Expanding in situ genome sequencing

Despite recent advances in measuring the transcriptome at cellular resolution, direct approaches to link genome organization to changes in nuclear structure are lacking. Labade et al. expand on a previous in situ genome sequencing approach by combining it with expansion microscopy (ExIGS) to simultaneously sequence genomic DNA and image nuclear features at nanoscale resolution. To validate the method, they use fibroblasts derived from patients with progeria to directly link morphological changes in nuclear structure to chromatin organization within individual cells. In progeria fibroblasts, chromosomes more closely follow the contours of the inner lamina topology, which is characterized by lamina thickening and invaginations that reach into the nuclear interior, compared with the uniform lamina layer found in control cells. Interestingly, chromatin organization is disrupted in local hotspots of lamina abnormalities, which are associated with aberrant gene silencing, thus potentially disrupting gene programs important for cell identity. Together, this work demonstrates the potential of combining genomic readout with super-resolution imaging to obtain enhanced spatial information future studies are needed to determine whether the observations are generalizable across diverse cellular and aging contexts.

Original reference: Science https://doi.org/10.1126/science.adt2781 (2025)