Chromosome acrobatics during embryonic development

How one genome generates a large diversity of cell types, each with unique spatiotemporal gene expression patterns and physiological roles, is an enduring fundamental question in cell and developmental biology. Recent work has indicated that nuclear organization may play an important role in controlling genome functions (transcription, replication, recombination, repair), and defects in genome organization are implicated in aberrant developmental and diseased states. However, the mechanisms of action are not well understood, nor is it clear what chromosome conformations are prevalent, or how they are formed in vivo. To study the forms and functions of genome organization at the single-cell level, I merged novel super-resolution imaging and computational approaches (Sawh* et al. Mol Cell 2020, Sawh* & Mango* STAR Protocols 2020). I developed high-throughput, multiplexed DNA FISH to trace the contours of entire chromosomes (‘chromosome tracing’) in intact tissues, and probe conformational dynamics during early development. Chromosome tracing enables the simultaneous localization of hundreds to thousands of fluorescently-labeled targets to directly map chromosome architecture and extract dense ‘spatial omics’ information even from rare samples. I have previously uncovered high chromosome-scale structural variability, and a novel topological role for the nuclear lamina in systemically stretching chromosomes, increasing structural heterogeneity, and weakening compartments. In the future, my new research group will investigate the genetic and molecular determinants of large-scale conformations, and the causal relationships between chromosome conformation and genome functions.