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Dissecting the Regulatory Strategies of NFkappaB RelA Target Genes in the Inflammatory Response
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Dissecting the Regulatory Strategies of NFkappaB RelA Target Genes in the Inflammatory Response. |
| 개인저자 | Ngo, Kim Anh. |
| 단체저자명 | University of California, Los Angeles. Microbiology, Immunology, & Molecular Genetics 0440. |
| 발행사항 | [S.l.]: University of California, Los Angeles., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 122 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-05B. Dissertation Abstract International |
| ISBN | 9781687964991 |
| 학위논문주기 | Thesis (Ph.D.)--University of California, Los Angeles, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-05, Section: B.
Includes supplementary digital materials. Advisor: Hoffmann, Alexander. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | The NFkappaB family member RelA is a ubiquitously expressed potent transcriptional activator that is induced by exposure to pathogens and inflammatory cytokines to activate the expression of a large number of inflammatory and immune-response genes. Its nuclear activity is induced from a latent cytoplasmic pool by stimulus-responsive degradation of IkappaB proteins, and the complex signaling mechanisms that regulate its activity are well understood. Less well characterized are the mechanisms that allow nuclear NFkappaB RelA activity to select its target genes and produce gene-specific expression. While many genes have been identified to be potentially NFkappaB regulated, there is no database that lists the NFkappaB target genes in a particular physiological condition, defined cell types and stimulus. Chapter 1 presents a general overview of IKK-IkappaB-NFkappaB signaling system. Chapter 2 reports the primary study in this dissertation in which includes approaches such as biochemistry, molecular biology, mouse genetics, Next-Generation Sequencing, and mathematical modeling to dissect the regulatory strategies of NFkappaB RelA endogenous target genes in the inflammatory response. Chapter 3 summarizes our findings and provide a future direction to this study.In Chapter 2, to dissect gene-specific regulatory strategies resulting from NFkappaB activation in response to inflammation, we stringently defined a list of direct RelA target genes by integrating physical/DNA binding (ChIP-seq) and functional/transcriptional data (RNA-seq) datasets. We then dissected each gene's regulatory strategy by testing RelA variants in a novel primary-cell genetic complementation assay. All endogenous target genes required that RelA makes DNA-base-specific contacts, and none could be activated by the DNA binding domain alone. However, endogenous target genes differed widely in how they employ the two transactivation domains (TAD). Through model-aided analysis of the dynamic timecourse data we reveal gene-specific synergy and redundancy of TA1 and TA2. Given that post-translational modifications control TA1 activity and affinity for coactivators determines TA2 activity, the differential TA logics suggests context-dependent vs. context-independent control of endogenous RelA-target genes. While some inflammatory initiators appear to require co-stimulatory TA1 activation, inflammatory resolvers are a part of the NFkappaB RelA core response where TA2 activity mediates activation even when TA1 is inactive. |
| 일반주제명 | Immunology. Biochemistry. Molecular biology. |
| 언어 | 영어 |
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