The 5′ region of <i>Xist</i> RNA has the potential to associate with chromatin through the A-repeat

Chigi, Yuta; Sasaki, Hidetada; Sado, Takashi

doi:10.1261/rna.062158.117

Cited by 8 publications

(7 citation statements)

References 36 publications

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“…Using Tiling CRISPR, we successfully identified the known Xist silencing domain, A-repeats. A-repeats reportedly mediate silencing through multiple mechanisms: interacting with silencing factors 2,35 , recruiting genes into a Xist-mediated silencing compartment 36 , regulating Xist spreading 37,38 , or regulating Xist splicing 39 . However, our findings suggest a novel function whereby A-repeats positively regulate Xist transcription.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Xist silencing domain by Tiling CRISPR

Wang

Yang

Zhou

et al. 2019

Sci Rep

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Despite essential roles played by long noncoding RNAs (lncRNAs) in development and disease, methods to determine lncRNA cis-elements are lacking. Here, we developed a screening method named “Tiling CRISPR” to identify lncRNA functional domains. Using this approach, we identified Xist A-Repeats as the silencing domain, an observation in agreement with published work, suggesting Tiling CRISPR feasibility. Mechanistic analysis suggested a novel function for Xist A-repeats in promoting Xist transcription. Overall, our method allows mapping of lncRNA functional domains in an unbiased and potentially high-throughput manner to facilitate the understanding of lncRNA functions.

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Section: Discussionmentioning

confidence: 99%

Identification of a Xist silencing domain by Tiling CRISPR

Wang

Yang

Zhou

et al. 2019

Sci Rep

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“…The mechanisms by which Repeat-A promotes Xist stability are unclear. Lastly, in transgenic Xist cDNA overexpression experiments, Repeat-A appears to be involved in targeting Xist to actively transcribed regions (27,28). How Repeat-A is involved in this targeting is unclear.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: A 5′ fragment of Xist can sequester RNA produced from adjacent genes on chromatin

Lee

Trotman

Cherney

et al. 2019

Nucleic Acids Research

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Xist requires Repeat-A, a protein-binding module in its first two kilobases (2kb), to repress transcription. We report that when expressed as a standalone transcript in mouse embryonic stem cells (ESCs), the first 2kb of Xist (Xist-2kb) does not induce transcriptional silencing. Instead, Xist-2kb sequesters RNA produced from adjacent genes on chromatin. Sequestration does not spread beyond adjacent genes, requires the same sequence elements in Repeat-A that full-length Xist requires to repress transcription and can be induced by lncRNAs with similar sequence composition to Xist-2kb. We did not detect sequestration by full-length Xist, but we did detect it by mutant forms of Xist with attenuated transcriptional silencing capability. Xist-2kb associated with SPEN, a Repeat-A binding protein required for Xist-induced transcriptional silencing, but SPEN was not necessary for sequestration. Thus, when expressed in mouse ESCs, a 5′ fragment of Xist that contains Repeat-A sequesters RNA from adjacent genes on chromatin and associates with the silencing factor SPEN, but it does not induce transcriptional silencing. Instead, Xist-induced transcriptional silencing requires synergy between Repeat-A and additional sequence elements in Xist. We propose that sequestration is mechanistically related to the Repeat-A dependent stabilization and tethering of Xist near actively transcribed regions of chromatin.

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“…The regulation of Tsix expression is beyond the scope of this review, and more specific details can be found in references ( Willard, 1996 ; Gontan et al, 2012 ; Gayen et al, 2015 ). Once Xist expression has been activated, Xist binds Polycomb repressive complex 2 (PRC2) via Repeat A formed Xist-PRC2 complex, and YY1 tethers the PRC2-Xist complex through Repeat C to the Xi nucleation center which obtains lncRNA Xist-PRC2 complex by the RNA polymerase II (RNA Pol II) ( Jeon and Lee, 2011 ; Thorvaldsen et al, 2011 ; Makhlouf et al, 2014 ; Chigi et al, 2017 ).…”

Section: The Role Of Lncrna Xist In X Chromosome Dosage Compensationmentioning

confidence: 99%

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

Wang

Min

Guo

et al. 2021

Front. Cell Dev. Biol.

124

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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.

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The 5′ region of Xist RNA has the potential to associate with chromatin through the A-repeat

Cited by 8 publications

References 36 publications

Identification of a Xist silencing domain by Tiling CRISPR

Identification of a Xist silencing domain by Tiling CRISPR

RETRACTED: A 5′ fragment of Xist can sequester RNA produced from adjacent genes on chromatin

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

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