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Post-translational Regulatory Mechan...

Dhaliwal, Navroop Kaur.

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Post-translational Regulatory Mechanisms Acting on KLF4 Mediate Pluripotency Exit in Naive Mouse Embryonic Stem Cells.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Post-translational Regulatory Mechanisms Acting on KLF4 Mediate Pluripotency Exit in Naive Mouse Embryonic Stem Cells./
Author:	Dhaliwal, Navroop Kaur.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	223 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-03, Section: B.
Contained By:	Dissertations Abstracts International81-03B.
Subject:	Molecular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13423669
ISBN:	9781085726931

Post-translational Regulatory Mechanisms Acting on KLF4 Mediate Pluripotency Exit in Naive Mouse Embryonic Stem Cells.
Dhaliwal, Navroop Kaur.

Post-translational Regulatory Mechanisms Acting on KLF4 Mediate Pluripotency Exit in Naive Mouse Embryonic Stem Cells. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 223 p.

Source: Dissertations Abstracts International, Volume: 81-03, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2019.

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

Pluripotent embryonic stem (ES) cells have the potential to self-renew and differentiate to generate all adult tissues. Pluripotency is regulated by an interconnected network of transcription factors including OCT4, SOX2, NANOG and KLF4. This transcriptional network is integrated with extracellular signaling pathways regulating pluripotency and differentiation. Mouse ES cells can be maintained in a state known as naive pluripotency by culture in leukemia inhibitory factor (LIF) and two signaling pathway inhibitors (LIF/2i). A previous study observed that a reduction in Klf4 transcript, due to LIF withdrawal, was the first change in pluripotency gene expression during differentiation. Based on this finding I hypothesized that removal of KLF4 protein from transcriptional network would be required for exit from pluripotency. To investigate this I examined the levels of pluripotency associated transcription factors in the nucleus of ES cells as they exit the pluripotent state. This investigation revealed that a reduction in KLF4 protein levels did not occur immediately following the reduction in Klf4 transcription; instead I identified nuclear export of KLF4 protein was required for the reduction in Klf4 transcription and pluripotency exit. Next, I investigated Klf4 gene and protein regulation and found that LIF/2i maintains Klf4 expression through both transcriptional and post-translational mechanisms. Specifically, KLF4 protein is highly stable in LIF/2i and this stability is maintained by physical interaction with active transcriptional complexes which ensure nuclear anchoring of the KLF4 protein. Surprisingly, KLF4 protein stability is so high (t½ >24 hr) that protein levels change by <2 fold when RNA levels are reduced by 17 fold. LIF/2i removal causes both nuclear export of KLF4 and reduced KLF4 stability which together lead to reduced gene expression of the other pluripotency transcription factors and exit from the pluripotent state. These mechanisms regulating KLF4 protein can inform the design of reprogramming and differentiation approaches for cellular therapies.

ISBN: 9781085726931Subjects--Topical Terms:

517296
Molecular biology.
Subjects--Index Terms:

Early embryogenesis

Post-translational Regulatory Mechanisms Acting on KLF4 Mediate Pluripotency Exit in Naive Mouse Embryonic Stem Cells.
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245 1 0 $a Post-translational Regulatory Mechanisms Acting on KLF4 Mediate Pluripotency Exit in Naive Mouse Embryonic Stem Cells.
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500 $a Source: Dissertations Abstracts International, Volume: 81-03, Section: B.
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520 $a Pluripotent embryonic stem (ES) cells have the potential to self-renew and differentiate to generate all adult tissues. Pluripotency is regulated by an interconnected network of transcription factors including OCT4, SOX2, NANOG and KLF4. This transcriptional network is integrated with extracellular signaling pathways regulating pluripotency and differentiation. Mouse ES cells can be maintained in a state known as naive pluripotency by culture in leukemia inhibitory factor (LIF) and two signaling pathway inhibitors (LIF/2i). A previous study observed that a reduction in Klf4 transcript, due to LIF withdrawal, was the first change in pluripotency gene expression during differentiation. Based on this finding I hypothesized that removal of KLF4 protein from transcriptional network would be required for exit from pluripotency. To investigate this I examined the levels of pluripotency associated transcription factors in the nucleus of ES cells as they exit the pluripotent state. This investigation revealed that a reduction in KLF4 protein levels did not occur immediately following the reduction in Klf4 transcription; instead I identified nuclear export of KLF4 protein was required for the reduction in Klf4 transcription and pluripotency exit. Next, I investigated Klf4 gene and protein regulation and found that LIF/2i maintains Klf4 expression through both transcriptional and post-translational mechanisms. Specifically, KLF4 protein is highly stable in LIF/2i and this stability is maintained by physical interaction with active transcriptional complexes which ensure nuclear anchoring of the KLF4 protein. Surprisingly, KLF4 protein stability is so high (t½ >24 hr) that protein levels change by <2 fold when RNA levels are reduced by 17 fold. LIF/2i removal causes both nuclear export of KLF4 and reduced KLF4 stability which together lead to reduced gene expression of the other pluripotency transcription factors and exit from the pluripotent state. These mechanisms regulating KLF4 protein can inform the design of reprogramming and differentiation approaches for cellular therapies.
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653 $a Post translational regulation
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