scholarly journals A novel cis regulatory element regulates human XIST in CTCF-dependent manner

2021 ◽  
Author(s):  
Rini Shah ◽  
Ankita Sharma ◽  
Ashwin Kelkar ◽  
Kundan Sengupta ◽  
Sanjeev Galande
Keyword(s):  
X Chromosome ◽  
Regulatory Element ◽  
Maintenance Phase ◽  
Transcriptional Regulators ◽  
X Chromosome Inactivation ◽  
Dependent Manner ◽  
Initiation Phase ◽  
Pluripotency Factors ◽  
Non Coding Rna ◽  
Long Non Coding Rna

The long non-coding RNA XIST is the master regulator for the process of X chromosome inactivation (XCI) in mammalian females. Here we report the existence of a hitherto uncharacterized cis regulatory element (cRE) within the first exon of human XIST , which determines the transcriptional status of XIST during the initiation and maintenance phases of XCI. In the initiation phase, pluripotency factors bind to this cRE and keep XIST repressed. In the maintenance phase of XCI, the cRE is enriched for CTCF which activates XIST transcription. By employing a CRISPR-dCas9-KRAB based interference strategy, we demonstrate that binding of CTCF to the newly identified cRE is critical for regulating XIST in a YY1-dependent manner. Collectively, our study uncovers the combinatorial effect of multiple transcriptional regulators influencing XIST expression during the initiation and maintenance phases of XCI.

scholarly journals A novel cis regulatory element regulates human XIST in CTCF-dependent manner

2019 ◽  
Author(s):  
Rini Shah ◽  
Ashwin Kelkar ◽  
Sanjeev Galande
Keyword(s):  
Transcription Factors ◽  
X Chromosome ◽  
Promoter Region ◽  
Regulatory Element ◽  
X Chromosome Inactivation ◽  
Dependent Manner ◽  
Pluripotency Factors ◽  
Factors Influencing ◽  
Non Coding Rna ◽  
Long Non Coding Rna

ABSTRACTThe long non-coding RNA XIST is the master regulator for the process of X chromosome inactivation in mammalian females. Here we report the existence of a hitherto uncharacterized cis regulatory element within the first exon of human XIST, which by associating with the promoter region through chromatin looping defines the transcriptional status of XIST. This interaction is brought about by CTCF, which in turn assists towards the maintenance of YY1 binding at the promoter and governs XIST transcription. Strikingly, the cis element is competitively bound by pluripotency factors and CTCF, wherein the enrichment of the former disrupts its interaction with the promoter, leading to downregulation of XIST. Collectively, our study uncovers the combinatorial effect of multiple epigenetic and transcription factors influencing XIST expression during the initiation and maintenance phases of inactivation.

scholarly journals Contiguous Erosion of the Inactive X in Human Pluripotency Concludes With Global DNA Hypomethylation

2020 ◽  
Author(s):  
Prakhar Bansal ◽  
Stefan F. Pinter
Keyword(s):  
X Chromosome ◽  
Pluripotent Stem Cells ◽  
Regulatory Element ◽  
Chromatin Accessibility ◽  
Integrated Analysis ◽  
Epigenetic Landscape ◽  
Dna Hypomethylation ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Long Non Coding Rna

SUMMARYFemale human pluripotent stem cells (hPSCs) are prone to undergoing X chromosome erosion (XCE), a progressive loss of key epigenetic features on the inactive X that initiates with repression of XIST, the long non-coding RNA required for X inactivation. As a result, previously silenced genes on the eroding X (Xe) reactivate, some of which are thought to provide selective advantages. To-date, the sporadic and progressive nature of XCE has largely obscured its scale, dynamics, and key transition events.To address this knowledge gap, we performed an integrated analysis of DNA methylation (DNAme), chromatin accessibility, and gene expression across hundreds of hPSC samples. Differential methylation across the Xe enables ordering female hPSCs across a trajectory of XCE from initiation to terminal stages. Our results identify a crucial cis-regulatory element for XIST expression, trace contiguously growing domains of reactivation to a few euchromatic origins on the Xi, and indicate that the late-stage Xe impairs DNAme genome-wide. Surprisingly, from this altered epigenetic landscape emerge select features of naïve pluripotency, suggesting its link to X chromosome dosage may be partially conserved in human embryonic development.

scholarly journals Differentiation-dependent requirement of Tsix long non-coding RNA in imprinted X-chromosome inactivation

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Emily Maclary ◽  
Emily Buttigieg ◽  
Michael Hinten ◽  
Srimonta Gayen ◽  
Clair Harris ◽  
...  
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Non Coding Rna ◽  
Long Non Coding Rna

scholarly journals Long non-coding RNA LINC00665 promotes gemcitabine resistance of Cholangiocarcinoma cells via regulating EMT and stemness properties through miR-424-5p/BCL9L axis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Min Lu ◽  
Xinglei Qin ◽  
Yajun Zhou ◽  
Gang Li ◽  
Zhaoyang Liu ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Transcriptional Regulators ◽  
First Line ◽  
Protein Coding ◽  
Gemcitabine Resistance ◽  
Non Coding Rna ◽  
Sphere Formation ◽  
Long Non Coding Rna ◽  
Line Chemotherapy

AbstractGemcitabine is the first-line chemotherapy drug for cholangiocarcinoma (CCA), but acquired resistance has been frequently observed in CCA patients. To search for potential long noncoding RNAs (lncRNAs) involved in gemcitabine resistance, two gemcitabine resistant CCA cell lines were established and dysregulated lncRNAs were identified by lncRNA microarray. Long intergenic non-protein coding RNA 665 (LINC00665) were found to rank the top 10 upregulated lncRNAs in our study, and high LINC00665 expression was closely associated with poor prognosis and chemoresistance of CCA patients. Silencing LINC00665 in gemcitabine resistant CCA cells impaired gemcitabine tolerance, while enforced LINC00665 expression increased gemcitabine resistance of sensitive CCA cells. The gemcitabine resistant CCA cells showed increased EMT and stemness properties, and silencing LINC00665 suppressed sphere formation, migration, invasion and expression of EMT and stemness markers. In addition, Wnt/β-Catenin signaling was activated in gemcitabine resistant CCA cells, but LINC00665 knockdown suppressed Wnt/β-Catenin activation. B-cell CLL/lymphoma 9-like (BCL9L), the nucleus transcriptional regulators of Wnt/β-Catenin signaling, plays a key role in the nucleus translocation of β-Catenin and promotes β-Catenin-dependent transcription. In our study, we found that LINC00665 regulated BCL9L expression by acting as a molecular sponge for miR-424-5p. Moreover, silencing BCL9L or miR-424-5p overexpression suppressed gemcitabine resistance, EMT, stemness and Wnt/β-Catenin activation in resistant CCA cells. In conclusion, our results disclosed the important role of LINC00665 in gemcitabine resistance of CCA cells, and provided a new biomarker or therapeutic target for CCA treament.

scholarly journals A role for YY1 in sex-biased transcription revealed through X-linked promoter activity and allelic binding analyses

2016 ◽  
Author(s):  
Chih-yu Chen ◽  
Wenqiang Shi ◽  
Allison M. Matthews ◽  
Yifeng Li ◽  
David J. Arenillas ◽  
...  
Keyword(s):  
X Chromosome ◽  
Specific Binding ◽  
Positive Association ◽  
Binding Motif ◽  
Transcription Start ◽  
Transcription Factor Binding Motif ◽  
Transcription Start Sites ◽  
Non Coding Rna ◽  
Allelic Gene ◽  
Long Non Coding Rna

AbstractSex differences in susceptibility and progression have been reported in numerous diseases. Female cells have two copies of the X chromosome with X-chromosome inactivation imparting mono-allelic gene silencing for dosage compensation. However, a subset of genes, named escapees, escape silencing and are transcribed bi-allelically resulting in sexual dimorphism. Here we conducted analyses of the sexes using human datasets to gain perspectives in such regulation. We identified transcription start sites of escapees (escTSSs) based on higher transcription levels in female cells using FANTOM5 CAGE data. Significant over-representations of YY1 transcription factor binding motif and ChIP-seq peaks around escTSSs highlighted its positive association with escapees. Furthermore, YY1 occupancy is significantly biased towards the inactive X (Xi) at long non-coding RNA loci that are frequent contacts of Xi-specific superloops. Our study elucidated the importance of YY1 on transcriptional activity on Xi in general through sequence-specific binding, and its involvement at superloop anchors.

scholarly journals Localized accumulation of Xist RNA in X chromosome inactivation

Open Biology ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 190213 ◽  
Author(s):  
Neil Brockdorff
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Non Coding Rna ◽  
Xist Rna ◽  
Analogous Manner ◽  
Mammalian Embryos ◽  
Non Coding Rnas ◽  
In Cis

The non-coding RNA Xist regulates the process of X chromosome inactivation, in which one of the two X chromosomes present in cells of early female mammalian embryos is selectively and coordinately shut down. Remarkably Xist RNA functions in cis , affecting only the chromosome from which it is transcribed. This feature is attributable to the unique propensity of Xist RNA to accumulate over the territory of the chromosome on which it is synthesized, contrasting with the majority of RNAs that are rapidly exported out of the cell nucleus. In this review I provide an overview of the progress that has been made towards understanding localized accumulation of Xist RNA, drawing attention to evidence that some other non-coding RNAs probably function in a highly analogous manner. I describe a simple model for localized accumulation of Xist RNA and discuss key unresolved questions that need to be addressed in future studies.

Role of Ca2+ entry in the modulation of airway tone by hypoxia

1993 ◽  
Vol 264 (3) ◽  
pp. L284-L289 ◽  
Author(s):  
L. B. Fernandes ◽  
K. Stuart-Smith ◽  
T. L. Croxton ◽  
C. A. Hirshman
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Soluble Guanylate Cyclase ◽  
Muscle Tone ◽  
Maintenance Phase ◽  
Dependent Manner ◽  
Cellular Mechanisms ◽  
Concentration Dependent Manner ◽  
Initiation Phase ◽  
Airway Tone

To evaluate the cellular mechanisms involved in hypoxic relaxation of airway smooth muscle, we investigated the effects of hypoxia on the behavior of third- and fourth-order porcine bronchial rings contracted with either carbachol or KCl. In one series of experiments, hypoxia (95% N2-5% CO2) was imposed and rings were then exposed to increasing concentrations of carbachol or KCl. In separate experiments, rings were first contracted with carbachol (10(-6) M) or KCl (40 mM) and were then exposed to solutions bubbled with decreasing concentrations of O2. The CO2 concentration was maintained constant at 5% in all experiments. The initial magnitude of KCl-induced but not carbachol-induced contractions was profoundly reduced by 95% N2-5% CO2. The sensitivity of the airway to carbachol was unchanged. In rings precontracted with either carbachol or KCl, hypoxia caused similar losses of airway smooth muscle tone in a reversible and concentration-dependent manner. The effects of hypoxia were independent of the presence of an intact epithelium and were not inhibited by the cyclooxygenase inhibitor indomethacin (5 microM), the soluble guanylate cyclase inhibitor methylene blue (50 microM), or the beta-adrenoceptor antagonist propranolol (1 microM). The impairment by hypoxia of the initiation phase of KCl-induced contractions and of the maintenance phase of both KCl- and carbachol-induced contractions, but not the initiation phase of carbachol-induced contractions, suggests that changes in O2 tension modulate airway tone by altering the entry of extracellular calcium into the airway smooth muscle.

scholarly journals CRISPR‐mediated deletion of a regulatory element downstream of the EDN1 gene increases expression of a long non‐coding RNA, EDN1‐AS

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Lauren G Douma ◽  
Sarah Masten ◽  
Kristen Solocinski ◽  
Dominique Barral ◽  
Charles S Wingo ◽  
...  
Keyword(s):  
Regulatory Element ◽  
Non Coding Rna ◽  
Long Non Coding Rna

scholarly journals X chromosome inactivation: new players in the initiation of gene silencing

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 344 ◽  
Author(s):  
Ines Pinheiro ◽  
Edith Heard
Keyword(s):  
Gene Silencing ◽  
X Chromosome ◽  
Gene Dosage ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Crucial Importance ◽  
Compensation Process ◽  
Repressive Chromatin ◽  
Non Coding Rna ◽  
Recent Developments

X chromosome inactivation (XCI) is a dosage compensation process that was adopted by female mammals to balance gene dosage between XX females and XY males. XCI starts with the upregulation of the non-coding RNA Xist, after which most X-linked genes are silenced and acquire a repressive chromatin state. Even though the chromatin marks of the inactive X have been fairly well described, the mechanisms responsible for the initiation of XCI remain largely unknown. In this review, we discuss recent developments that revealed unexpected factors playing a role in XCI and that might be of crucial importance to understand the mechanisms responsible for the very first steps of this chromosome-wide gene-silencing event.

Sign in / Sign up

Export Citation Format

Share Document