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Gene regulation in the context of variability in DNA sequence and structure

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If you have a question about this talk, please contact Dr Madan Babu Mohan.

New experimental techniques facilitating genome-wide measurements of various molecular quantities provide us with an unprecedented opportunity to gain new insights into functioning of cellular systems. Perhaps most dramatic recent advances relate to gaining understanding of the complexity of gene regulation. In this talk, I will discuss our outgoing research on the impact of two types of genomic changes – (i) gene copy number variations (CNV) and (ii) DNA secondary structure.

Gene duplication and deletions are common features of somatic cell mutations in cancer. How the genotypic changes are propagated along molecular pathways? On one hand, in complex diseases, different genotypic perturbations often lead to the same disease phenotype by dys-regulating common pathways. Discovering such pathways is the focus on our computational study of brain cancer. On the other hand, our studies in fly (collaboration with experimental group of Brian Oliver, NIDDK /NIH) suggest that the effect of gene copy number variations is often “buffered” through cellular feedback. Both studies underscore of importance considering cellular network in studies of the effect of CNV on gene expression.

The so called non-B-DNA structures, including G4, Z-DNA, SIDD , have been long implied to play regulatory roles. However capturing these structures in vivo on genome-wide scale has been elusive. We have been able to achieve this goal using deep sequencing technology (collaboration with groups of David Leven’s NCI /NIH and Rafael Casellas, NIAMS /NIH). We have compared, for the first time on such scale, the experimental data and to the genomic regions computationally predicted to have a high propensity to form non-B DNA conformations. We found that not only experimentally detected non-B DNA regions have a significant overlap with computationally predicted regions, but also various computationally classified non-B DNA conformations have different experimentally derived signatures. This study offers not only strong evidence for the in vivo formation of the alternative but also provides the first look at their genome-wide landscape and possible role in gene regulation.

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