-type mice were observed for 6 weeks in a single cage. The in vitro cellular model of HD cells were treated by the 200 μg/mlblood serum of the young or old mice, and by the exosomes isolated from thereof. Thein vitro cellular model of HD were developed by differentiating neural stem cells cultured from SVZ of the brain.Results:After the heterochronic parabiosis, the weight loss and survival of HD mice was improved, and also, mutant Huntingtin aggregation (EM48 p<0.005), improvement of mitochondria dysfunction (PGC-1a p<0.05, p-CREB/CREB p<0.005), cell death (p53 p<0.05, Bax p<0.05, Cleaved-caspase3 p<0.05),and cognition (DCX p<0.5) showed a near complete restoration. In addition, treatment of exosomes from young blood serum to thein vitro cellular model of HD improved mutant Huntingtin aggregation (EM48 p<0.05), mitochondria biogenesis (p-CREB/CREB p<0.005), cell death (p53 p<0.05, Bax p<0.005, Cleaved-caspase3 p<0.05, Bcl-2 p<0.05), and cell proliferation (WST-1 p<0.005).Conclusions:We found that the overall pathology of HD is improved by the shared blood circulation through heterochronic parabiosis, furthermore, we demonstrated that the exosomes are messengers for transferring positive factors,showing the potential of exosomes from young bloodfor the amelioration of HD.

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“…We also showed that electroporation can introduce mRNAs into EVs for a later functional translation in the recipient cells [ 49 ]. Non-coding RNA found in EVs include small non-coding RNA, such as small nucleolar RNAs [ 129 ], microRNAs [ 130 ], and piwi-interacting RNAs [ 131 ], and other long non-coding RNAs [ 132 ]. The most studied among them are microRNAs, given the well-known regulatory role of microRNAs and their abundance in EVs [ 133 ].…”

Section: Biochemical Properties Of Evs and Their Intrinsic Advantamentioning

confidence: 99%

Extracellular Vesicles as an Efficient and Versatile System for Drug Delivery

Dang

Kavishka

Zhang

et al. 2020

Cells

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Despite the recent advances in drug development, the majority of novel therapeutics have not been successfully translated into clinical applications. One of the major factors hindering their clinical translation is the lack of a safe, non-immunogenic delivery system with high target specificity upon systemic administration. In this respect, extracellular vesicles (EVs), as natural carriers of bioactive cargo, have emerged as a promising solution and can be further modified to improve their therapeutic efficacy. In this review, we provide an overview of the biogenesis pathways, biochemical features, and isolation methods of EVs with an emphasis on their many intrinsic properties that make them desirable as drug carriers. We then describe in detail the current advances in EV therapeutics, focusing on how EVs can be engineered to achieve improved target specificity, better circulation kinetics, and efficient encapsulation of therapeutic payloads. We also identify the challenges and obstacles ahead for clinical translation and provide an outlook on the future perspective of EV-based therapeutics.

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Long-range function of secreted small nucleolar RNAs that direct 2′-O-methylation

Cited by 54 publications

References 48 publications

A mouse tissue atlas of small noncoding RNA

A mouse tissue atlas of small noncoding RNA

Identifying Exosomes as a Messenger Unit During Heterochronic Parabiosis for Amelioration of Huntington’s Disease

Extracellular Vesicles as an Efficient and Versatile System for Drug Delivery

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