lncRNA 5430416N02Rik Promotes the Proliferation of Mouse Embryonic Stem Cells by Activating Mid1 Expression through 3D Chromatin Architecture

Zhao, Tong; Cai, Mingyang; Liu, Man; Su, Guanghao; An, Daniel; Moon, Byoung-San; Lyu, Guochang; Si, Yibo; Chen, Lingyi; Lu, Wange

doi:10.1016/j.stemcr.2020.02.002

Cited by 18 publications

(16 citation statements)

References 31 publications

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“…Recruitment of Nostrill to the gene locus of the secondary response gene iNOS was further confirmed by ChIRP. Interestingly, Nostrill was recently identified as a chromatin architectural protein (CAP) associated lincRNA but Nostrill’s functional role was not studied [ 67 ]. As one of two recently identified CAP-associated lincRNAs, Nostrill could readily act as a scaffold in long-range chromatin and protein interactions to assist with iNOS transcription [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, Nostrill was recently identified as a chromatin architectural protein (CAP) associated lincRNA but Nostrill’s functional role was not studied [ 67 ]. As one of two recently identified CAP-associated lincRNAs, Nostrill could readily act as a scaffold in long-range chromatin and protein interactions to assist with iNOS transcription [ 67 ]. Several reports have speculated that lincRNAs may function as scaffold molecules to affect gene expression [ 25 , 48 , 68 ].…”

Section: Discussionmentioning

confidence: 99%

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A novel long intergenic non-coding RNA, Nostrill, regulates iNOS gene transcription and neurotoxicity in microglia

Mathy

Burleigh

Kochvar

et al. 2021

J Neuroinflammation

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Background Microglia are resident immunocompetent and phagocytic cells in the CNS. Pro-inflammatory microglia, stimulated by microbial signals such as bacterial lipopolysaccharide (LPS), viral RNAs, or inflammatory cytokines, are neurotoxic and associated with pathogenesis of several neurodegenerative diseases. Long non-coding RNAs (lncRNA) are emerging as important tissue-specific regulatory molecules directing cell differentiation and functional states and may help direct proinflammatory responses of microglia. Characterization of lncRNAs upregulated in proinflammatory microglia, such as NR_126553 or 2500002B13Rik, now termed Nostrill (iNOS Transcriptional Regulatory Intergenic LncRNA Locus) increases our understanding of molecular mechanisms in CNS innate immunity. Methods Microglial gene expression array analyses and qRT-PCR were used to identify a novel long intergenic non-coding RNA, Nostrill, upregulated in LPS-stimulated microglial cell lines, LPS-stimulated primary microglia, and LPS-injected mouse cortical tissue. Silencing and overexpression studies, RNA immunoprecipitation, chromatin immunoprecipitation, chromatin isolation by RNA purification assays, and qRT-PCR were used to study the function of this long non-coding RNA in microglia. In vitro assays were used to examine the effects of silencing the novel long non-coding RNA in LPS-stimulated microglia on neurotoxicity. Results We report here characterization of intergenic lncRNA, NR_126553, or 2500002B13Rik now termed Nostrill (iNOS Transcriptional Regulatory Intergenic LncRNA Locus). Nostrill is induced by LPS stimulation in BV2 cells, primary murine microglia, and in cortical tissue of LPS-injected mice. Induction of Nostrill is NF-κB dependent and silencing of Nostrill decreased inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in BV2 and primary microglial cells. Overexpression of Nostrill increased iNOS expression and NO production. RNA immunoprecipitation assays demonstrated that Nostrill is physically associated with NF-κB subunit p65 following LPS stimulation. Silencing of Nostrill significantly reduced NF-κB p65 and RNA polymerase II recruitment to the iNOS promoter and decreased H3K4me3 activating histone modifications at iNOS gene loci. In vitro studies demonstrated that silencing of Nostrill in microglia reduced LPS-stimulated microglial neurotoxicity. Conclusions Our data indicate a new regulatory role of the NF-κB-induced Nostrill and suggest that Nostrill acts as a co-activator of transcription of iNOS resulting in the production of nitric oxide by microglia through modulation of epigenetic chromatin remodeling. Nostrill may be a target for reducing the neurotoxicity associated with iNOS-mediated inflammatory processes in microglia during neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A novel long intergenic non-coding RNA, Nostrill, regulates iNOS gene transcription and neurotoxicity in microglia

Mathy

Burleigh

Kochvar

et al. 2021

J Neuroinflammation

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show abstract

“…Recruitment of Nostrill to the gene locus of the secondary response gene iNOS was further con rmed by ChIRP. Interestingly, Nostrill was recently identi ed as a CAP-associated lincRNA but Nostrill's functional role was not studied (68). As one of two recently identi ed CAP-associated lincRNAs, Nostrill could readily act as a scaffold in long-range chromatin and protein interactions to assist with iNOS transcription (68).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, Nostrill was recently identi ed as a CAP-associated lincRNA but Nostrill's functional role was not studied (68). As one of two recently identi ed CAP-associated lincRNAs, Nostrill could readily act as a scaffold in long-range chromatin and protein interactions to assist with iNOS transcription (68). Several reports have speculated that lincRNAs may function as scaffold molecules to affect gene expression (25,47,63).…”

Section: Discussionmentioning

confidence: 99%

A novel long non-coding RNA, Nostrill, regulates iNOS gene transcription and neurotoxicity in microglia.

Mathy

Burleigh

Kochvar

et al. 2020

Preprint

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Background Microglia are resident immunocompetent and phagocytic cells in the CNS. Pro-inflammatory microglia, stimulated by environmental microbial signals such as bacterial lipopolysaccharide (LPS), viral RNAs, or inflammatory cytokines, are neurotoxic and associated with pathogenesis of several neurodegenerative diseases. Long non-coding RNA (lncRNA) are emerging as important tissue-specific regulators directing cell differentiation and functional states and may help direct proinflammatory responses of microglia. Methods Microglial gene expression array analyses and qRT-PCR was used to identify a novel intergenic long-noncoding RNA that was upregulated in LPS-stimulated microglial cell lines, LPS-stimulated primary microglia, and LPS-injected mouse cortical tissue. Silencing and overexpression studies, RNA immunoprecipitation, chromatin immunoprecipitation, chromatin RNA immunoprecipitation assays, and qRT-PCR were used to study the function of this long-noncoding RNA in microglia. In vitro cytotoxicity assays were used to examine the effects of silencing the novel long-noncoding RNA in LPS-stimulated microglia on neurotoxicity. Results We report here that the previously uncharacterized intergenic lncRNA we termed Nostrill is induced by LPS stimulation in both BV2 cells and primary murine microglia, as well as in cortical tissue of LPS-injected mice. Induction of Nostrill is NF-κB dependent and silencing of Nostrill decreased inducible nitric oxide synthase (iNOS) expression and nitric oxide production in BV2 and primary microglial cells. Overexpression of Nostrill increased iNOS expression and nitric oxide production. RNA immunoprecipitation assays demonstrated that Nostrill is physically associated with NF-κB subunit p65 following LPS stimulation. Silencing of Nostrill significantly reduced NF-κB p65 and RNA polymerase II recruitment to the iNOS promoter and decreased H3K4me3 activating histone modifications at iNOS gene loci. In vitro studies demonstrate that silencing of Nostrill in microglia reduced LPS-stimulated microglia neurotoxicity. Conclusions Our data indicate a new regulatory role of NF-κB-induced Nostrill and suggest that Nostrill acts as a co-activator of transcription of iNOS resulting in the production of nitric oxide in microglia through modulation of epigenetic chromatin remodeling. Nostrill may be a target for reducing the neurotoxicity associated with iNOS-mediated inflammatory processes in microglia during neurodegeneration.

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“…Dario renio LPI are also observed to interface with transcription factors and other RNA-binding proteins during embryonic development, although their exact mechanism of action is not well known [14]. LPI also act as mediators of other epigenetic mechanisms, for instance as chromatin scaffolds to organize the three-dimensional structure of the genome in Mus musculus [15] Due to the widespread involvement of LPI in epigenetics, dysregulation of certain LPI contributes to disease states, particularly cancers. Severity of a human pancreatic cancer phenotype is driven by a lncRNA-protein complex, which triggers a positive feedback loop of protein overexpression leading to poor patient outcomes [16].…”

Section: Introductionmentioning

confidence: 99%

A Survey of Current Resources to Study lncRNA-protein Interactions.

Philip

Chen

Tyagi

2021

Preprint

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Phenotypes are driven by regulated gene expression, which in turn are mediated by complex interactions between diverse biological molecules. Protein-DNA interactions such as histone and transcription factor binding are well studied, along with RNA-RNA interactions in short RNA silencing of genes. In contrast, lncRNA-protein interaction (LPI) mechanisms are comparatively unknown, likely driven by the difficulties in studying LPI. However, LPI are emerging as key interactions in epigenetic mechanism, playing a role in development and disease. Their importance is further highlighted by their conservation across kingdoms. Hence, interest in LPI research is increasing. We therefore review the current state of the art in lncRNA-protein interactions. We specifically surveyed recent computational methods and databases which researchers can exploit for LPI investigation. We discovered that algorithm development is heavily reliant on a few generic databases containing curated LPI information. We show that early methods predict LPI using molecular docking, have limited scope and are slow, creating a data processing bottleneck. Recently, machine learning has become the strategy of choice in LPI prediction, likely due to the rapid growth in machine learning infrastructure and expertise. While many of these methods have notable limitations, machine learning is expected to be the basis of modern LPI prediction algorithms.

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lncRNA 5430416N02Rik Promotes the Proliferation of Mouse Embryonic Stem Cells by Activating Mid1 Expression through 3D Chromatin Architecture

Cited by 18 publications

References 31 publications

A novel long intergenic non-coding RNA, Nostrill, regulates iNOS gene transcription and neurotoxicity in microglia

A novel long intergenic non-coding RNA, Nostrill, regulates iNOS gene transcription and neurotoxicity in microglia

A novel long non-coding RNA, Nostrill, regulates iNOS gene transcription and neurotoxicity in microglia.

A Survey of Current Resources to Study lncRNA-protein Interactions.

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