+publisher:"University of North Carolina" +contributor:("Wang, Greg")

University of North Carolina

1. Perfetti, Michael. Discovery of Small Molecule and Peptide-based Ligands for the Methyl-Lysine Binding Proteins 53BP1 and PHF1/PHF19.

Degree: 2015, University of North Carolina

URL: https://cdr.lib.unc.edu/record/uuid:10ee9105-3039-4676-88e9-b1619e8893d7

► Improving the understanding of the role of chromatin regulators in the initiation, development, and suppression of cancer and other devastating diseases is critical, as they… (more)

▼ Improving the understanding of the role of chromatin regulators in the initiation, development, and suppression of cancer and other devastating diseases is critical, as they are integral players in the regulation of DNA integrity and gene expression. Developing chemical tools for histone binding proteins that possess cellular activity will allow for further elucidation of the specific function of this class of histone regulating proteins. This research specifically targeted two different classes of Tudor domain containing histone binding proteins that are directly involved in the DNA damage response and modulation of gene transcription activities. The first methyl-lysine binding protein targeted was 53BP1, which is a DNA damage response protein. 53BP1 uses a tandem tudor domain (TTD) to recognize histone H4 dimethylated on lysine 20 (H4K20me2), a post-translational modification (PTM) induced by double-strand DNA breaks. Through a cross-screening approach, two different small molecule ligands were identified for the 53BP1 TTD. Medicinal chemistry and structure-based design techniques were used, in addition to the development of a fragment-based screen, toward the goal of optimizing the potency and selectivity of the identified small molecule ligands. The later small molecule ligand, 61 (UNC2170), was further optimized as a micromolar inhibitor of 53BP1, which demonstrated a 17-fold selectivity for 53BP1 TTD as compared to other screened methyl-lysine (Kme) binding proteins. Structural studies revealed that the N-tert-butyl amine of 61 (UNC2170) anchors the compound in the Kme binding pocket of 53BP1 TTD, making it competitive with endogenous Kme substrates. X-ray crystallography demonstrated that 61 (UNC2170) bound at the interface between two tudor domains of a 53BP1 TTD dimer. Importantly, this compound functions as a 53BP1 antagonist in cellular lysates and shows cellular activity by suppressing class switch recombination, a process that requires a functional 53BP1 tudor domain. These results demonstrate that 61 (UNC2170) is a functionally active, fragment-like ligand for 53BP1 and the first selective small molecule ligand discovered for 53BP1 TTD. Additional research efforts were focused toward development of peptide-based ligands for the histone binding proteins PHF1 and PHF19. These proteins play an active role in the modulation of PRC2 activity that in turn controls various gene expression and repression outcomes. Structure-based design techniques were used to design peptide-based inhibitors for PHF1 and PHF19. Research efforts were focused on conducting an initial Structure Activity Relationship (SAR) study to develop a short, low molecular weight peptide via truncation of the endogenous histone 3 peptide. Structure based design techniques were used to develop a shorter 6- or 7-mer peptide that possessed various amino acid substitutions that specifically bound within the Tudor domain of PHF1 and PHF19 with emphasis on determining a quaternary amine mimic for the tri-methyl lysine 36 residue. These efforts… Advisors/Committee Members: Perfetti, Michael, Frye, Stephen, Lawrence, David, Strahl, Brian, Wang, Greg, Bowers, Albert, Lee, Andrew.

Subjects/Keywords: Pharmaceutical chemistry; Eshelman School of Pharmacy; Division of Chemical Biology and Medicinal Chemistry

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Perfetti, M. (2015). Discovery of Small Molecule and Peptide-based Ligands for the Methyl-Lysine Binding Proteins 53BP1 and PHF1/PHF19. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:10ee9105-3039-4676-88e9-b1619e8893d7

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Perfetti, Michael. “Discovery of Small Molecule and Peptide-based Ligands for the Methyl-Lysine Binding Proteins 53BP1 and PHF1/PHF19.” 2015. Thesis, University of North Carolina. Accessed January 18, 2021. https://cdr.lib.unc.edu/record/uuid:10ee9105-3039-4676-88e9-b1619e8893d7.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Perfetti, Michael. “Discovery of Small Molecule and Peptide-based Ligands for the Methyl-Lysine Binding Proteins 53BP1 and PHF1/PHF19.” 2015. Web. 18 Jan 2021.

Vancouver:

Perfetti M. Discovery of Small Molecule and Peptide-based Ligands for the Methyl-Lysine Binding Proteins 53BP1 and PHF1/PHF19. [Internet] [Thesis]. University of North Carolina; 2015. [cited 2021 Jan 18]. Available from: https://cdr.lib.unc.edu/record/uuid:10ee9105-3039-4676-88e9-b1619e8893d7.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Perfetti M. Discovery of Small Molecule and Peptide-based Ligands for the Methyl-Lysine Binding Proteins 53BP1 and PHF1/PHF19. [Thesis]. University of North Carolina; 2015. Available from: https://cdr.lib.unc.edu/record/uuid:10ee9105-3039-4676-88e9-b1619e8893d7

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of North Carolina

2. Konze, Kyle. Chemical Probes for the Lysine Methyltransferases EZH2 and G9a: Design, Development, and Application.

Degree: 2015, University of North Carolina

URL: https://cdr.lib.unc.edu/record/uuid:da38a8c1-f466-4bee-bd85-519ff6454876

► In eukaryotic genomes, DNA is wrapped around histone proteins to form repeating units known as nucleosomes, which are further condensed into chromosomes. This high level… (more)

▼ In eukaryotic genomes, DNA is wrapped around histone proteins to form repeating units known as nucleosomes, which are further condensed into chromosomes. This high level of structure creates a barrier to transcription, which is maintained or reversed via modifications to the N-terminal tails of histone proteins. Histone lysine methyltransferases catalyze the mono-, di-, and/or trimethylation of lysine residues within histone tails; the methylation state of histone tails has profound effects on transcription. For example, polycomb repressive complex 2 (PRC2) is responsible for regulating the methylation status of histone 3 lysine 27 (H3K27) via the catalytic subunit EZH1 or EZH2, and the lysine methyltransferase G9a catalyzes mono- and dimethylation of histone 3 lysine 9 (H3K9). These methyltransferases are of great interest, because trimethylation of H3K27 and dimethylation of H3K9 are transcriptionally repressive marks that play a key role in the progression of many diseases. Chemical probes that selectively inhibit the methyltransferase of interest are valuable tools to drive further understanding of the biological function of these proteins and assess their potential as therapeutic targets. Here we describe the design, development, and application of chemical probes and tools for both EZH1 and EZH2 (UNC1999), and G9a (UNC0965). UNC1999 was the first orally bioavailable chemical probe of EZH1 and EZH2. This discovery led to the design of a biotinylated tool (UNC2399), which allows for selective chemiprecipitation of EZH1 and EZH2 from cellular lysates. UNC1999 is also the most panactive EZH1 and EZH2 chemical probe to date. We exploited this feature to demonstrate the potential therapeutic application of small molecule inhibition of both EZH1 and EZH2 in MLL-rearranged leukemia. Lastly, we detail the in vitro and ex vivo use of a biotinylated G9a inhibitor (UNC0965) in a chemical-based chromatin immunoprecipitation (chem-ChIP) assay for studying G9a chromatin occupancy. Advisors/Committee Members: Konze, Kyle, Jin, Jian, Jarstfer, Michael, Frye, Stephen, Wang, Greg, Strahl, Brian.

Subjects/Keywords: Pharmaceutical chemistry; Eshelman School of Pharmacy; Division of Chemical Biology and Medicinal Chemistry

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Konze, K. (2015). Chemical Probes for the Lysine Methyltransferases EZH2 and G9a: Design, Development, and Application. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:da38a8c1-f466-4bee-bd85-519ff6454876

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Konze, Kyle. “Chemical Probes for the Lysine Methyltransferases EZH2 and G9a: Design, Development, and Application.” 2015. Thesis, University of North Carolina. Accessed January 18, 2021. https://cdr.lib.unc.edu/record/uuid:da38a8c1-f466-4bee-bd85-519ff6454876.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Konze, Kyle. “Chemical Probes for the Lysine Methyltransferases EZH2 and G9a: Design, Development, and Application.” 2015. Web. 18 Jan 2021.

Vancouver:

Konze K. Chemical Probes for the Lysine Methyltransferases EZH2 and G9a: Design, Development, and Application. [Internet] [Thesis]. University of North Carolina; 2015. [cited 2021 Jan 18]. Available from: https://cdr.lib.unc.edu/record/uuid:da38a8c1-f466-4bee-bd85-519ff6454876.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Konze K. Chemical Probes for the Lysine Methyltransferases EZH2 and G9a: Design, Development, and Application. [Thesis]. University of North Carolina; 2015. Available from: https://cdr.lib.unc.edu/record/uuid:da38a8c1-f466-4bee-bd85-519ff6454876

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of North Carolina

3. Waldron, Lauren. Identification and Characterization of the TBX5 proteome provides mechanistic insight into Holt-Oram syndrome.

Degree: 2016, University of North Carolina

URL: https://cdr.lib.unc.edu/record/uuid:af537cdc-2c0c-4c04-a62f-06090c261dbf

► Congenital heart disease (CHD) remains the most common congenital malformation, with defects in cardiac chamber septation accounting for almost half of all CHD-related deaths in… (more)

▼ Congenital heart disease (CHD) remains the most common congenital malformation, with defects in cardiac chamber septation accounting for almost half of all CHD-related deaths in children. The health problem is compounded by the fact that most children are otherwise asymptomatic. The cardiac transcription factor TBX5 has been shown to be causative in patients with septal defects; however, its mechanism of action in normal development and in CHD has not been determined. To begin to address this question we have developed two different model systems that express an epitope-tagged version of TBX5 for in vivo isolation of endogenous tissue. In the Xenopus model, I have developed lines in two different species with the intent to isolate endogenous TBX5 protein complexes. In the mouse model, we have isolated and characterized the endogenous TBX5 cardiac interactome and report that TBX5, long considered to be a cardiac transcriptional activator, interacts biochemically and genetically with the chromatin remodeling repressor machinery of the Nucleosome Remodeling and Deacetylase (NuRD) complex. We report that the TBX5-NuRD interaction is essential for normal heart development and that patients with atrioventricular septal defects (AVSD) have mutations that disrupt the TBX5- NuRD interaction. We identify the direct transcriptional targets of TBX5 and show TBX5 acts to repress expression of neural and cancer associated gene programs in cardiac tissue and that a subset of these genes are disregulated by CHD patient mutations. We also define a new structural-functional domain of TBX5 that is essential for interaction with the NuRD complex and show through phylogenetic analysis that this domain, and hence the interaction with NuRD, evolved during the early diversification of the vertebrates, simultaneous with the evolution of atrial septation. Thus, we report that the TBX5-NuRD interaction identified here plays a central role in cardiac development and in human CHD, as well as in the evolution of the mammalian heart. Advisors/Committee Members: Waldron, Lauren, Conlon, Frank, Duronio, Robert, Graves, Lee, Cristea, Ileana, Wang, Greg.

Subjects/Keywords: School of Medicine; Curriculum in Genetics and Molecular Biology

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Waldron, L. (2016). Identification and Characterization of the TBX5 proteome provides mechanistic insight into Holt-Oram syndrome. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:af537cdc-2c0c-4c04-a62f-06090c261dbf

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Waldron, Lauren. “Identification and Characterization of the TBX5 proteome provides mechanistic insight into Holt-Oram syndrome.” 2016. Thesis, University of North Carolina. Accessed January 18, 2021. https://cdr.lib.unc.edu/record/uuid:af537cdc-2c0c-4c04-a62f-06090c261dbf.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Waldron, Lauren. “Identification and Characterization of the TBX5 proteome provides mechanistic insight into Holt-Oram syndrome.” 2016. Web. 18 Jan 2021.

Vancouver:

Waldron L. Identification and Characterization of the TBX5 proteome provides mechanistic insight into Holt-Oram syndrome. [Internet] [Thesis]. University of North Carolina; 2016. [cited 2021 Jan 18]. Available from: https://cdr.lib.unc.edu/record/uuid:af537cdc-2c0c-4c04-a62f-06090c261dbf.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Waldron L. Identification and Characterization of the TBX5 proteome provides mechanistic insight into Holt-Oram syndrome. [Thesis]. University of North Carolina; 2016. Available from: https://cdr.lib.unc.edu/record/uuid:af537cdc-2c0c-4c04-a62f-06090c261dbf

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of North Carolina

4. Annayev, Yunus. Characterization of a New Circadian Clock Gene Gm129.

Degree: Biochemistry and Biophysics, 2014, University of North Carolina

URL: https://cdr.lib.unc.edu/record/uuid:318a73c2-7cfa-40be-aaad-b8f45422646a

► Circadian clock is a 24hr rhythmicity that controls behavioral, metabolic events in most of the organisms. It has been reported that around 10% of all… (more)

Subjects/Keywords: Biochemistry; Molecular biology; School of Medicine; Department of Biochemistry and Biophysics

Record Details Similar Records Cite « Share

❌

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Annayev, Y. (2014). Characterization of a New Circadian Clock Gene Gm129. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:318a73c2-7cfa-40be-aaad-b8f45422646a

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Annayev, Yunus. “Characterization of a New Circadian Clock Gene Gm129.” 2014. Thesis, University of North Carolina. Accessed January 18, 2021. https://cdr.lib.unc.edu/record/uuid:318a73c2-7cfa-40be-aaad-b8f45422646a.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Annayev, Yunus. “Characterization of a New Circadian Clock Gene Gm129.” 2014. Web. 18 Jan 2021.

Vancouver:

Annayev Y. Characterization of a New Circadian Clock Gene Gm129. [Internet] [Thesis]. University of North Carolina; 2014. [cited 2021 Jan 18]. Available from: https://cdr.lib.unc.edu/record/uuid:318a73c2-7cfa-40be-aaad-b8f45422646a.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Annayev Y. Characterization of a New Circadian Clock Gene Gm129. [Thesis]. University of North Carolina; 2014. Available from: https://cdr.lib.unc.edu/record/uuid:318a73c2-7cfa-40be-aaad-b8f45422646a

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

		in
And / Or
		in
And / Or
		in
And / Or
		in

Open Access Theses and Dissertations