Functional Conservation of LncRNA JPX Despite Sequence and Structural Divergence

Karner, Heather; Webb, Chiu-Ho; Carmona, Sarah; Liu, Yu; Lin, Bryan; Erhard, Micaela; Chan, Dalen; Baldi, Pierre; Spitale, Robert C.; Sun, Sha

doi:10.1016/j.jmb.2019.09.002

Cited by 38 publications

(31 citation statements)

References 90 publications

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“…Overexpression of human JPX RNA in trans was recently shown to complement heterozygous deletion of mouse Jpx during the establishment of XCI, suggesting that the human RNA might be functional in an ectopic context (Karner et al, 2019). Such rescue experiments using orthologous LRGs, as opposed to our strategy to tackle the role of mouse and human Jpx/JPX in the respective 5 species, reveal the effect of the environment on LRG mode of action but do not interrogate LRGs' function in their endogenous contexts.…”

Section: Xist P510mentioning

confidence: 96%

Mechanistic diversification of XIST regulatory network in mammals

Rosspopoff¹,

Huret²,

Collier³

et al. 2019

Preprint

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X chromosome inactivation (XCI) is a developmental regulatory process that initiates with remarkable diversity in various mammalian species. Here we addressed the contribution of XCI 15 regulators, most of which are lncRNA genes characterized in the mouse, to this mechanistic diversity.By combining analysis of single-cell RNA-seq data from early human embryogenesis with various functional assays in naïve and primed pluripotent stem cells and in differentiated cells, we demonstrate that JPX is a major regulator of XIST expression in human and in mouse. However, the underlying mechanisms differ radically between species and require Jpx RNA in the mouse and the 20 act of transcription of JPX locus in the human. Moreover, biogenesis of XIST is affected at different regulatory steps between these species. This study illustrates how diversification of LRGs modes of action during evolution provide opportunities for innovations within constrained gene regulatory networks. 25 KEYWORDSX chromosome inactivation, XIST, JPX, lncRNA, pluripotency, single-cell RNA-seq, human embryogenesis, evolution, gene regulatory networks 30 Graphical abstract Xist RNA Ftx Jpx lncRNA Post-transcriptional effect JPX transcription XIST transcription FTX RNAPII recruitment Ht1 Mouse Human RNAPII CTCF mature RNA

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Section: Xist P510mentioning

confidence: 96%

Mechanistic diversification of XIST regulatory network in mammals

Rosspopoff¹,

Huret²,

Collier³

et al. 2019

Preprint

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show abstract

“…First, as mentioned above, many lncRNAs have been found only in cell lines and their patterns of expression in vivo are not known. Second, due to low sequence conservation of mammalian lncRNAs [138], the homologs of human transcripts in animal models may be unknown due to deep divergence in sequence and structure [216] or may not even exist. Third, human lncRNAs found only in cell lines can still have properties making them attractive for in-depth analysis, for example involvement in drug resistance, leaving the cell lines as the only logical choice for these assays.…”

Section: Emerging Solutions To Address the Challenge Of Uncovering Trmentioning

confidence: 99%

Reverse-genetics studies of lncRNAs—what we have learnt and paths forward

et al. 2020

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Long non-coding RNAs (lncRNAs) represent a major fraction of the transcriptome in multicellular organisms. Although a handful of well-studied lncRNAs are broadly recognized as biologically meaningful, the fraction of such transcripts out of the entire collection of lncRNAs remains a subject of vigorous debate. Here we review the evidence for and against biological functionalities of lncRNAs and attempt to arrive at potential modes of lncRNA functionality that would reconcile the contradictory conclusions. Finally, we discuss different strategies of phenotypic analyses that could be used to investigate such modes of lncRNA functionality.

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“…Plasmid preparation and transfection were carried out as previously described [9]. Hela cells were cultured in minimum essential medium (MEM; Thermo fisher, USA), supplemented with 10% fetal bovine serum, and incubated under 5% CO 2 at 37 °C.…”

Section: Plasmid Construction and Transfectionmentioning

confidence: 99%

“…RNA extraction and quantitative real-time PCR (qRT-PCR) were carried out as previously described [9]. Total RNAs were extracted using Trizol reagent (Invitrogen, Carlsbad, CA).…”

Section: Rna Extraction and Quantitative Real-time Pcr (Qrt-pcr)mentioning

confidence: 99%

LncRNA JPX promotes cervical cancer progression by modulating miR-25-3p/SOX4 axis

2020

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Background The long noncoding RNA (lncRNA) JPX is a molecular switch for X-chromosome inactivation. Accumulating studies have shown that the aberrant expression and function of lncRNAs are involved in the occurrence and development of tumors. However, the functional importance and mechanism of the action of lncRNA JPX in cervical cancer (CC) remain unknown. Method In this study, qRT-PCR and western blotting were used to evaluate the mRNA or protein expression of JPX, miR-25-3p and SOX4 in CC tissues and cell lines. StarBase v2.0 database, luciferase reporter assay and RNA immunoprecipitation assay were used to explore the relationship between JPX and miR-25-3p. EdU assay, CCK-8 assay and transwell assay were utilized to evaluate the proliferation, migration and invasion of CC cells. The tumor xenograft assay in nude mice was performed to demonstrate the role of the JPX/miR-25-3p/SOX4 axis in CC. Results We found that JPX was markedly upregulated, whereas miR-25-3p was markedly downregulated in CC tissues and cell lines, and the expression of JPX was negatively correlated with miR-25-3p in CC tissues. Moreover, overexpression of JPX increased proliferation, migration and invasion of HeLa cells, whereas knockdown of JPX decreased proliferation, migration and invasion of HeLa cells. In contrast to JPX, overexpression of miR-25-3p decreased proliferation, migration and invasion of HeLa cells. In addition, knockdown of JPX was found to inhibit HeLa cell viability and tumor development via up-regulating the expression of miR-25-3p and inhibiting the expression of SOX4. Conclusions Our study demonstrates that JPX promotes cervical cancer progression through modulating the miR-25-3p/SOX4 axis, and may serve as a potential target for CC therapy.

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Functional Conservation of LncRNA JPX Despite Sequence and Structural Divergence

Cited by 38 publications

References 90 publications

Mechanistic diversification of XIST regulatory network in mammals

Mechanistic diversification of XIST regulatory network in mammals

Reverse-genetics studies of lncRNAs—what we have learnt and paths forward

LncRNA JPX promotes cervical cancer progression by modulating miR-25-3p/SOX4 axis

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