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Regulation of Neutrophil Development and Function by Tet Proteins.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Regulation of Neutrophil Development and Function by Tet Proteins./
Author:	Banks, Kelly Madigan.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	179 p.
Notes:	Source: Dissertations Abstracts International, Volume: 83-01, Section: B.
Contained By:	Dissertations Abstracts International83-01B.
Subject:	Developmental biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28264825
ISBN:	9798516945571

Regulation of Neutrophil Development and Function by Tet Proteins.
Banks, Kelly Madigan.

Regulation of Neutrophil Development and Function by Tet Proteins. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 179 p.

Source: Dissertations Abstracts International, Volume: 83-01, Section: B.

Thesis (Ph.D.)--Weill Medical College of Cornell University, 2021.

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

Tet proteins (Tet1/2/3) convert 5-methylcytosine (5-mC) to 5-hydroxy-methylcytosine (5-hmC) and further oxidized derivatives, initiating the process of active demethylation to epigenetically regulate gene expression. Tets are required for generation of hematopoietic stem cells, while mutations in Tet genes are associated with blood disorders including age related clonal hematopoiesis. Demethylation has been investigated primarily in the context of DNA, but recently Tet enzymes have also been shown to mediate demethylation of 5mC in RNA as an additional level of epigenetic or "epitranscriptomic" regulation. We analyzed compound tet2/3 mutant zebrafish and discovered a role for Tet enzymes in the maturation of neutrophils during granulation. Transcript profiling showed dysregulation of cytokine signaling in tet mutant neutrophils, including up-regulation of a key negative cytokine signaling regulator, socs3b. We show that Tet normally demethylates socs3b mRNA during granulation, thereby destabilizing the transcript leading to its down-regulation. Failure of this process leads to accumulation of socs3b mRNA and repression of cytokine signaling at this crucial step of neutrophil maturation. Additionally, in response to inflammatory challenge, tet2/3 mutant neutrophils display aberrant hyper-activated behaviors and inappropriately release Neutrophil Extracellular Traps (NETs). Though important in the normal immune response, hyperactive NETosis can be highly destructive and is involved in the pathogenesis of certain inflammatory and vascular disorders. NETosis can be initiated in a variety of ways including metabolically through mitochondrial reactive oxygen species (mROS). In tet2/3 mutant neutrophils, we observed a marked increase in mROS and a metabolic shift toward fatty acid oxidation. Collectively, this research uncovers an essential role for epigenetic regulation in neutrophil biology and provides novel insight into how neutrophils mature and behave in blood disorders where Tet proteins are dysfunctional.

ISBN: 9798516945571Subjects--Topical Terms:

592588
Developmental biology.
Subjects--Index Terms:

Epigenetics

Regulation of Neutrophil Development and Function by Tet Proteins.
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100 1 $a Banks, Kelly Madigan. $0 (orcid)0000-0001-5543-0639 $3 3685225
245 1 0 $a Regulation of Neutrophil Development and Function by Tet Proteins.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2021
300 $a 179 p.
500 $a Source: Dissertations Abstracts International, Volume: 83-01, Section: B.
500 $a Advisor: Evans, Todd R.
502 $a Thesis (Ph.D.)--Weill Medical College of Cornell University, 2021.
506 $a This item must not be sold to any third party vendors.
520 $a Tet proteins (Tet1/2/3) convert 5-methylcytosine (5-mC) to 5-hydroxy-methylcytosine (5-hmC) and further oxidized derivatives, initiating the process of active demethylation to epigenetically regulate gene expression. Tets are required for generation of hematopoietic stem cells, while mutations in Tet genes are associated with blood disorders including age related clonal hematopoiesis. Demethylation has been investigated primarily in the context of DNA, but recently Tet enzymes have also been shown to mediate demethylation of 5mC in RNA as an additional level of epigenetic or "epitranscriptomic" regulation. We analyzed compound tet2/3 mutant zebrafish and discovered a role for Tet enzymes in the maturation of neutrophils during granulation. Transcript profiling showed dysregulation of cytokine signaling in tet mutant neutrophils, including up-regulation of a key negative cytokine signaling regulator, socs3b. We show that Tet normally demethylates socs3b mRNA during granulation, thereby destabilizing the transcript leading to its down-regulation. Failure of this process leads to accumulation of socs3b mRNA and repression of cytokine signaling at this crucial step of neutrophil maturation. Additionally, in response to inflammatory challenge, tet2/3 mutant neutrophils display aberrant hyper-activated behaviors and inappropriately release Neutrophil Extracellular Traps (NETs). Though important in the normal immune response, hyperactive NETosis can be highly destructive and is involved in the pathogenesis of certain inflammatory and vascular disorders. NETosis can be initiated in a variety of ways including metabolically through mitochondrial reactive oxygen species (mROS). In tet2/3 mutant neutrophils, we observed a marked increase in mROS and a metabolic shift toward fatty acid oxidation. Collectively, this research uncovers an essential role for epigenetic regulation in neutrophil biology and provides novel insight into how neutrophils mature and behave in blood disorders where Tet proteins are dysfunctional.
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650 4 $a Developmental biology. $3 592588
650 4 $a Immunology. $3 611031
650 4 $a Molecular biology. $3 517296
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653 $a Epitranscriptomics
653 $a Hematopoiesis
653 $a Inflammation
653 $a Neutrophil
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690 $a 0982
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710 2 $a Weill Medical College of Cornell University. $b Cell & Developmental Biology. $3 3685226
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791 $a Ph.D.
792 $a 2021
793 $a English
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