Expansion in situ genomic sequencing datasets

Microscopy and genomics are both used to characterize cell function, but
approaches to connect the two types of information are lacking,
particularly at subnuclear resolution. While emerging multiplexed imaging
methods can simultaneously localize genomic regions and nuclear proteins,
their ability to accurately measure DNA-protein interactions is
constrained by targeting restrictions and the diffraction limit of optical
microscopy. Here, we describe expansion in situ genome sequencing (ExIGS),
a technology that enables sequencing of genomic DNA and superresolution
localization of nuclear proteins in single cells. We applied ExIGS to
fibroblast cells derived from an individual with Hutchinson-Gilford
progeria syndrome to characterize how variation in nuclear morphology
affects spatial chromatin organization. We discovered that lamin
abnormalities are linked to hotspots of disrupted chromatin regulation
that may erode cell identity. Further, we show that lamin generally
represses transcription and posit that variations in nuclear morphology
may play a regulatory role in tissues and aged cells. These results
demonstrate that ExIGS may serve as a generalizable platform for
connecting nuclear abnormalities to changes in gene regulation across
disease contexts.