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dc.contributor.advisorGary S. Stein, PhD
dc.contributor.advisorAnthony N. Imbalzano, PhD
dc.contributor.authorBarutcu, Ahmet Rasim
dc.date2022-08-11T08:08:45.000
dc.date.accessioned2022-08-23T16:07:11Z
dc.date.available2022-08-23T16:07:11Z
dc.date.issued2016-02-11
dc.date.submitted2016-10-06
dc.identifier.doi10.13028/M2T01Z
dc.identifier.urihttp://hdl.handle.net/20.500.14038/32198
dc.description.abstractHigher-order genome organization is important for the regulation of gene expression by bringing different cis-regulatory elements and promoters in proximity. The establishment and maintenance of long-range chromatin interactions occur in response to cellular and environmental cues with the binding of transcription factors and chromatin modifiers. Understanding the organization of the nucleus in differentiation and cancer has been a long standing challenge and is still not well-understood. In this thesis, I explore the dynamic changes in the higher-order chromatin structure in bone differentiation and breast cancer. First, we show dynamic chromatin contact between a distal regulatory element and the promoter of Runx2 gene, which encodes the Runtrelated transcription factor 2 (RUNX2) that is essential for bone development. Next, via using a genome-wide approach, we show that breast cancer cells have altered long-range chromatin contacts among small, gene-rich chromosomes and at telomeres when compared with mammary epithelial cells. Furthermore, we assess the changes in nuclear structure and gene expression of breast cancer cells following Runt-related transcription factor 1 (RUNX1) deficiency, an event frequently observed in breast cancer. Finally, I present the role of the central ATPase subunit of the SWI/SNF complex, SMARCA4 (BRG1), in mediating nuclear structure and gene expression. Taken together, the research presented in this thesis reveals novel insight and paradigm for the dynamic changes in disease and differentiation, as well as uncovers previously unidentified roles for two chromatin regulatory proteins, RUNX1 and SMARCA4.
dc.language.isoen_US
dc.publisherUniversity of Massachusetts Medical School
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectDissertations, UMMS
dc.subjectCell Differentiation
dc.subjectBone Development
dc.subjectBreast Neoplasms
dc.subjectChromatin
dc.subjectCore Binding Factor Alpha 1 Subunit
dc.subjectTranscription Factors
dc.subjectCell Differentiation
dc.subjectBone Development
dc.subjectBreast Neoplasms
dc.subjectChromatin
dc.subjectCore Binding Factor Alpha 1 Subunit
dc.subjectTranscription Factors
dc.subjectCancer Biology
dc.subjectCell Biology
dc.subjectGenetics and Genomics
dc.subjectNeoplasms
dc.titleCharacterization of Higher-order Chromatin Structure in Bone Differentiation and Breast Cancer: A Dissertation
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1829&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/827
dc.legacy.embargo2017-03-07T00:00:00-08:00
dc.identifier.contextkey9240637
refterms.dateFOA2022-08-30T15:27:05Z
html.description.abstract<p>Higher-order genome organization is important for the regulation of gene expression by bringing different cis-regulatory elements and promoters in proximity. The establishment and maintenance of long-range chromatin interactions occur in response to cellular and environmental cues with the binding of transcription factors and chromatin modifiers. Understanding the organization of the nucleus in differentiation and cancer has been a long standing challenge and is still not well-understood. In this thesis, I explore the dynamic changes in the higher-order chromatin structure in bone differentiation and breast cancer. First, we show dynamic chromatin contact between a distal regulatory element and the promoter of Runx2 gene, which encodes the Runtrelated transcription factor 2 (RUNX2) that is essential for bone development. Next, via using a genome-wide approach, we show that breast cancer cells have altered long-range chromatin contacts among small, gene-rich chromosomes and at telomeres when compared with mammary epithelial cells. Furthermore, we assess the changes in nuclear structure and gene expression of breast cancer cells following Runt-related transcription factor 1 (RUNX1) deficiency, an event frequently observed in breast cancer. Finally, I present the role of the central ATPase subunit of the SWI/SNF complex, SMARCA4 (BRG1), in mediating nuclear structure and gene expression. Taken together, the research presented in this thesis reveals novel insight and paradigm for the dynamic changes in disease and differentiation, as well as uncovers previously unidentified roles for two chromatin regulatory proteins, RUNX1 and SMARCA4.</p>
dc.identifier.submissionpathgsbs_diss/827
dc.contributor.departmentCell and Developmental Biology
dc.description.thesisprogramCell Biology


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