scholarly journals KDM6A Lysine Demethylase Directs Epigenetic Polarity of MDSCs during Murine Sepsis

2021 ◽  
pp. 1-12
Author(s):  
Isatou Bah ◽  
Tuqa Alkhateeb ◽  
Dima Youssef ◽  
Zhi Q. Yao ◽  
Charles E. McCall ◽  
...  
Keyword(s):  
Suppressor Cells ◽  
Transcription Activation ◽  
Myeloid Derived Suppressor Cells ◽  
Molecular Processes ◽  
Epigenetic Switch ◽  
Translation Research ◽  
Non Coding Rna ◽  
Genetic Deletion ◽  
Lysine Demethylase ◽  
Long Non Coding Rna

Sepsis-induced myeloid-derived suppressor cells (MDSCs) increase mortality risk. We previously identified that long non-coding RNA Hotairm1 supports myeloid precursor shifts to Gr1<sup>+</sup>CD11b<sup>+</sup> MDSCs during mouse sepsis. A major unanswered question is what molecular processes control Hotairm1 expression. In this study, we found by a genetic deletion that a specific PU.1-binding site is indispensable in controlling Hotairm1 transcription. We then identified H3K4me3 and H3K27me3 at the PU.1 site on the Hotairm1 promoter. Controlling an epigenetic switch of Hotairm1 transcription by PU.1 was histone KDM6A demethylase for H3K27me3 that derepressed its transcription with possible contributions from Ezh2 methyltransferase for H3K27me3. KDM6A knockdown in MDSCs increased H3K27me3, decreased H3K4me3, and inhibited Hotairm1 transcription activation by PU.1. These results enlighten clinical translation research of PU.1 epigenetic regulation as a potential sepsis immune-checkpoint treatment site.

scholarly journals Genome-wide screening of circadian and non-circadian impact of Neat1 genetic deletion

2021 ◽  
Author(s):  
Audrey Jacq ◽  
Denis Becquet ◽  
Maria-Montserrat Bello-Goutierrez ◽  
Bénédicte Boyer ◽  
Séverine Guillen ◽  
...  
Keyword(s):  
Biological Processes ◽  
Circadian Expression ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Independent Functions ◽  
Rat Pituitary ◽  
Genetic Deletion ◽  
The Impact ◽  
Long Non Coding Rna ◽  
Abundant Transcript

AbstractThe functions of the long non-coding RNA, Nuclear enriched abundant transcript 1 (Neat1), are poorly understood. Neat1 is required for the formation of paraspeckles, but its respective paraspeckle-dependent or independent functions are unknown. Several studies including ours reported that Neat1 is involved in the regulation of circadian rhythms. We characterized the impact of Neat1 genetic deletion in a rat pituitary cell line. The mRNAs whose circadian expression pattern or expression level is regulated by Neat1 were identified after high-throughput RNA sequencing of the circadian transcriptome of wild-type cells compared to cells in which Neat1 was deleted by CRISPR/Cas9. The numerous RNAs affected by Neat1 deletion were found to be circadian or non-circadian, targets or non-targets of paraspeckles, and to be associated with many key biological processes showing that Neat1, interacting or independently of the circadian system, could play crucial roles in key physiological functions through diverse mechanisms.

scholarly journals Long non-coding RNA KIKAT/LINC01061 as a novel epigenetic regulator that relocates KDM4A on chromatin and modulates viral reactivation

2021 ◽  
Vol 17 (6) ◽  
pp. e1009670
Author(s):  
Wan-Shan Yang ◽  
Wayne W. Yeh ◽  
Mel Campbell ◽  
Lung Chang ◽  
Pei-Ching Chang
Keyword(s):  
Viral Reactivation ◽  
Epigenetic Mechanism ◽  
Endothelial Cell Migration ◽  
Open Chromatin ◽  
Migration Ability ◽  
Non Coding Rna ◽  
Pathological Mechanism ◽  
Rna Immunoprecipitation ◽  
Lysine Demethylase ◽  
Long Non Coding Rna

KDM4A is a histone lysine demethylase that has been described as an oncogene in various types of cancer. The importance of KDM4A-mediated epigenetic regulation in tumorigenesis is just emerging. Here, by using Kaposi’s sarcoma associated herpesvirus (KSHV) as a screening model, we identified 6 oncogenic virus-induced long non-coding RNAs (lncRNAs) with the potential to open chromatin. RNA immunoprecipitation revealed KSHV-induced KDM4A-associated transcript (KIKAT)/LINC01061 as a binding partner of KDM4A. Integrated ChIP-seq and RNA-seq analysis showed that the KIKAT/LINC01061 interaction may mediate relocalization of KDM4A from the transcription start site (TSS) of the AMOT promoter region and transactivation of AMOT, an angiostatin binding protein that regulates endothelial cell migration. Knockdown of AMOT diminished the migration ability of uninfected SLK and iSLK-BAC16 cells in response to KIKAT/LINC01061 overexpression. Thus, we conclude that KIKAT/LINC01061 triggered shifting of KDM4A as a potential epigenetic mechanism regulating gene transactivation. Dysregulation of KIKAT/LINC01061 expression may represent a novel pathological mechanism contributing to KDM4A oncogenicity.

scholarly journals LncRNA HOTAIRM1 promotes MDSC expansion and suppressive functions through the HOXA1-miR124 axis during HCV infection

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Bal Krishna Chand Thakuri ◽  
Jinyu Zhang ◽  
Juan Zhao ◽  
Lam N. Nguyen ◽  
Lam N. T. Nguyen ◽  
...  
Keyword(s):  
Viral Infection ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Hiv Infections ◽  
Arginase 1 ◽  
Non Coding Rna ◽  
Immature Myeloid Cells ◽  
Oxide Synthase ◽  
Long Non Coding Rna

AbstractHOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA (lncRNA) that plays a pivotal role in regulating myeloid cell development via targeting HOXA1 gene expression. We and others have previously shown that myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature myeloid cells, expand during chronic viral (HCV, HIV) infections. However, the role of HOTAIRM1 in the development and suppression of MDSCs during viral infection remains unknown. In this study, we demonstrate that the expressions of HOTAIRM1 and its target HOXA1 are substantially upregulated to promote the expressions of immunosuppressive molecules, including arginase 1, inducible nitric oxide synthase, signal transducer and activator of transcription 3, and reactive oxygen species, in CD33+ myeloid cells derived from hepatitis C virus (HCV)-infected patients. We show that HCV-associated exosomes (HCV-Exo) can modulate HOTAIRM1, HOXA1, and miR124 expressions to regulate MDSC development. Importantly, overexpression of HOTAIRM1 or HOXA1 in healthy CD33+ myeloid cells promoted the MDSC differentiation and suppressive functions; conversely, silencing of HOTAIRM1 or HOXA1 expression in MDSCs from HCV patients significantly reduced the MDSC frequency and their suppressive functions. In essence, these results indicate that the HOTAIRM1-HOXA1-miR124 axis enhances the differentiation and suppressive functions of MDSCs and may be a potential target for immunomodulation in conjunction with antiviral therapy during chronic viral infection.

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