Biophysical Characterization of the Dynamic Regulation of Chromatin Structure and Rheology in Human Cell Nuclei.

摘要

Out of the growing body of evidence demonstrating the role of higher-order chromatin organization within the nucleus in regulating the functions of the linear sequence of DNA emerges the genome as a physical entity. DNA packs into hierarchical levels of chromatin condensation, which then tailor accessibility to the linear sequence for nuclear processes while also serving as a central feature of nuclear organization. Further, varying condensation state alters the physical properties of the chromatin fiber. These may then exert or facilitate forces aiding in the spatial organization within the nucleus. Yet, this complex concept of nuclear structure even neglects the dynamic aspects of the genome continuously fluctuating and undergoing structural remodeling within the nucleus. Thus, while chromatin position within the nucleus is critical for biological functions including transcription, we must reconcile a particular position of a gene locus with the dynamic and physical nature of chromatin. Here we characterize the physical aspects of the genome associated with its dynamic properties that aid in regulation. We focus on developing techniques that measure the evolution of physical properties associated with nuclear processes. We leverage these techniques, capable of quantifying and spatially resolving its structural state within the nucleus and elucidating the underlying physics of its dynamics, to illuminate physical features associated with cellular processes. Specifically, we investigate the nuclear structural changes associated with growth factor stimulation on primary human cells known to impact large scale gene expression pathways. We also demonstrate dysfunction associated with these physical mechanisms accompany disease pathologies. Thus, we unify the biological understanding of cellular processes within the context of physical features of genome structure, organization and dynamics that are critical to human health and disease.