Contrasting the association between spatial genome organization and transcriptional programs that determine cell identity or induced by p53.

3C-based deep sequencing techniques have revolutionized our ability to explore the spatial genome organization. In this study, we examined associations between spatial chromatin organization and gene expression in two different biological contexts: transcriptional programs that determine cell identity, and transcriptional responses to cellular stress, using p53 activation as a model. We selected ten cell lines of diverse tissue of origin, and in each performed micro-C, RNA-seq, and p53 ChIP-seq, both without and after treatment with the potent p53 activator - Nutlin-3a. Notably, while we found marked correlations between cell-type specific gene expression programs and differential 3D genome organization, no such links were observed upon p53 activation. Our analysis points to a fundamental difference between chromatin interactions that define cell identity and those that are established in response to cellular stress, the former being much stronger and associated with much larger differential expression, while the latter being weaker, and only loosely correlated with transcriptional responses.