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

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.

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

Molecular and Cellular Biology ◽

10.1128/mcb.00382-20 ◽

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.

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

10.1101/2020.05.20.100891 ◽

2020 ◽

Cited By ~ 1

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.

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

Nature Communications ◽

10.1038/ncomms5209 ◽

2014 ◽

Vol 5 (1) ◽

Cited By ~ 25

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

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LncRNA AERRIE Is Required for Sulfatase 1 Expression, but Not for Endothelial-to-Mesenchymal Transition

International Journal of Molecular Sciences ◽

10.3390/ijms22158088 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8088

Author(s):

Tan Phát Pham ◽

Anke S. van Bergen ◽

Veerle Kremer ◽

Simone F. Glaser ◽

Stefanie Dimmeler ◽

...

Keyword(s):

Endothelial Cells ◽

Pulmonary Hypertension ◽

Transcription Factors ◽

Mesenchymal Phenotype ◽

Mesenchymal Transition ◽

Inflammatory Signals ◽

Pathological Conditions ◽

Non Coding Rna ◽

Endothelial To Mesenchymal Transition ◽

Long Non Coding Rna

Endothelial cells can acquire a mesenchymal phenotype through a process called Endothelial-to-Mesenchymal transition (EndMT). This event is found in embryonic development, but also in pathological conditions. Blood vessels lose their ability to maintain vascular homeostasis and ultimately develop atherosclerosis, pulmonary hypertension, or fibrosis. An increase in inflammatory signals causes an upregulation of EndMT transcription factors, mesenchymal markers, and a decrease in endothelial markers. In our study, we show that the induction of EndMT results in an increase in long non-coding RNA AERRIE expression. JMJD2B, a known EndMT regulator, induces AERRIE and subsequently SULF1. Silencing of AERRIE shows a partial regulation of SULF1 but showed no effect on the endothelial and mesenchymal markers. Additionally, the overexpression of AERRIE results in no significant changes in EndMT markers, suggesting that AERRIE is marginally regulating mesenchymal markers and transcription factors. This study identifies AERRIE as a novel factor in EndMT, but its mechanism of action still needs to be elucidated.

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

10.1101/044172 ◽

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.

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Localized accumulation of Xist RNA in X chromosome inactivation

Open Biology ◽

10.1098/rsob.190213 ◽

2019 ◽

Vol 9 (12) ◽

pp. 190213 ◽

Cited By ~ 2

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.

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H19, a Long Non-coding RNA, Mediates Transcription Factors and Target Genes through Interference of MicroRNAs in Pan-Cancer

Molecular Therapy — Nucleic Acids ◽

10.1016/j.omtn.2020.05.028 ◽

2020 ◽

Vol 21 ◽

pp. 180-191 ◽

Cited By ~ 2

Author(s):

Aimin Li ◽

Saurav Mallik ◽

Haidan Luo ◽

Peilin Jia ◽

Dung-Fang Lee ◽

...

Keyword(s):

Transcription Factors ◽

Target Genes ◽

Non Coding Rna ◽

Long Non Coding Rna ◽

Pan Cancer

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PhoP-Responsive Expression of the Salmonella enterica Serovar Typhimurium slyA Gene

Journal of Bacteriology ◽

10.1128/jb.185.12.3508-3514.2003 ◽

2003 ◽

Vol 185 (12) ◽

pp. 3508-3514 ◽

Cited By ~ 42

Author(s):

Valia A. Norte ◽

Melanie R. Stapleton ◽

Jeffrey Green

Keyword(s):

Transcription Factors ◽

Salmonella Enterica ◽

Promoter Region ◽

External Signal ◽

Dependent Manner ◽

Factors Analysis ◽

Upstream Promoter ◽

Serovar Typhimurium ◽

Transcription Regulators ◽

Upstream Promoter Region

ABSTRACT The SlyA protein of Salmonella enterica serovar Typhimurium is a member of the MarR family of transcription regulators and is required for virulence and survival in professional macrophages. Isolated SlyA protein was able to bind a specific DNA target without posttranslational modification. This suggested that SlyA might not be activated by directly sensing an external signal but rather that the intracellular concentration of SlyA is enhanced in appropriate environments through the action of other transcription factors. Analysis of slyA transcription reveals the presence of a promoter region located upstream of the previously recognized SlyA repressed promoter. The newly identified upstream promoter region did not respond to SlyA but was activated by Mg(II) starvation in a PhoP-dependent manner. We present here evidence for a direct link between two transcription factors (PhoP and SlyA) crucial for Salmonella virulence.

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