One overarching goal of the Lakadamyali lab is to determine the interplay between epigenetics, the physical architecture of chromosomes and gene regulation. The human genome folds in a highly complex manner inside the nucleus and this folding is fundamentally important for regulating gene expression. However, how the genome is folded at the kilo-to-megabase genomic scales (10-300 nm spatial scale), which are the scales most relevant for gene regulation, has been difficult to determine since these length scales are inaccessible to conventional light microscopy. We have been overcoming this technical challenge by applying quantitative super-resolution microscopy methods to study the 3D organization of the genome in intact nuclei at the single cell level with nanoscale spatial resolution. We are determining how mechanical and chemical cues remodel the genome structure and how this remodeling regulates gene activity and cell fate determination.