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Protein-protein and Protein-DNA Inte...

Radovani, Ernest.

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Protein-protein and Protein-DNA Interactions of the Human C2H2 Zinc Finger Proteins.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Protein-protein and Protein-DNA Interactions of the Human C2H2 Zinc Finger Proteins./
作者:	Radovani, Ernest.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	303 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-10, Section: B.
Contained By:	Dissertations Abstracts International80-10B.
標題:	Biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13426788
ISBN:	9781392018262

Protein-protein and Protein-DNA Interactions of the Human C2H2 Zinc Finger Proteins.
Radovani, Ernest.

Protein-protein and Protein-DNA Interactions of the Human C2H2 Zinc Finger Proteins. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 303 p.

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

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

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

TFs (transcription factors) bind DNA in a sequence specific manner and regulate transcription. Humans encode ∼1600 TFs, which have been identified almost entirely on the basis of a putative DNA-binding domain. Knowledge of the mechanisms by which they regulate transcription is sparse. TFs sometimes contain effector domains, but often utilize uncharacterized regions to recruit various cofactors, including chromatin modifiers, components of the general transcription machinery, and other TFs. This thesis focuses on describing the interactome of C2H2-ZNFs (C2H2 zinc finger proteins) which have been classified as TFs due to their ability to bind DNA and regulate transcription in some studied cases. With ∼750 proteins, C2H2-ZNFs have greatly expanded in mammals and are the largest and least well characterized subfamily of DNA-binding proteins in humans. Through AP/MS (affinity purification and mass spectrometry), we have identified PPIs (protein-protein interactions) for 345 C2H2-ZNFs and, through ChIP-seq (chromatin immunoprecipitation followed by next generation sequencing), we have identified genomic binding sites for 217 C2H2-ZNFs. From the AP/MS data it appears that, overall, the C2H2-ZNFs exhibit a diverse set of interactions that may give them the ability to perform dual functions in transcription activation and repression, therefore suggesting that they may act as TFs. However, they also exhibit PPIs suggestive of roles additional to what the conventional definition of a TF entails, such as in AS (alternative splicing), which provides evidence that they are multifunctional proteins. Furthermore, C2H2-ZNFs are enriched for binding to AS exons and 3'-ends of genes, providing additional evidence for involvement in co-transcriptional processes. Strikingly, from the AP/MS data, C2H2-ZNFs extensively associate with each other and, based on their DNA-binding patterns, I show that interacting pairs may co-bind DNA, since they bind in closer proximity to each other in the genome compared to pairs that were not found to interact. Lastly, by integrating the PPI data with ChIP-seq, ChIA-PET (chromatin interaction analysis by paired-end tag sequencing), and HiC data, I show that C2H2-ZNF interacting pairs may mediate long range DNA interactions and thus organize chromatin architecture. Altogether, this work provides a snapshot of the C2H2-ZNF interactome and its potential to regulate gene expression.

ISBN: 9781392018262Subjects--Topical Terms:

522710
Biology.

Protein-protein and Protein-DNA Interactions of the Human C2H2 Zinc Finger Proteins.
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520 $a TFs (transcription factors) bind DNA in a sequence specific manner and regulate transcription. Humans encode ∼1600 TFs, which have been identified almost entirely on the basis of a putative DNA-binding domain. Knowledge of the mechanisms by which they regulate transcription is sparse. TFs sometimes contain effector domains, but often utilize uncharacterized regions to recruit various cofactors, including chromatin modifiers, components of the general transcription machinery, and other TFs. This thesis focuses on describing the interactome of C2H2-ZNFs (C2H2 zinc finger proteins) which have been classified as TFs due to their ability to bind DNA and regulate transcription in some studied cases. With ∼750 proteins, C2H2-ZNFs have greatly expanded in mammals and are the largest and least well characterized subfamily of DNA-binding proteins in humans. Through AP/MS (affinity purification and mass spectrometry), we have identified PPIs (protein-protein interactions) for 345 C2H2-ZNFs and, through ChIP-seq (chromatin immunoprecipitation followed by next generation sequencing), we have identified genomic binding sites for 217 C2H2-ZNFs. From the AP/MS data it appears that, overall, the C2H2-ZNFs exhibit a diverse set of interactions that may give them the ability to perform dual functions in transcription activation and repression, therefore suggesting that they may act as TFs. However, they also exhibit PPIs suggestive of roles additional to what the conventional definition of a TF entails, such as in AS (alternative splicing), which provides evidence that they are multifunctional proteins. Furthermore, C2H2-ZNFs are enriched for binding to AS exons and 3'-ends of genes, providing additional evidence for involvement in co-transcriptional processes. Strikingly, from the AP/MS data, C2H2-ZNFs extensively associate with each other and, based on their DNA-binding patterns, I show that interacting pairs may co-bind DNA, since they bind in closer proximity to each other in the genome compared to pairs that were not found to interact. Lastly, by integrating the PPI data with ChIP-seq, ChIA-PET (chromatin interaction analysis by paired-end tag sequencing), and HiC data, I show that C2H2-ZNF interacting pairs may mediate long range DNA interactions and thus organize chromatin architecture. Altogether, this work provides a snapshot of the C2H2-ZNF interactome and its potential to regulate gene expression.
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