{"@context":"http://iiif.io/api/presentation/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/manifest.json","@type":"sc:Manifest","label":"Breaking \nthe genomic cis-regulatory code by an experimental and theoretical \nanalysis of eve enhancer fusions","metadata":[{"label":"dc.description.sponsorship","value":"This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree."},{"label":"dc.format","value":"Monograph"},{"label":"dc.format.medium","value":"Electronic Resource"},{"label":"dc.identifier.uri","value":"http://hdl.handle.net/1951/59724"},{"label":"dc.language.iso","value":"en_US"},{"label":"dc.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.abstract","value":"Encoded within DNA sequence \nis the cis-regulatory logic responsible for controlling gene expression \nin metazoans. The precise and predictive decryption of this code is on \ngoing endeavor at the heart of modern genomics. Even though state of the \nart technologies in genomics have been generated tremendous amount of \ndata, how the interplay of multiple transcriptional mechanisms give rise \nto the complex expression changes has remain elusive. This dissertation \npresents a theoretical model that reconstitutes even-skipped \ntranscriptional control in silico by implementing molecular regulatory \nmechanisms that are essential for the even-skipped gene expression, then \napplies the model to even-skipped enhancer fusions in order to elucidate \nthe underlying rules governing the transcriptional control of the \nDrosophila genome. Rearrangements of about 2.5 kb of regulatory DNA \nlocated 5' of the transcription start site of the Drosophila \neven-skipped locus generate large scale changes in the expression of \neven-skipped stripes 2, 3 and 7. The most radical effects are generated \nby juxtaposing the minimal stripe enhancers MSE2 and MSE3 for stripes 2 \nand 3 with and without small 'spacer' segments less than 360 \nbp in length. The model reproduced gene expression of the arrangements \nwith high fidelity and was able to predict expression patterns driven by \na variety of segments of the genomic DNA totaling 50 kb for gap and \npair-rule genes, even-skipped enhancers not included in the training \nset, stripe 2, 3 and 7 enhancers from various Drosophilidae and Sepsidae \nspecies. These results suggest that the molecular mechanisms implemented \nin the model are essential not only for Drosophila melanogaster \neven-skipped but also for many genes of early Drosophila and Sepsid \nembryo development. In addition, the model predicted gene expression of \nlong segments of even-skipped regulatory DNA which contain multiple \nenhancers. This result opens the door to quantitative and predictive \nmodels of entire loci, the physiological units of the genome. The model \ndemonstrated that two mechanisms, short-range quenching and \ncoactivation, are key mechanisms conferring the independent action of \nenhancers in the large even-skipped regulatory DNA. I establish that \nelevated expression driven by a fusion of MSE2 and MSE3 is a consequence \nof the recruitment of a portion of MSE3 to become a functional component \nof MSE2, demonstrating that cis-regulatory 'elements' are \nnot elementary objects. Finally, I demonstrate that the conservation of \nstripe 2 expression driven by six Drosophila and Sepsid stripe 2 \nenhancers requires novel molecular interactions, not seen in the \nDrosophila melanogaster S2E, presenting a clear example of compensatory \nadaptation with a precise mathematical description of the essential \nmolecular mechanisms."},{"label":"dcterms.available","value":"2013-05-22T17:34:54Z"},{"label":"dcterms.contributor","value":"Reinitz, John"},{"label":"dcterms.creator","value":"Kim, Ah-Ram"},{"label":"dcterms.dateAccepted","value":"2015-04-24T14:45:38Z"},{"label":"dcterms.dateSubmitted","value":"2015-04-24T14:45:38Z"},{"label":"dcterms.description","value":"Department of Biochemistry and Structural Biology"},{"label":"dcterms.extent","value":"189 pg."},{"label":"dcterms.format","value":"Application/PDF"},{"label":"dcterms.identifier","value":"Kim_grad.sunysb_0771E_10818"},{"label":"dcterms.issued","value":"2012-08-01"},{"label":"dcterms.language","value":"en_US"},{"label":"dcterms.provenance","value":"Made available in DSpace on 2015-04-24T14:45:38Z (GMT). No. of bitstreams: 3\nKim_grad.sunysb_0771E_11106.pdf.jpg: 1894 bytes, checksum: a6009c46e6ec8251b348085684cba80d (MD5)\nKim_grad.sunysb_0771E_11106.pdf.txt: 294179 bytes, checksum: e56c51eb5b311f1a58bb31ceb2cf2401 (MD5)\nKim_grad.sunysb_0771E_11106.pdf: 3283971 bytes, checksum: 53a005539dd0c61ce4b0cb28f8dd7168 (MD5)\n  Previous issue date:    1"},{"label":"dcterms.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.subject","value":"cis-regulatory element, Computational modeling, \nDrosophila melanogaster even-skipped, Eukaryotic transcriptional \nregulation, Prediction of gene expression, Quantitative gene \nexpression"},{"label":"dcterms.title","value":"Breaking \nthe genomic cis-regulatory code by an experimental and theoretical \nanalysis of eve enhancer fusions"},{"label":"dcterms.type","value":"Dissertation"},{"label":"dc.type","value":"Dissertation"}],"description":"This manifest was generated dynamically","viewingDirection":"left-to-right","sequences":[{"@type":"sc:Sequence","canvases":[{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json","@type":"sc:Canvas","label":"Page 1","height":1650,"width":1275,"images":[{"@type":"oa:Annotation","motivation":"sc:painting","resource":{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/81%2F33%2F25%2F81332554873368324590842964137579608676/full/full/0/default.jpg","@type":"dctypes:Image","format":"image/jpeg","height":1650,"width":1275,"service":{"@context":"http://iiif.io/api/image/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/81%2F33%2F25%2F81332554873368324590842964137579608676","profile":"http://iiif.io/api/image/2/level2.json"}},"on":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json"}]}]}]}