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Ethanol (EtOH)-Mediated Differentiat...

Serio, Ryan Neil.

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Ethanol (EtOH)-Mediated Differentiation of Embryonic Stem Cells via Retinoic Acid (RA)-Retinoic Acid Receptor-Gamma (RARγ) Signaling.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Ethanol (EtOH)-Mediated Differentiation of Embryonic Stem Cells via Retinoic Acid (RA)-Retinoic Acid Receptor-Gamma (RARγ) Signaling./
Author:	Serio, Ryan Neil.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	144 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-10, Section: B.
Contained By:	Dissertations Abstracts International80-10B.
Subject:	Toxicology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13805870
ISBN:	9781392017609

Ethanol (EtOH)-Mediated Differentiation of Embryonic Stem Cells via Retinoic Acid (RA)-Retinoic Acid Receptor-Gamma (RARγ) Signaling.
Serio, Ryan Neil.

Ethanol (EtOH)-Mediated Differentiation of Embryonic Stem Cells via Retinoic Acid (RA)-Retinoic Acid Receptor-Gamma (RARγ) Signaling. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 144 p.

Source: Dissertations Abstracts International, Volume: 80-10, Section: B.

Thesis (Ph.D.)--Weill Medical College of Cornell University, 2019.

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

Ethanol (EtOH) is a teratogen, but the mechanisms by which EtOH exerts its teratogenic effects aren't fully understood. Vitamin A (all- trans retinol/ROL) can be oxidized to all-trans-retinoic acid (RA), which plays a critical role in differentiation and development. Using an embryonic stem cell (ESC) model to analyze effects of EtOH on differentiation, we show that mRNAs associated with differentiation are increased by EtOH and its metabolite acetaldehyde, but not its acid metabolite acetate. EtOH also decreases pluripotency-related mRNA levels. Kinetics assays showed that ALDH2, and not ALDH1A2, is responsible for metabolizing most of the acetaldehyde in ESCs. Using reporter assays, chromatin immunoprecipitation assays, and RARγ-knockout ESC lines generated by CRISPR/Cas9 or homologous recombination, we demonstrate that EtOH signals via RARγ binding to RA response elements (RAREs) in differentiation-associated genes. We also demonstrate that EtOH-mediated increases in Hoxa1 and Cyp26a1 transcripts, used as examples of direct RA target genes, require expression of the RA-synthesizing enzyme ALDH1A2. This result suggests that EtOH-mediated induction of Hoxa1 and Cyp26a1 transcripts requires ROL from serum. The retinol dehydrogenase gene RDH10 and a functional RARE in the ROL transporter Stra6 gene are required for EtOH induction of Hoxa1 and Cyp26a1 mRNAs, as shown with CRISPR/Cas9 knockout lines. Thus, we identify a mechanism by which EtOH stimulates stem cell differentiation via increased influx and metabolism of ROL for downstream RARγ-dependent transcription. Our data suggest that in stem cells EtOH may shift cell fate decisions to alter developmental outcomes by increasing endogenous ROL/RA signaling via increased STRA6 expression and ROL oxidation. Furthermore, we suggest that stem cells, which generally cannot produce retinyl esters, may be particularly vulnerable to EtOH teratogenesis.

ISBN: 9781392017609Subjects--Topical Terms:

556884
Toxicology.

Ethanol (EtOH)-Mediated Differentiation of Embryonic Stem Cells via Retinoic Acid (RA)-Retinoic Acid Receptor-Gamma (RARγ) Signaling.
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245 1 0 $a Ethanol (EtOH)-Mediated Differentiation of Embryonic Stem Cells via Retinoic Acid (RA)-Retinoic Acid Receptor-Gamma (RARγ) Signaling.
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500 $a Source: Dissertations Abstracts International, Volume: 80-10, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Gudas, Lorraine J.
502 $a Thesis (Ph.D.)--Weill Medical College of Cornell University, 2019.
506 $a This item must not be sold to any third party vendors.
520 $a Ethanol (EtOH) is a teratogen, but the mechanisms by which EtOH exerts its teratogenic effects aren't fully understood. Vitamin A (all- trans retinol/ROL) can be oxidized to all-trans-retinoic acid (RA), which plays a critical role in differentiation and development. Using an embryonic stem cell (ESC) model to analyze effects of EtOH on differentiation, we show that mRNAs associated with differentiation are increased by EtOH and its metabolite acetaldehyde, but not its acid metabolite acetate. EtOH also decreases pluripotency-related mRNA levels. Kinetics assays showed that ALDH2, and not ALDH1A2, is responsible for metabolizing most of the acetaldehyde in ESCs. Using reporter assays, chromatin immunoprecipitation assays, and RARγ-knockout ESC lines generated by CRISPR/Cas9 or homologous recombination, we demonstrate that EtOH signals via RARγ binding to RA response elements (RAREs) in differentiation-associated genes. We also demonstrate that EtOH-mediated increases in Hoxa1 and Cyp26a1 transcripts, used as examples of direct RA target genes, require expression of the RA-synthesizing enzyme ALDH1A2. This result suggests that EtOH-mediated induction of Hoxa1 and Cyp26a1 transcripts requires ROL from serum. The retinol dehydrogenase gene RDH10 and a functional RARE in the ROL transporter Stra6 gene are required for EtOH induction of Hoxa1 and Cyp26a1 mRNAs, as shown with CRISPR/Cas9 knockout lines. Thus, we identify a mechanism by which EtOH stimulates stem cell differentiation via increased influx and metabolism of ROL for downstream RARγ-dependent transcription. Our data suggest that in stem cells EtOH may shift cell fate decisions to alter developmental outcomes by increasing endogenous ROL/RA signaling via increased STRA6 expression and ROL oxidation. Furthermore, we suggest that stem cells, which generally cannot produce retinyl esters, may be particularly vulnerable to EtOH teratogenesis.
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