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Breaking the genomic cis-regulatory code by an experimental and theoretical analysis of eve enhancer fusions

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dc.contributor.advisor Reinitz, John en_US
dc.contributor.author Kim, Ah-Ram en_US
dc.contributor.other Department of Biochemistry and Structural Biology en_US
dc.date.accessioned 2013-05-22T17:34:54Z
dc.date.accessioned 2015-04-24T14:45:38Z
dc.date.available 2013-05-22T17:34:54Z
dc.date.available 2015-04-24T14:45:38Z
dc.date.issued 2012-08-01
dc.identifier Kim_grad.sunysb_0771E_10818 en_US
dc.identifier.uri http://hdl.handle.net/1951/59724 en_US
dc.identifier.uri http://hdl.handle.net/11401/71028 en_US
dc.description 189 pg. en_US
dc.description.abstract Encoded within DNA sequence is the cis-regulatory logic responsible for controlling gene expression in metazoans. The precise and predictive decryption of this code is on going endeavor at the heart of modern genomics. Even though state of the art technologies in genomics have been generated tremendous amount of data, how the interplay of multiple transcriptional mechanisms give rise to the complex expression changes has remain elusive. This dissertation presents a theoretical model that reconstitutes even-skipped transcriptional control in silico by implementing molecular regulatory mechanisms that are essential for the even-skipped gene expression, then applies the model to even-skipped enhancer fusions in order to elucidate the underlying rules governing the transcriptional control of the Drosophila genome. Rearrangements of about 2.5 kb of regulatory DNA located 5' of the transcription start site of the Drosophila even-skipped locus generate large scale changes in the expression of even-skipped stripes 2, 3 and 7. The most radical effects are generated by juxtaposing the minimal stripe enhancers MSE2 and MSE3 for stripes 2 and 3 with and without small 'spacer' segments less than 360 bp in length. The model reproduced gene expression of the arrangements with high fidelity and was able to predict expression patterns driven by a variety of segments of the genomic DNA totaling 50 kb for gap and pair-rule genes, even-skipped enhancers not included in the training set, stripe 2, 3 and 7 enhancers from various Drosophilidae and Sepsidae species. These results suggest that the molecular mechanisms implemented in the model are essential not only for Drosophila melanogaster even-skipped but also for many genes of early Drosophila and Sepsid embryo development. In addition, the model predicted gene expression of long segments of even-skipped regulatory DNA which contain multiple enhancers. This result opens the door to quantitative and predictive models of entire loci, the physiological units of the genome. The model demonstrated that two mechanisms, short-range quenching and coactivation, are key mechanisms conferring the independent action of enhancers in the large even-skipped regulatory DNA. I establish that elevated expression driven by a fusion of MSE2 and MSE3 is a consequence of the recruitment of a portion of MSE3 to become a functional component of MSE2, demonstrating that cis-regulatory 'elements' are not elementary objects. Finally, I demonstrate that the conservation of stripe 2 expression driven by six Drosophila and Sepsid stripe 2 enhancers requires novel molecular interactions, not seen in the Drosophila melanogaster S2E, presenting a clear example of compensatory adaptation with a precise mathematical description of the essential molecular mechanisms. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Genetics--Developmental biology--Biochemistry en_US
dc.subject.other cis-regulatory element, Computational modeling, Drosophila melanogaster even-skipped, Eukaryotic transcriptional regulation, Prediction of gene expression, Quantitative gene expression en_US
dc.title Breaking the genomic cis-regulatory code by an experimental and theoretical analysis of eve enhancer fusions en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US

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