Biophysical Society Thematic Meeting| Santa Cruz 2018

Genome Biophysics: Integrating Genomics and Biophysics to Understand Structural and Functional Aspects of Genomes

Poster Abstracts

1-POS Board 1 Bridging Chromatin Nanoimaging and Molecular Modeling – What Can We Learn About Chromatin Packing as a Regulator of Transcription? Vadim Backman 1 . 1 Robert H. Lurie Comprehensive Cancer Center, Evanston, IL, USA, 2 Northwestern University, Evanston, IL, USA. The behavior of organisms is determined by both their genetic code and their capacity to explore a transcriptional landscape of thousands of genes to create new functional states. The talk will discuss the development of two synergistic platforms to study 3D chromatin structure and its regulation of transcription: The chromatin nanoimaging platform co-registers 3D electron tomography for chromatin imaging at the scale of individual DNA strands, spectroscopic photo- localization optical nanoscopy for imaging of targeted genes and transcriptional regulators, and partial wave spectroscopic microscopy for the quantification of the statistics of chromatin packing and contact probability at genomic length-scales from ~kbp to ~10Mbp in live cells, real-time, label-free in hundreds of cells simultaneously with single cell resolution. The computational platform enables predictive modeling of gene transcription in the context of a realistic chromatin nanoscale structure from atomistic details of DNA to whole chromatin and is based on a multi-scale analysis, which includes molecular dynamics, Brownian dynamics, and molecular theory. By combining the imaging and computational platforms, we show how differential chromatin packing works across length-scales from individual DNA strands to topologically associated domains as a key regulator of intercellular transcriptional heterogeneity, transcriptional diversity, and gene-network heterogeneity, which in turn affect cells’ transcriptional access to their genomic space and have implications on cellular processes that depend on cells’ ability to adapt or respond to external stresses. Carcinogenesis provides a particularly significant testbed. We show that the regulation of the physical structure of chromatin packing allows for the predictable modulation of transcriptional heterogeneity in cancer cells during chemotherapeutic response to achieve near-complete cancer cell killing in vitro .

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