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Andrology Jul 2023The germline perpetuates genetic information across generations. To maintain the integrity of the germline, transposable elements in the genome must be silenced, as... (Review)
Review
BACKGROUND
The germline perpetuates genetic information across generations. To maintain the integrity of the germline, transposable elements in the genome must be silenced, as these mobile elements would otherwise engender widespread mutations passed on to subsequent generations. There are several well-established mechanisms that are dedicated to providing defense against transposable elements, including DNA methylation, RNA interference, and the PIWI-interacting RNA pathway.
OBJECTIVES
Recently, several studies have provided evidence that transposon defense is not only provided by factors dedicated to this purpose but also factors with other roles, including in germline development. Many of these are transcription factors. Our objective is to summarize what is known about these "bi-functional" transcriptional regulators.
MATERIALS AND METHODS
Literature search.
RESULTS AND CONCLUSION
We summarize the evidence that six transcriptional regulators-GLIS3, MYBL1, RB1, RHOX10, SETDB1, and ZBTB16-are both developmental regulators and transposable element-defense factors. These factors act at different stages of germ cell development, including in pro-spermatogonia, spermatogonial stem cells, and spermatocytes. Collectively, the data suggest a model in which specific key transcriptional regulators have acquired multiple functions over evolutionary time to influence developmental decisions and safeguard transgenerational genetic information. It remains to be determined whether their developmental roles were primordial and their transposon defense roles were co-opted, or vice versa.
Topics: Male; Humans; DNA Transposable Elements; Gene Expression Regulation, Developmental; Spermatogonia; Transcription Factors; Spermatocytes; RNA, Small Interfering; Germ Cells
PubMed: 36895139
DOI: 10.1111/andr.13427 -
Experimental & Molecular Medicine Jul 2023RNA interference mediated by small interfering RNAs (siRNAs) has been exploited for the development of therapeutics. siRNAs can be a powerful therapeutic tool because... (Review)
Review
RNA interference mediated by small interfering RNAs (siRNAs) has been exploited for the development of therapeutics. siRNAs can be a powerful therapeutic tool because the working mechanisms of siRNAs are straightforward. siRNAs determine targets based on their sequence and specifically regulate the gene expression of the target gene. However, efficient delivery of siRNAs to the target organ has long been an issue that needs to be solved. Tremendous efforts regarding siRNA delivery have led to significant progress in siRNA drug development, and from 2018 to 2022, a total of five siRNA drugs were approved for the treatment of patients. Although all FDA-approved siRNA drugs target the hepatocytes of the liver, siRNA-based drugs targeting different organs are in clinical trials. In this review, we introduce siRNA drugs in the market and siRNA drug candidates in clinical trials that target cells in multiple organs. The liver, eye, and skin are the preferred organs targeted by siRNAs. Three or more siRNA drug candidates are in phase 2 or 3 clinical trials to suppress gene expression in these preferred organs. On the other hand, the lungs, kidneys, and brain are challenging organs with relatively few clinical trials. We discuss the characteristics of each organ related to the advantages and disadvantages of siRNA drug targeting and strategies to overcome the barriers in delivering siRNAs based on organ-specific siRNA drugs that have progressed to clinical trials.
Topics: Humans; RNA, Small Interfering; Pharmaceutical Preparations; RNA Interference; Lung; Liver
PubMed: 37430086
DOI: 10.1038/s12276-023-00998-y -
Science Advances Oct 2023In worms, epigenetic information transmits transgenerationally. Still, it is unknown whether the effects transfer to the next generation inside or outside of the...
In worms, epigenetic information transmits transgenerationally. Still, it is unknown whether the effects transfer to the next generation inside or outside of the nucleus. Here, we use the tractability of gene-specific double-stranded RNA-induced silencing to demonstrate that RNA interference can be inherited independently of any nuclear factors via mothers that are genetically engineered to transmit only their ooplasm but not the oocytes' nuclei to the next generation. We characterize the mechanisms and, using RNA sequencing, chimeric worms, and sequence polymorphism between different isolates, identify endogenous small RNAs which, similarly to exogenous siRNAs, are inherited in a nucleus-independent manner. From a historical perspective, these results might be regarded as partial vindication of discredited cytoplasmic inheritance theories from the 19th century, such as Darwin's "pangenesis" theory.
Topics: Animals; Caenorhabditis elegans; RNA, Small Interfering; RNA Interference; Caenorhabditis elegans Proteins; Gene Silencing; RNA, Double-Stranded
PubMed: 37878696
DOI: 10.1126/sciadv.adj8618 -
The New Phytologist Oct 2023RNA interference (RNAi) is arguably one of the more versatile mechanisms in cell biology, facilitating the fine regulation of gene expression and protection against... (Review)
Review
RNA interference (RNAi) is arguably one of the more versatile mechanisms in cell biology, facilitating the fine regulation of gene expression and protection against mobile genomic elements, whilst also constituting a key aspect of induced plant immunity. More recently, the use of this mechanism to regulate gene expression in heterospecific partners - cross-kingdom RNAi (ckRNAi) - has been shown to form a critical part of bidirectional interactions between hosts and endosymbionts, regulating the interplay between microbial infection mechanisms and host immunity. Here, we review the current understanding of ckRNAi as it relates to interactions between plants and their pathogenic and mutualistic endosymbionts, with particular emphasis on evidence in support of ckRNAi in the arbuscular mycorrhizal symbiosis.
Topics: Symbiosis; Mycorrhizae; RNA Interference; Plants
PubMed: 37452489
DOI: 10.1111/nph.19122 -
International Journal of Molecular... Dec 2023Small interfering RNA (siRNA) represents a novel, fascinating therapeutic strategy that allows for selective reduction in the production of a specific protein through... (Review)
Review
Small interfering RNA (siRNA) represents a novel, fascinating therapeutic strategy that allows for selective reduction in the production of a specific protein through RNA interference. In the cardiovascular (CV) field, several siRNAs have been developed in the last decade. Inclisiran has been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) circulating levels with a reassuring safety profile, also in older patients, by hampering proprotein convertase subtilisin/kexin type 9 (PCSK9) production. Olpasiran, directed against apolipoprotein(a) mRNA, prevents the assembly of lipoprotein(a) [Lp(a)] particles, a lipoprotein linked to an increased risk of ischemic CV disease and heart valve damage. Patisiran, binding transthyretin (TTR) mRNA, has demonstrated an ability to improve heart failure and polyneuropathy in patients with TTR amyloidosis, even in older patients with wild-type form. Zilebesiran, designed to reduce angiotensinogen secretion, significantly decreases systolic and diastolic blood pressure (BP). Thanks to their effectiveness, safety, and tolerability profile, and with a very low number of administrations in a year, thus overcoming adherence issues, these novel drugs are the leaders of a new era in molecular therapies for CV diseases.
Topics: Humans; Aged; Cardiovascular Diseases; Proprotein Convertase 9; Heart Failure; Hypertension; RNA, Small Interfering; Atherosclerosis; RNA, Messenger
PubMed: 38203499
DOI: 10.3390/ijms25010328 -
Frontiers in Cardiovascular Medicine 2023RNA-based therapies are currently used for immunisation against infections and to treat metabolic diseases. They can modulate gene expression in immune cells and... (Review)
Review
RNA-based therapies are currently used for immunisation against infections and to treat metabolic diseases. They can modulate gene expression in immune cells and hepatocytes, but their use in other cell types has been limited by an inability to selectively target specific tissues. Potential solutions to this targeting problem involve packaging therapeutic RNA molecules into delivery vehicles that are preferentially delivered to cells of interest. In this review, we consider why the kidney is a desirable target for RNA-based therapies in cardiovascular disease and discuss how such therapy could be delivered. Because the kidney plays a central role in maintaining cardiovascular homeostasis, many extant drugs used for preventing cardiovascular disease act predominantly on renal tubular cells. Moreover, kidney disease is a major independent risk factor for cardiovascular disease and a global health problem. Chronic kidney disease is projected to become the fifth leading cause of death by 2040, with around half of affected individuals dying from cardiovascular disease. The most promising strategies for delivering therapeutic RNA selectively to kidney cells make use of synthetic polymers and engineered extracellular vesicles to deliver an RNA cargo. Future research should focus on establishing the safety of these novel delivery platforms in humans, on developing palatable routes of administration and on prioritising the gene targets that are likely to have the biggest impact in cardiovascular disease.
PubMed: 37868774
DOI: 10.3389/fcvm.2023.1250073 -
Advanced Science (Weinheim,... Nov 2023Skin is the first barrier against external threats, and skin immune dysfunction leads to multiple diseases. Psoriasis is an inflammatory, chronic, common, immune-related...
Skin is the first barrier against external threats, and skin immune dysfunction leads to multiple diseases. Psoriasis is an inflammatory, chronic, common, immune-related skin disease that affects more than 125 million people worldwide. RNA interference (RNAi) therapy is superior to traditional therapies, but rapid degradation and poor cell uptake are the greatest obstacles to its clinical transformation. The transdermal delivery of siRNA and controllable assembly/disassembly of nanodrug delivery systems can maximize the therapeutic effect. Tetrahedral framework nucleic acid (tFNA) is undoubtedly the best carrier for the transdermal transport of genes due to its excellent noninvasive transdermal effect and editability. The authors combine acid-responsive tannic acid (TA), RNase H-responsive sequences, siRNA, and tFNA into a novel transdermal RNAi drug with controllable assembly and disassembly: STT. STT has heightened resistance to enzyme, serum, and lysosomal degradation, and its size is similar to that of tFNA, enabling easy transdermal transport. After transdermal administration, STT can specifically silence nuclear factor kappa-B (NF-κB) p65, thereby maintaining the stability of the skin's microenvironment and reshaping normal skin immune defense. This work demonstrates the advantages of STT in RNAi therapy and the potential for future treatment of skin-related diseases.
Topics: Humans; RNA Interference; Nucleic Acids; Polyphenols; RNA, Small Interfering; Psoriasis; Skin Diseases; Immunotherapy
PubMed: 37797168
DOI: 10.1002/advs.202303706 -
PLoS Biology Aug 2023The human genome encodes approximately 20,000 proteins, many still uncharacterised. It has become clear that scientific research tends to focus on well-studied proteins,...
The human genome encodes approximately 20,000 proteins, many still uncharacterised. It has become clear that scientific research tends to focus on well-studied proteins, leading to a concern that poorly understood genes are unjustifiably neglected. To address this, we have developed a publicly available and customisable "Unknome database" that ranks proteins based on how little is known about them. We applied RNA interference (RNAi) in Drosophila to 260 unknown genes that are conserved between flies and humans. Knockdown of some genes resulted in loss of viability, and functional screening of the rest revealed hits for fertility, development, locomotion, protein quality control, and resilience to stress. CRISPR/Cas9 gene disruption validated a component of Notch signalling and 2 genes contributing to male fertility. Our work illustrates the importance of poorly understood genes, provides a resource to accelerate future research, and highlights a need to support database curation to ensure that misannotation does not erode our awareness of our own ignorance.
Topics: Animals; Male; Humans; Drosophila; RNA Interference; Fertility
PubMed: 37552676
DOI: 10.1371/journal.pbio.3002222 -
Journal of Nanobiotechnology Jul 2023Although RNA interference (RNAi) therapy has emerged as a potential tool in cancer therapeutics, the application of RNAi to glioblastoma (GBM) remains a hurdle. Herein,...
Although RNA interference (RNAi) therapy has emerged as a potential tool in cancer therapeutics, the application of RNAi to glioblastoma (GBM) remains a hurdle. Herein, to improve the therapeutic effect of RNAi on GBM, a cancer cell membrane (CCM)-disguised hypoxia-triggered RNAi nanomedicine was developed for short interfering RNA (siRNA) delivery to sensitize cells to chemotherapy and radiotherapy. Our synthesized CCM-disguised RNAi nanomedicine showed prolonged blood circulation, high BBB transcytosis and specific accumulation in GBM sites via homotypic recognition. Disruption and effective anti-GBM agents were triggered in the hypoxic region, leading to efficient tumor suppression by using phosphoglycerate kinase 1 (PGK1) silencing to enhance paclitaxel-induced chemotherapy and sensitize hypoxic GBM cells to ionizing radiation. In summary, a biomimetic intelligent RNAi nanomedicine has been developed for siRNA delivery to synergistically mediate a combined chemo/radiotherapy that presents immune-free and hypoxia-triggered properties with high survival rates for orthotopic GBM treatment.
Topics: Humans; Glioblastoma; RNA Interference; Brain Neoplasms; Nanomedicine; Biomimetics; RNA, Small Interfering; Hypoxia; Cell Line, Tumor
PubMed: 37408007
DOI: 10.1186/s12951-023-01960-w -
Nature Communications Aug 2023Small interference RNAs are the key components of RNA interference, a conserved RNA silencing or viral defense mechanism in many eukaryotes. In Drosophila melanogaster,...
Small interference RNAs are the key components of RNA interference, a conserved RNA silencing or viral defense mechanism in many eukaryotes. In Drosophila melanogaster, Dicer-2 (DmDcr-2)-mediated RNAi pathway plays important roles in defending against viral infections and protecting genome integrity. During the maturation of siRNAs, two cofactors can regulate DmDcr-2's functions: Loqs-PD that is required for dsRNA processing, and R2D2 that is essential for the subsequent loading of siRNAs into effector Ago2 to form RISC complexes. However, due to the lack of structural information, it is still unclear whether R2D2 and Loqs-PD affect the functions of DmDcr-2 simultaneously. Here we present several cryo-EM structures of DmDcr-2/R2D2/Loqs-PD complex bound to dsRNAs with various lengths by the Helicase domain. These structures revealed that R2D2 and Loqs-PD can bind to different regions of DmDcr-2 without interfering with each other. Furthermore, the cryo-EM results demonstrate that these complexes can form large oligomers and assemble into fibers. The formation and depolymerization of these oligomers are associated with ATP hydrolysis. These findings provide insights into the structural mechanism of DmDcr-2 and its cofactors during siRNA processing.
Topics: Animals; DNA Helicases; Drosophila melanogaster; Drosophila Proteins; RNA Interference; RNA, Double-Stranded; RNA, Small Interfering; RNA-Binding Proteins
PubMed: 37633971
DOI: 10.1038/s41467-023-40919-1