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Non-Canonical Translation Regulatory Function of G9a in Chronic Inflammation Associated Diseases.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Non-Canonical Translation Regulatory Function of G9a in Chronic Inflammation Associated Diseases./
Author:	Muneer, Adil.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
Description:	152 p.
Notes:	Source: Dissertations Abstracts International, Volume: 85-07, Section: B.
Contained By:	Dissertations Abstracts International85-07B.
Subject:	Biophysics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30811396
ISBN:	9798381383423

Non-Canonical Translation Regulatory Function of G9a in Chronic Inflammation Associated Diseases.
Muneer, Adil.

Non-Canonical Translation Regulatory Function of G9a in Chronic Inflammation Associated Diseases. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 152 p.

Source: Dissertations Abstracts International, Volume: 85-07, Section: B.

Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2023.

This item must not be sold to any third party vendors.

We report a novel translation-regulatory function of G9a, a histone methyltransferase and well-understood transcriptional repressor, in promoting hyperinflammation and lymphopenia; two hallmarks of endotoxin tolerance (ET)-associated chronic inflammatory complications including sepsis and COVID-19.Following an overview of sepsis and role of G9a in endotoxin tolerance in the opening chapter, we show that G9a interacts with multiple translation regulators during ET, particularly the N6-methyladenosine (m6A) RNA methyltransferase METTL3, to co-upregulate expression of select m6A-modified mRNAs encoding immune-checkpoint and anti-inflammatory response related proteins. Mechanistically, G9a promotes m6A methyltransferase activity of METTL3 at translational/post-translational level by regulating its expression, its methylation, and its cytosolic localization during ET. Additionally, from a broader view extended from the G9a-METTL3-m6A translation regulatory axis, our translatome proteomics approach identified numerous ‘G9a-translated’ proteins that unite the networks associated with inflammation dysregulation, T cell dysfunction, and systemic cytokine response. In sum, we identified a previously unrecognized function of G9a in protein-specific translation that can be leveraged to treat ET-related chronic inflammatory diseases.Several RNA viruses, including SARS-CoV-2, exploit the m6A-modification pathway for their persistence and survival, making it a potential host-directed antiviral target. As there are no clinically approved inhibitors for the pathway, we decided to target our newly identified G9a driven m6A-modification pathway to hinder SARS-CoV-2 replication. We combine results from ET macrophage and COVID-19 patient-derived PBMCs to show that, indeed, G9a facilitates SARS-CoV-2 mediated rewiring of viral/host m6A epi-transcriptome to ultimately promote expression of viral transcripts and facilitate translation of host immune & inflammatory response related mRNAs. More importantly, drugs targeting G9a (UNC0642, YX59-126) and its associated protein EZH2 (UNC1999, tazemetostat) were shown to inhibit SARS-CoV-2 replication and reverse multiomic effects of coronavirus infection in human alveolar epithelial cells (A549-hACE2) and/or COVID-19 patient PBMCs. COVID-19 patient correlated analyses showed that G9a inhibitors restore patient proteomes altered by SARS-CoV-2 infection. Similarity of G9a-translated COVID-19 proteo-pathology across cell-model and patient levels makes G9a/Ezh2 inhibitors attractive candidates for drug repurposing. Concluding remarks are provided in the last chapter.In sum, we identified a previously unrecognized function of G9a in protein-specific translation that can be leveraged to treat ET-related chronic inflammatory diseases.

ISBN: 9798381383423Subjects--Topical Terms:

581576
Biophysics.
Subjects--Index Terms:

Inflammation

Non-Canonical Translation Regulatory Function of G9a in Chronic Inflammation Associated Diseases.
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245 1 0 $a Non-Canonical Translation Regulatory Function of G9a in Chronic Inflammation Associated Diseases.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2023
300 $a 152 p.
500 $a Source: Dissertations Abstracts International, Volume: 85-07, Section: B.
500 $a Advisor: Chen, Xian.
502 $a Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2023.
506 $a This item must not be sold to any third party vendors.
520 $a We report a novel translation-regulatory function of G9a, a histone methyltransferase and well-understood transcriptional repressor, in promoting hyperinflammation and lymphopenia; two hallmarks of endotoxin tolerance (ET)-associated chronic inflammatory complications including sepsis and COVID-19.Following an overview of sepsis and role of G9a in endotoxin tolerance in the opening chapter, we show that G9a interacts with multiple translation regulators during ET, particularly the N6-methyladenosine (m6A) RNA methyltransferase METTL3, to co-upregulate expression of select m6A-modified mRNAs encoding immune-checkpoint and anti-inflammatory response related proteins. Mechanistically, G9a promotes m6A methyltransferase activity of METTL3 at translational/post-translational level by regulating its expression, its methylation, and its cytosolic localization during ET. Additionally, from a broader view extended from the G9a-METTL3-m6A translation regulatory axis, our translatome proteomics approach identified numerous ‘G9a-translated’ proteins that unite the networks associated with inflammation dysregulation, T cell dysfunction, and systemic cytokine response. In sum, we identified a previously unrecognized function of G9a in protein-specific translation that can be leveraged to treat ET-related chronic inflammatory diseases.Several RNA viruses, including SARS-CoV-2, exploit the m6A-modification pathway for their persistence and survival, making it a potential host-directed antiviral target. As there are no clinically approved inhibitors for the pathway, we decided to target our newly identified G9a driven m6A-modification pathway to hinder SARS-CoV-2 replication. We combine results from ET macrophage and COVID-19 patient-derived PBMCs to show that, indeed, G9a facilitates SARS-CoV-2 mediated rewiring of viral/host m6A epi-transcriptome to ultimately promote expression of viral transcripts and facilitate translation of host immune & inflammatory response related mRNAs. More importantly, drugs targeting G9a (UNC0642, YX59-126) and its associated protein EZH2 (UNC1999, tazemetostat) were shown to inhibit SARS-CoV-2 replication and reverse multiomic effects of coronavirus infection in human alveolar epithelial cells (A549-hACE2) and/or COVID-19 patient PBMCs. COVID-19 patient correlated analyses showed that G9a inhibitors restore patient proteomes altered by SARS-CoV-2 infection. Similarity of G9a-translated COVID-19 proteo-pathology across cell-model and patient levels makes G9a/Ezh2 inhibitors attractive candidates for drug repurposing. Concluding remarks are provided in the last chapter.In sum, we identified a previously unrecognized function of G9a in protein-specific translation that can be leveraged to treat ET-related chronic inflammatory diseases.
590 $a School code: 0153.
650 4 $a Biophysics. $3 581576
650 4 $a Biochemistry. $3 582831
650 4 $a Cellular biology. $3 1148666
653 $a Inflammation
653 $a Sepsis
653 $a Translation
653 $a COVID-19
653 $a Endotoxin tolerance
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710 2 $a The University of North Carolina at Chapel Hill. $b Biochemistry and Biophysics. $3 1437829
773 0 $t Dissertations Abstracts International $g 85-07B.
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792 $a 2023
793 $a English
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