Chromatin organization and dynamics in live cells

Simon Mochrie, Yale University

A central goal of chromatin biology is to determine how the three-dimensional configuration of the chromatin polymer changes over time in individual living cells. While live-cell imaging can track a small number of genomic loci, and powerful assays can characterize static conformations in fixed cells, no existing approach can reconstruct time-resolved chromatin configurations involving many loci in vivo. The fundamental barrier is identity: when multiple genomic loci are labeled with the same fluorophore, their genomic positions cannot be distinguished. In this talk, I will describe progress towards developing a polymer-physics-informed, machine-learning-based framework, that will allow us to infer time-dependent chromatin configurations from 4D microscopy of five or more identically labeled loci.  Our approach seeks to use partial supervision, training classifiers on single-locus data and locus-pair data and integrating their probabilistic outputs using polymer constraints. I will also describe new insights into the geography of the fission yeast nucleus, and a new principle for how fission-yeast chromatin is organized, that have emerged from our measurements to-date.