ingest cdrApp 2018-08-23T19:55:30.085Z d39a25df-af15-48e9-aec2-c9af81a997a2 modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-08-23T19:56:21.111Z Setting exclusive relation addDatastream MD_TECHNICAL fedoraAdmin 2018-08-23T19:56:32.217Z Adding technical metadata derived by FITS addDatastream MD_FULL_TEXT fedoraAdmin 2018-08-23T19:56:55.350Z Adding full text metadata extracted by Apache Tika modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-08-23T19:57:17.561Z Setting exclusive relation modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-25T20:21:45.593Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-26T18:27:41.309Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-02-28T02:34:03.031Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-03-19T21:51:23.906Z Caralynn Wilczewski Author Curriculum in Genetics and Molecular Biology School of Medicine CHD4 AND THE NURD COMPLEX ORCHESTRATE A TRANSCRIPTIONAL NETWORK TO CONTROL CARDIAC SARCOMERE FORMATION Cardiac development relies on proper cardiomyocyte differentiation, including expression and assembly of cell-type specific actomyosin subunits into a functional cardiac sarcomere. Control of this process involves not only promoting expression of cardiac sarcomere subunits but also repressing expression of non-cardiac myofibril paralogs. This level of transcriptional control requires broadly expressed multiprotein machines that modify and remodel the chromatin landscape to restrict transcription machinery access. Prominent among these is the Nucleosome Remodeling and Deacetylase (NuRD) complex, which includes the catalytic core subunit CHD4. Here, we demonstrate that direct CHD4-mediated repression of skeletal and smooth muscle myofibril isoforms is required for normal cardiac sarcomere formation, function, and embryonic survival early in gestation. Through transcriptomic and genome-wide analyses of CHD4 localization, we identified novel CHD4 binding sites in smooth muscle myosin heavy chain, fast skeletal α-actin, and the fast skeletal troponin complex genes. We further demonstrate that in the absence of CHD4, cardiomyocytes in the developing heart form a hybrid muscle cell that contains cardiac, skeletal and smooth muscle myofibril components. These misexpressed paralogs intercalate into the nascent cardiac sarcomere to disrupt sarcomere formation and cause impaired cardiac function in utero. We further identify two new binding partners of CHD4, GATA4 and NKX2-5, which are predicted to recruit the NuRD complex to these regulatory loci to mediate non-cardiac myofibril isoform repression in cardiomyocytes. These results demonstrate the genomic and physiological requirements for CHD4 in mammalian cardiac development and cardiomyocyte differentiation. Summer 2018 2018 Genetics CHD4, chromatin, congenital heart disease, heart, Nucleosome Remodeling and Deacetylase complex, sarcomere eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology Frank Conlon Thesis advisor Brian Strahl Thesis advisor Li Qian Thesis advisor Paul Wade Thesis advisor Scott Williams Thesis advisor text Caralynn Wilczewski Creator Curriculum in Genetics and Molecular Biology School of Medicine CHD4 AND THE NURD COMPLEX ORCHESTRATE A TRANSCRIPTIONAL NETWORK TO CONTROL CARDIAC SARCOMERE FORMATION Cardiac development relies on proper cardiomyocyte differentiation, including expression and assembly of cell-type specific actomyosin subunits into a functional cardiac sarcomere. Control of this process involves not only promoting expression of cardiac sarcomere subunits but also repressing expression of non-cardiac myofibril paralogs. This level of transcriptional control requires broadly expressed multiprotein machines that modify and remodel the chromatin landscape to restrict transcription machinery access. Prominent among these is the Nucleosome Remodeling and Deacetylase (NuRD) complex, which includes the catalytic core subunit CHD4. Here, we demonstrate that direct CHD4-mediated repression of skeletal and smooth muscle myofibril isoforms is required for normal cardiac sarcomere formation, function, and embryonic survival early in gestation. Through transcriptomic and genome-wide analyses of CHD4 localization, we identified novel CHD4 binding sites in smooth muscle myosin heavy chain, fast skeletal α-actin, and the fast skeletal troponin complex genes. We further demonstrate that in the absence of CHD4, cardiomyocytes in the developing heart form a hybrid muscle cell that contains cardiac, skeletal and smooth muscle myofibril components. These misexpressed paralogs intercalate into the nascent cardiac sarcomere to disrupt sarcomere formation and cause impaired cardiac function in utero. We further identify two new binding partners of CHD4, GATA4 and NKX2-5, which are predicted to recruit the NuRD complex to these regulatory loci to mediate non-cardiac myofibril isoform repression in cardiomyocytes. These results demonstrate the genomic and physiological requirements for CHD4 in mammalian cardiac development and cardiomyocyte differentiation. Genetics CHD4; chromatin; congenital heart disease; heart; Nucleosome Remodeling and Deacetylase complex; sarcomere Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology Frank Conlon Thesis advisor Brian Strahl Thesis advisor Li Qian Thesis advisor Paul Wade Thesis advisor Scott Williams Thesis advisor 2018 2018-08 eng text Caralynn Wilczewski Creator Curriculum in Genetics and Molecular Biology School of Medicine CHD4 AND THE NURD COMPLEX ORCHESTRATE A TRANSCRIPTIONAL NETWORK TO CONTROL CARDIAC SARCOMERE FORMATION Cardiac development relies on proper cardiomyocyte differentiation, including expression and assembly of cell-type specific actomyosin subunits into a functional cardiac sarcomere. Control of this process involves not only promoting expression of cardiac sarcomere subunits but also repressing expression of non-cardiac myofibril paralogs. This level of transcriptional control requires broadly expressed multiprotein machines that modify and remodel the chromatin landscape to restrict transcription machinery access. Prominent among these is the Nucleosome Remodeling and Deacetylase (NuRD) complex, which includes the catalytic core subunit CHD4. Here, we demonstrate that direct CHD4-mediated repression of skeletal and smooth muscle myofibril isoforms is required for normal cardiac sarcomere formation, function, and embryonic survival early in gestation. Through transcriptomic and genome-wide analyses of CHD4 localization, we identified novel CHD4 binding sites in smooth muscle myosin heavy chain, fast skeletal α-actin, and the fast skeletal troponin complex genes. We further demonstrate that in the absence of CHD4, cardiomyocytes in the developing heart form a hybrid muscle cell that contains cardiac, skeletal and smooth muscle myofibril components. These misexpressed paralogs intercalate into the nascent cardiac sarcomere to disrupt sarcomere formation and cause impaired cardiac function in utero. We further identify two new binding partners of CHD4, GATA4 and NKX2-5, which are predicted to recruit the NuRD complex to these regulatory loci to mediate non-cardiac myofibril isoform repression in cardiomyocytes. These results demonstrate the genomic and physiological requirements for CHD4 in mammalian cardiac development and cardiomyocyte differentiation. Genetics CHD4; chromatin; congenital heart disease; heart; Nucleosome Remodeling and Deacetylase complex; sarcomere Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology Frank Conlon Thesis advisor Brian Strahl Thesis advisor Li Qian Thesis advisor Paul Wade Thesis advisor Scott Williams Thesis advisor 2018 2018-08 eng text Caralynn Wilczewski Creator Curriculum in Genetics and Molecular Biology School of Medicine Cardiac development relies on proper cardiomyocyte differentiation, including expression and assembly of cell-type specific actomyosin subunits into a functional cardiac sarcomere. Control of this process involves not only promoting expression of cardiac sarcomere subunits but also repressing expression of non-cardiac myofibril paralogs. This level of transcriptional control requires broadly expressed multiprotein machines that modify and remodel the chromatin landscape to restrict transcription machinery access. Prominent among these is the Nucleosome Remodeling and Deacetylase (NuRD) complex, which includes the catalytic core subunit CHD4. Here, we demonstrate that direct CHD4-mediated repression of skeletal and smooth muscle myofibril isoforms is required for normal cardiac sarcomere formation, function, and embryonic survival early in gestation. Through transcriptomic and genome-wide analyses of CHD4 localization, we identified novel CHD4 binding sites in smooth muscle myosin heavy chain, fast skeletal α-actin, and the fast skeletal troponin complex genes. We further demonstrate that in the absence of CHD4, cardiomyocytes in the developing heart form a hybrid muscle cell that contains cardiac, skeletal and smooth muscle myofibril components. These misexpressed paralogs intercalate into the nascent cardiac sarcomere to disrupt sarcomere formation and cause impaired cardiac function in utero. We further identify two new binding partners of CHD4, GATA4 and NKX2-5, which are predicted to recruit the NuRD complex to these regulatory loci to mediate non-cardiac myofibril isoform repression in cardiomyocytes. These results demonstrate the genomic and physiological requirements for CHD4 in mammalian cardiac development and cardiomyocyte differentiation. Genetics CHD4; chromatin; congenital heart disease; heart; Nucleosome Remodeling and Deacetylase complex; sarcomere Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Genetics and Molecular Biology Frank Conlon Thesis advisor Brian Strahl Thesis advisor Li Qian Thesis advisor Paul Wade Thesis advisor Scott Williams Thesis advisor 2018 2018-08 eng text Caralynn Wilczewski Creator Curriculum in Genetics and Molecular Biology School of Medicine Cardiac development relies on proper cardiomyocyte differentiation, including expression and assembly of cell-type specific actomyosin subunits into a functional cardiac sarcomere. Control of this process involves not only promoting expression of cardiac sarcomere subunits but also repressing expression of non-cardiac myofibril paralogs. This level of transcriptional control requires broadly expressed multiprotein machines that modify and remodel the chromatin landscape to restrict transcription machinery access. Prominent among these is the Nucleosome Remodeling and Deacetylase (NuRD) complex, which includes the catalytic core subunit CHD4. Here, we demonstrate that direct CHD4-mediated repression of skeletal and smooth muscle myofibril isoforms is required for normal cardiac sarcomere formation, function, and embryonic survival early in gestation. Through transcriptomic and genome-wide analyses of CHD4 localization, we identified novel CHD4 binding sites in smooth muscle myosin heavy chain, fast skeletal α-actin, and the fast skeletal troponin complex genes. We further demonstrate that in the absence of CHD4, cardiomyocytes in the developing heart form a hybrid muscle cell that contains cardiac, skeletal and smooth muscle myofibril components. These misexpressed paralogs intercalate into the nascent cardiac sarcomere to disrupt sarcomere formation and cause impaired cardiac function in utero. We further identify two new binding partners of CHD4, GATA4 and NKX2-5, which are predicted to recruit the NuRD complex to these regulatory loci to mediate non-cardiac myofibril isoform repression in cardiomyocytes. These results demonstrate the genomic and physiological requirements for CHD4 in mammalian cardiac development and cardiomyocyte differentiation. Genetics CHD4; chromatin; congenital heart disease; heart; Nucleosome Remodeling and Deacetylase complex; sarcomere Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Frank Conlon Thesis advisor Brian Strahl Thesis advisor Li Qian Thesis advisor Paul Wade Thesis advisor Scott Williams Thesis advisor 2018 2018-08 eng text Wilczewski_unc_0153D_18010.pdf uuid:ae158119-fa9d-4e2b-807e-f9efb68e274e 2020-08-23T00:00:00 2018-07-18T15:14:08Z proquest application/pdf 13636758