For over a century, pathologists have used nuclear structure to diagnose and subtype cancer. The most consistent histomorphologic feature of malignant cells is nuclear atypia. Nuclei of cancer cells are enlarged, have irregular shapes and abnormal chromatin. This feature can even distinguish one type of cancer from another. Nevertheless, the molecular underpinnings of these changes are poorly understood.
Both imaging and genomics studies have demonstrated that chromatin undergoes orchestrated spatial organization within the nucleus. This is well characterized at the level of the linear genome. The genome can be subdivided into decompact, transcriptionally active euchromatin or condensed, silent heterochromatin. Proximity ligation assays across the genome have shown that chromatin also has a 3D organization that spatially segregates euchromatin (active, A compartment) from heterochromatin (inactive, B compartment). We have demonstrated that this spatial separation is perturbed in cancer cells (Johnstone et al,. Cell, 2020). Intriguingly, the disorganization of chromatin in tumor cells is related to global loss of DNA methylation, which occurs in both cancer and aging cells. We propose that as cells proliferate, DNA methylation levels are reduced and this associates with large-scale disruption of chromatin organization. This appears to associate with down-regulation of pro-tumorigenic processes and upregulation of anti-tumor immunity. It is thought that these changes are overcome by other tumor-specific changes but suggest that tumors have partially-executed senescent programs (Johnstone et al., Science, 2022).
Our laboratory is focused on understanding the mechanisms that underlie disrupted chromatin organization in cancer. We use imaging and genomics tools query cells with altered nuclear structure and understand its impact on gene regulatory programs. We are interested in all scales of topological structure, from compartments, to TADS and chromatin loops. To study topological changes in cancer, we use both cell models and primary tumor samples. Ongoing projects are focused on several areas: -Deep characterization of how DNA hypomethylation impacts chromatin structure and tumor cell phenotype
-Understanding how architectural protein mutation and misregulation alters chromatin structure and gene expression
-Relating structural variants in cancer genomes, including neochromosomes, to altered 3D structure and consequent transcriptional changes