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Aminah
Wali
Author
Curriculum in Genetics and Molecular Biology
School of Medicine
Biological characterization of chromatin-targeted small molecules
Chromatin regulation is commonly disrupted in human cancers. The identification of chemical probes that reverse chromatin defects can provide mechanistic insights as well as therapeutic opportunities for these cancers. One such cancer is Ewing sarcoma, a pediatric bone tumor characterized by the EWSR1-FLI1 fusion protein. EWSR1-FLI1 activates an oncogenic transcriptional program by remodeling chromatin at characteristic genomic loci. To identify inhibitors of oncoprotein-mediated chromatin modulation, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE) for high-throughput use and screened a library of small molecules designed to inhibit a wide range of chromatin regulators. Among the compounds that selectively decreased chromatin accessibility at EWSR1-FLI1 binding sites, the class of histone deacetylase inhibitors was highly enriched. We found that treatment with these HDAC inhibitors altered both EWSR1-FLI1 transcript and protein levels. In addition, we identified a novel small molecule inhibitor of chromatin accessibility, UNC0621. This compound interacts directly with chromatin through nuclear protein intermediates. UNC0621 also inhibits the proliferation of Ewing sarcoma cells by inducing a cell cycle arrest. These data demonstrate the effect of chromatin-targeted small molecules on the biology of Ewing sarcoma cells, and validate the potential of chromatin-based assays to screen for compounds with therapeutic potential in cancers with epigenetic alterations.
Winter 2017
2017
Molecular biology
Genetics
cancer, chromatin, epigenetic, small molecule
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Genetics and Molecular Biology
Ian
Davis
Thesis advisor
Scott
Bultman
Thesis advisor
Albert
Baldwin
Thesis advisor
Nate
Hathaway
Thesis advisor
Bernard
Weissman
Thesis advisor
text
Aminah
Wali
Creator
Curriculum in Genetics and Molecular Biology
School of Medicine
Biological characterization of chromatin-targeted small molecules
Chromatin regulation is commonly disrupted in human cancers. The identification of chemical probes that reverse chromatin defects can provide mechanistic insights as well as therapeutic opportunities for these cancers. One such cancer is Ewing sarcoma, a pediatric bone tumor characterized by the EWSR1-FLI1 fusion protein. EWSR1-FLI1 activates an oncogenic transcriptional program by remodeling chromatin at characteristic genomic loci. To identify inhibitors of oncoprotein-mediated chromatin modulation, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE) for high-throughput use and screened a library of small molecules designed to inhibit a wide range of chromatin regulators. Among the compounds that selectively decreased chromatin accessibility at EWSR1-FLI1 binding sites, the class of histone deacetylase inhibitors was highly enriched. We found that treatment with these HDAC inhibitors altered both EWSR1-FLI1 transcript and protein levels. In addition, we identified a novel small molecule inhibitor of chromatin accessibility, UNC0621. This compound interacts directly with chromatin through nuclear protein intermediates. UNC0621 also inhibits the proliferation of Ewing sarcoma cells by inducing a cell cycle arrest. These data demonstrate the effect of chromatin-targeted small molecules on the biology of Ewing sarcoma cells, and validate the potential of chromatin-based assays to screen for compounds with therapeutic potential in cancers with epigenetic alterations.
2017-12
2017
Molecular biology
Genetics
cancer, chromatin, epigenetic, small molecule
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Genetics and Molecular Biology
Ian
Davis
Thesis advisor
Scott
Bultman
Thesis advisor
Albert
Baldwin
Thesis advisor
Nate
Hathaway
Thesis advisor
Bernard
Weissman
Thesis advisor
text
Aminah
Wali
Creator
Curriculum in Genetics and Molecular Biology
School of Medicine
Biological Characterization of Chromatin-Targeted Small Molecules
Chromatin regulation is commonly disrupted in human cancers. The identification of chemical probes that reverse chromatin defects can provide mechanistic insights as well as therapeutic opportunities for these cancers. One such cancer is Ewing sarcoma, a pediatric bone tumor characterized by the EWSR1-FLI1 fusion protein. EWSR1-FLI1 activates an oncogenic transcriptional program by remodeling chromatin at characteristic genomic loci. To identify inhibitors of oncoprotein-mediated chromatin modulation, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE) for high-throughput use and screened a library of small molecules designed to inhibit a wide range of chromatin regulators. Among the compounds that selectively decreased chromatin accessibility at EWSR1-FLI1 binding sites, the class of histone deacetylase inhibitors was highly enriched. We found that treatment with these HDAC inhibitors altered both EWSR1-FLI1 transcript and protein levels. In addition, we identified a novel small molecule inhibitor of chromatin accessibility, UNC0621. This compound interacts directly with chromatin through nuclear protein intermediates. UNC0621 also inhibits the proliferation of Ewing sarcoma cells by inducing a cell cycle arrest. These data demonstrate the effect of chromatin-targeted small molecules on the biology of Ewing sarcoma cells, and validate the potential of chromatin-based assays to screen for compounds with therapeutic potential in cancers with epigenetic alterations.
2017-12
2017
Molecular biology
Genetics
cancer, chromatin, epigenetic, small molecule
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Genetics and Molecular Biology
Ian
Davis
Thesis advisor
Scott
Bultman
Thesis advisor
Albert
Baldwin
Thesis advisor
Nate
Hathaway
Thesis advisor
Bernard
Weissman
Thesis advisor
text
Aminah
Wali
Creator
Curriculum in Genetics and Molecular Biology
School of Medicine
Biological Characterization of Chromatin-Targeted Small Molecules
Chromatin regulation is commonly disrupted in human cancers. The identification of chemical probes that reverse chromatin defects can provide mechanistic insights as well as therapeutic opportunities for these cancers. One such cancer is Ewing sarcoma, a pediatric bone tumor characterized by the EWSR1-FLI1 fusion protein. EWSR1-FLI1 activates an oncogenic transcriptional program by remodeling chromatin at characteristic genomic loci. To identify inhibitors of oncoprotein-mediated chromatin modulation, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE) for high-throughput use and screened a library of small molecules designed to inhibit a wide range of chromatin regulators. Among the compounds that selectively decreased chromatin accessibility at EWSR1-FLI1 binding sites, the class of histone deacetylase inhibitors was highly enriched. We found that treatment with these HDAC inhibitors altered both EWSR1-FLI1 transcript and protein levels. In addition, we identified a novel small molecule inhibitor of chromatin accessibility, UNC0621. This compound interacts directly with chromatin through nuclear protein intermediates. UNC0621 also inhibits the proliferation of Ewing sarcoma cells by inducing a cell cycle arrest. These data demonstrate the effect of chromatin-targeted small molecules on the biology of Ewing sarcoma cells, and validate the potential of chromatin-based assays to screen for compounds with therapeutic potential in cancers with epigenetic alterations.
2017-12
2017
Molecular biology
Genetics
cancer, chromatin, epigenetic, small molecule
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Genetics and Molecular Biology
Ian
Davis
Thesis advisor
Scott
Bultman
Thesis advisor
Albert
Baldwin
Thesis advisor
Nate
Hathaway
Thesis advisor
Bernard
Weissman
Thesis advisor
text
Aminah
Wali
Creator
Curriculum in Genetics and Molecular Biology
School of Medicine
Biological Characterization of Chromatin-Targeted Small Molecules
Chromatin regulation is commonly disrupted in human cancers. The identification of chemical probes that reverse chromatin defects can provide mechanistic insights as well as therapeutic opportunities for these cancers. One such cancer is Ewing sarcoma, a pediatric bone tumor characterized by the EWSR1-FLI1 fusion protein. EWSR1-FLI1 activates an oncogenic transcriptional program by remodeling chromatin at characteristic genomic loci. To identify inhibitors of oncoprotein-mediated chromatin modulation, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE) for high-throughput use and screened a library of small molecules designed to inhibit a wide range of chromatin regulators. Among the compounds that selectively decreased chromatin accessibility at EWSR1-FLI1 binding sites, the class of histone deacetylase inhibitors was highly enriched. We found that treatment with these HDAC inhibitors altered both EWSR1-FLI1 transcript and protein levels. In addition, we identified a novel small molecule inhibitor of chromatin accessibility, UNC0621. This compound interacts directly with chromatin through nuclear protein intermediates. UNC0621 also inhibits the proliferation of Ewing sarcoma cells by inducing a cell cycle arrest. These data demonstrate the effect of chromatin-targeted small molecules on the biology of Ewing sarcoma cells, and validate the potential of chromatin-based assays to screen for compounds with therapeutic potential in cancers with epigenetic alterations.
2017-12
2017
Molecular biology
Genetics
cancer, chromatin, epigenetic, small molecule
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Genetics and Molecular Biology
Ian
Davis
Thesis advisor
Scott
Bultman
Thesis advisor
Albert
Baldwin
Thesis advisor
Nate
Hathaway
Thesis advisor
Bernard
Weissman
Thesis advisor
text
Aminah
Wali
Creator
Curriculum in Genetics and Molecular Biology
School of Medicine
Biological Characterization of Chromatin-Targeted Small Molecules
Chromatin regulation is commonly disrupted in human cancers. The identification of chemical probes that reverse chromatin defects can provide mechanistic insights as well as therapeutic opportunities for these cancers. One such cancer is Ewing sarcoma, a pediatric bone tumor characterized by the EWSR1-FLI1 fusion protein. EWSR1-FLI1 activates an oncogenic transcriptional program by remodeling chromatin at characteristic genomic loci. To identify inhibitors of oncoprotein-mediated chromatin modulation, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE) for high-throughput use and screened a library of small molecules designed to inhibit a wide range of chromatin regulators. Among the compounds that selectively decreased chromatin accessibility at EWSR1-FLI1 binding sites, the class of histone deacetylase inhibitors was highly enriched. We found that treatment with these HDAC inhibitors altered both EWSR1-FLI1 transcript and protein levels. In addition, we identified a novel small molecule inhibitor of chromatin accessibility, UNC0621. This compound interacts directly with chromatin through nuclear protein intermediates. UNC0621 also inhibits the proliferation of Ewing sarcoma cells by inducing a cell cycle arrest. These data demonstrate the effect of chromatin-targeted small molecules on the biology of Ewing sarcoma cells, and validate the potential of chromatin-based assays to screen for compounds with therapeutic potential in cancers with epigenetic alterations.
2017-12
2017
Molecular biology
Genetics
cancer, chromatin, epigenetic, small molecule
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Genetics and Molecular Biology
Ian
Davis
Thesis advisor
Scott
Bultman
Thesis advisor
Albert
Baldwin
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Bernard
Weissman
Thesis advisor
text
Aminah
Wali
Creator
Curriculum in Genetics and Molecular Biology
School of Medicine
Biological Characterization of Chromatin-Targeted Small Molecules
Chromatin regulation is commonly disrupted in human cancers. The identification of chemical probes that reverse chromatin defects can provide mechanistic insights as well as therapeutic opportunities for these cancers. One such cancer is Ewing sarcoma, a pediatric bone tumor characterized by the EWSR1-FLI1 fusion protein. EWSR1-FLI1 activates an oncogenic transcriptional program by remodeling chromatin at characteristic genomic loci. To identify inhibitors of oncoprotein-mediated chromatin modulation, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE) for high-throughput use and screened a library of small molecules designed to inhibit a wide range of chromatin regulators. Among the compounds that selectively decreased chromatin accessibility at EWSR1-FLI1 binding sites, the class of histone deacetylase inhibitors was highly enriched. We found that treatment with these HDAC inhibitors altered both EWSR1-FLI1 transcript and protein levels. In addition, we identified a novel small molecule inhibitor of chromatin accessibility, UNC0621. This compound interacts directly with chromatin through nuclear protein intermediates. UNC0621 also inhibits the proliferation of Ewing sarcoma cells by inducing a cell cycle arrest. These data demonstrate the effect of chromatin-targeted small molecules on the biology of Ewing sarcoma cells, and validate the potential of chromatin-based assays to screen for compounds with therapeutic potential in cancers with epigenetic alterations.
2017-12
2017
Molecular biology
Genetics
cancer, chromatin, epigenetic, small molecule
eng
Doctor of Philosophy
Dissertation
Genetics and Molecular Biology
Ian
Davis
Thesis advisor
Scott
Bultman
Thesis advisor
Albert
Baldwin
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Bernard
Weissman
Thesis advisor
text
University of North Carolina at Chapel Hill
Degree granting institution
Aminah
Wali
Creator
Curriculum in Genetics and Molecular Biology
School of Medicine
Biological Characterization of Chromatin-Targeted Small Molecules
Chromatin regulation is commonly disrupted in human cancers. The identification of chemical probes that reverse chromatin defects can provide mechanistic insights as well as therapeutic opportunities for these cancers. One such cancer is Ewing sarcoma, a pediatric bone tumor characterized by the EWSR1-FLI1 fusion protein. EWSR1-FLI1 activates an oncogenic transcriptional program by remodeling chromatin at characteristic genomic loci. To identify inhibitors of oncoprotein-mediated chromatin modulation, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE) for high-throughput use and screened a library of small molecules designed to inhibit a wide range of chromatin regulators. Among the compounds that selectively decreased chromatin accessibility at EWSR1-FLI1 binding sites, the class of histone deacetylase inhibitors was highly enriched. We found that treatment with these HDAC inhibitors altered both EWSR1-FLI1 transcript and protein levels. In addition, we identified a novel small molecule inhibitor of chromatin accessibility, UNC0621. This compound interacts directly with chromatin through nuclear protein intermediates. UNC0621 also inhibits the proliferation of Ewing sarcoma cells by inducing a cell cycle arrest. These data demonstrate the effect of chromatin-targeted small molecules on the biology of Ewing sarcoma cells, and validate the potential of chromatin-based assays to screen for compounds with therapeutic potential in cancers with epigenetic alterations.
2017-12
2017
Molecular biology
Genetics
cancer, chromatin, epigenetic, small molecule
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Genetics and Molecular Biology
Ian
Davis
Thesis advisor
Scott
Bultman
Thesis advisor
Albert
Baldwin
Thesis advisor
Nate
Hathaway
Thesis advisor
Bernard
Weissman
Thesis advisor
text
Aminah
Wali
Creator
Curriculum in Genetics and Molecular Biology
School of Medicine
Biological Characterization of Chromatin-Targeted Small Molecules
Chromatin regulation is commonly disrupted in human cancers. The identification of chemical probes that reverse chromatin defects can provide mechanistic insights as well as therapeutic opportunities for these cancers. One such cancer is Ewing sarcoma, a pediatric bone tumor characterized by the EWSR1-FLI1 fusion protein. EWSR1-FLI1 activates an oncogenic transcriptional program by remodeling chromatin at characteristic genomic loci. To identify inhibitors of oncoprotein-mediated chromatin modulation, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE) for high-throughput use and screened a library of small molecules designed to inhibit a wide range of chromatin regulators. Among the compounds that selectively decreased chromatin accessibility at EWSR1-FLI1 binding sites, the class of histone deacetylase inhibitors was highly enriched. We found that treatment with these HDAC inhibitors altered both EWSR1-FLI1 transcript and protein levels. In addition, we identified a novel small molecule inhibitor of chromatin accessibility, UNC0621. This compound interacts directly with chromatin through nuclear protein intermediates. UNC0621 also inhibits the proliferation of Ewing sarcoma cells by inducing a cell cycle arrest. These data demonstrate the effect of chromatin-targeted small molecules on the biology of Ewing sarcoma cells, and validate the potential of chromatin-based assays to screen for compounds with therapeutic potential in cancers with epigenetic alterations.
2017-12
2017
Molecular biology
Genetics
cancer; chromatin; epigenetic; small molecule
eng
Doctor of Philosophy
Dissertation
Genetics and Molecular Biology
Ian
Davis
Thesis advisor
Scott
Bultman
Thesis advisor
Albert
Baldwin
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Bernard
Weissman
Thesis advisor
text
University of North Carolina at Chapel Hill
Degree granting institution
Aminah
Wali
Creator
Curriculum in Genetics and Molecular Biology
School of Medicine
Biological Characterization of Chromatin-Targeted Small Molecules
Chromatin regulation is commonly disrupted in human cancers. The identification of chemical probes that reverse chromatin defects can provide mechanistic insights as well as therapeutic opportunities for these cancers. One such cancer is Ewing sarcoma, a pediatric bone tumor characterized by the EWSR1-FLI1 fusion protein. EWSR1-FLI1 activates an oncogenic transcriptional program by remodeling chromatin at characteristic genomic loci. To identify inhibitors of oncoprotein-mediated chromatin modulation, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE) for high-throughput use and screened a library of small molecules designed to inhibit a wide range of chromatin regulators. Among the compounds that selectively decreased chromatin accessibility at EWSR1-FLI1 binding sites, the class of histone deacetylase inhibitors was highly enriched. We found that treatment with these HDAC inhibitors altered both EWSR1-FLI1 transcript and protein levels. In addition, we identified a novel small molecule inhibitor of chromatin accessibility, UNC0621. This compound interacts directly with chromatin through nuclear protein intermediates. UNC0621 also inhibits the proliferation of Ewing sarcoma cells by inducing a cell cycle arrest. These data demonstrate the effect of chromatin-targeted small molecules on the biology of Ewing sarcoma cells, and validate the potential of chromatin-based assays to screen for compounds with therapeutic potential in cancers with epigenetic alterations.
2017-12
2017
Molecular biology
Genetics
cancer, chromatin, epigenetic, small molecule
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Genetics and Molecular Biology
Ian
Davis
Thesis advisor
Scott
Bultman
Thesis advisor
Albert
Baldwin
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Bernard
Weissman
Thesis advisor
text
Aminah
Wali
Creator
Curriculum in Genetics and Molecular Biology
School of Medicine
Biological Characterization of Chromatin-Targeted Small Molecules
Chromatin regulation is commonly disrupted in human cancers. The identification of chemical probes that reverse chromatin defects can provide mechanistic insights as well as therapeutic opportunities for these cancers. One such cancer is Ewing sarcoma, a pediatric bone tumor characterized by the EWSR1-FLI1 fusion protein. EWSR1-FLI1 activates an oncogenic transcriptional program by remodeling chromatin at characteristic genomic loci. To identify inhibitors of oncoprotein-mediated chromatin modulation, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE) for high-throughput use and screened a library of small molecules designed to inhibit a wide range of chromatin regulators. Among the compounds that selectively decreased chromatin accessibility at EWSR1-FLI1 binding sites, the class of histone deacetylase inhibitors was highly enriched. We found that treatment with these HDAC inhibitors altered both EWSR1-FLI1 transcript and protein levels. In addition, we identified a novel small molecule inhibitor of chromatin accessibility, UNC0621. This compound interacts directly with chromatin through nuclear protein intermediates. UNC0621 also inhibits the proliferation of Ewing sarcoma cells by inducing a cell cycle arrest. These data demonstrate the effect of chromatin-targeted small molecules on the biology of Ewing sarcoma cells, and validate the potential of chromatin-based assays to screen for compounds with therapeutic potential in cancers with epigenetic alterations.
2017-12
2017
Molecular biology
Genetics
cancer; chromatin; epigenetic; small molecule
eng
Doctor of Philosophy
Dissertation
University of North Carolina at Chapel Hill Graduate School
Degree granting institution
Ian
Davis
Thesis advisor
Scott
Bultman
Thesis advisor
Albert
Baldwin
Thesis advisor
Nathaniel
Hathaway
Thesis advisor
Bernard
Weissman
Thesis advisor
text
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