<i>Xist</i> Intron 1 Repression by Transcriptional-Activator-Like Effectors Designer Transcriptional Factor Improves Somatic Cell Reprogramming in Mice

Zhai

et al. 2020

Front. Cell Dev. Biol.

N6-methyladenosine (m 6 A) is one of the most abundant internal mRNA modifications, and it affects multiple biological processes related to eukaryotic mRNA. The majority of m 6 A sites are located in stop codons and 3 UTR regions of mRNAs. m 6 A regulates RNA metabolism, including alternative splicing (AS), alternative polyadenylation (APA), mRNA export, decay, stabilization, and translation. The m 6 A metabolic pathway is regulated by a series of m 6 A writers, erasers and readers. Recent studies indicate that m 6 A is essential for the regulation of gene expression, tumor formation, stem cell fate, gametogenesis, and animal development. In this systematic review, we summarized the recent advances in newly identified m 6 A effectors and the effects of m 6 A on RNA metabolism. Subsequently, we reviewed the functional roles of RNA m 6 A modification in diverse cellular bioprocesses, such as stem cell fate decisions, cell reprogramming and early embryonic development, and we discussed the potential of m 6 A modification to be applied to regenerative medicine, disease treatment, organ transplantation, and animal reproduction.

Section: Role Of M 6 a In Cell Reprogrammingmentioning

confidence: 99%

Roles of N6-Methyladenosine (m6A) in Stem Cell Fate Decisions and Early Embryonic Development in Mammals

Zhai

et al. 2020

Front. Cell Dev. Biol.

“…However, the RNAi-based method is disadvantageous because it can only enhance the developmental competence of male but not female mouse SCNT embryos [28], whereas the knockout of maternal Xist allele can improve the developmental efficiency of both male and female mouse SCNT embryos [11]. Interestingly, a recent study reported that a new method via the epigenetic modification of the Xist gene can increase the developmental ability of mouse embryos [31].…”

Section: Discussionmentioning

confidence: 99%

Improvement of developmental competence of cloned male pig embryos by short hairpin ribonucleic acid (shRNA) vector-based but not small interfering RNA (siRNA)-mediated RNA interference (RNAi) of <i>Xist</i> expression

Yang

et al. 2019

J. Reprod. Dev.

Xist is an X-linked ribonucleic acid (RNA) gene responsible for the cis induction of X chromosome inactivation (XCI). In cloned mammalian embryos, Xist is ectopically activated at the morula to blastocyst stage on the X chromosome that is supposed to be active, thus resulting in abnormal XCI. Suppression of erroneous Xist expression by injecting small interfering RNA (siRNA) remarkably increased the developmental efficiency of cloned male mouse embryos by approximately 10-fold. However, injection of anti-Xist siRNA resulted in only a slight increase in the developmental ability of injected cloned male pig embryos because the blocking effect of the injected siRNA was not maintained beyond the morula stage, which is 5 days post-activation. To develop a more effective approach for suppressing the ectopic expression of Xist in cloned pig embryos, we compared the silencing effect of short hairpin RNA (shRNA) and siRNA on Xist expression and the effects of these two Xist knockdown methods on the developmental competence of cloned male pig embryos. Results indicated that an shRNA-based RNA interference (RNAi) has a longer blocking effect on Xist expression than an siRNA-mediated RNAi. Injection of anti-Xist shRNA plasmid into two-cell-stage cloned male pig embryos effectively suppressed Xist expression, rescued XCI at the blastocyst stage, and improved the in vitro developmental ability of injected cloned embryos. These positive effects, however, were not observed in cloned male pig embryos injected with anti-Xist siRNA. This study demonstrates that vector-based rather than siRNA-mediated RNAi of Xist expression can be employed to improve pig cloning efficiency.

“…This study suggested that lncRNA Xist may play a role in a new approach for improving the quality of porcine parthenogenetic embryos. lncRNA Xist ( Zhang et al, 2019b ) facilitates cells development in somatic cells by TALE-based designer transcriptional factor, and regulates embryonic stem cells’ fates ( Chelmicki et al, 2014 ; An et al, 2020 ). lncRNA Xist promotes hair follicle regeneration in Dermal papilla cells via regulating miR-424/Shh axis to activate hedgehog signaling ( Lin B.J.…”

Section: The Role Of Lncrna Xist In Non-cancer Diseasesmentioning

confidence: 99%

Biological Function of Long Non-coding RNA (LncRNA) Xist

Wang

Min

Guo

et al. 2021

Front. Cell Dev. Biol.

124

Long non-coding RNAs (lncRNAs) regulate gene expression in a variety of ways at epigenetic, chromatin remodeling, transcriptional, and translational levels. Accumulating evidence suggests that lncRNA X-inactive specific transcript (lncRNA Xist) serves as an important regulator of cell growth and development. Despites its original roles in X-chromosome dosage compensation, lncRNA Xist also participates in the development of tumor and other human diseases by functioning as a competing endogenous RNA (ceRNA). In this review, we comprehensively summarized recent progress in understanding the cellular functions of lncRNA Xist in mammalian cells and discussed current knowledge regarding the ceRNA network of lncRNA Xist in various diseases. Long non-coding RNAs (lncRNAs) are transcripts that are more than 200 nt in length and without an apparent protein-coding capacity (Furlan and Rougeulle, 2016; Maduro et al., 2016). These RNAs are believed to be transcribed by the approximately 98–99% non-coding regions of the human genome (Derrien et al., 2012; Fu, 2014; Montalbano et al., 2017; Slack and Chinnaiyan, 2019), as well as a large variety of genomic regions, such as exonic, tronic, and intergenic regions. Hence, lncRNAs are also divided into eight categories: Intergenic lncRNAs, Intronic lncRNAs, Enhancer lncRNAs, Promoter lncRNAs, Natural antisense/sense lncRNAs, Small nucleolar RNA-ended lncRNAs (sno-lncRNAs), Bidirectional lncRNAs, and non-poly(A) lncRNAs (Ma et al., 2013; Devaux et al., 2015; St Laurent et al., 2015; Chen, 2016; Quinn and Chang, 2016; Richard and Eichhorn, 2018; Connerty et al., 2020). A range of evidence has suggested that lncRNAs function as key regulators in crucial cellular functions, including proliferation, differentiation, apoptosis, migration, and invasion, by regulating the expression level of target genes via epigenomic, transcriptional, or post-transcriptional approaches (Cao et al., 2018). Moreover, lncRNAs detected in body fluids were also believed to serve as potential biomarkers for the diagnosis, prognosis, and monitoring of disease progression, and act as novel and potential drug targets for therapeutic exploitation in human disease (Jiang W. et al., 2018; Zhou et al., 2019a). Long non-coding RNA X-inactive specific transcript (lncRNA Xist) are a set of 15,000–20,000 nt sequences localized in the X chromosome inactivation center (XIC) of chromosome Xq13.2 (Brown et al., 1992; Debrand et al., 1998; Kay, 1998; Lee et al., 2013; da Rocha and Heard, 2017; Yang Z. et al., 2018; Brockdorff, 2019). Previous studies have indicated that lncRNA Xist regulate X chromosome inactivation (XCI), resulting in the inheritable silencing of one of the X-chromosomes during female cell development. Also, it serves a vital regulatory function in the whole spectrum of human disease (notably cancer) and can be used as a novel diagnostic and prognostic biomarker and as a potential therapeutic target for human disease in the clinic (Liu et al., 2018b; Deng et al., 2019; Dinescu et al., 2019; Mutzel and Schulz, 2020; Patrat et al., 2020; Wang et al., 2020a). In particular, lncRNA Xist have been demonstrated to be involved in the development of multiple types of tumors including brain tumor, Leukemia, lung cancer, breast cancer, and liver cancer, with the prominent examples outlined in Table 1. It was also believed that lncRNA Xist (Chaligne and Heard, 2014; Yang Z. et al., 2018) contributed to other diseases, such as pulmonary fibrosis, inflammation, neuropathic pain, cardiomyocyte hypertrophy, and osteoarthritis chondrocytes, and more specific details can be found in Table 2. This review summarizes the current knowledge on the regulatory mechanisms of lncRNA Xist on both chromosome dosage compensation and pathogenesis (especially cancer) processes, with a focus on the regulatory network of lncRNA Xist in human disease.