Transcriptional programs of cell identity and p53-induced stress responses are associated with distinctive features of spatial genome organization.

To date, most studies explored changes in 3D-genome organization between different tissues or during differentiation, which involve massive reprogramming of transcriptional programs. Much fewer studies examined alterations in genome organization in response to cellular stress, which involves less pervasive transcriptional modulation. Here, we examined associations between spatial chromatin organization and gene expression in two different biological contexts: transcriptional programs determining cell identity and transcriptional responses to stress, using p53 activation as a model. We selected 10 cell lines of diverse tissues, and in each performed micro-C, RNA-seq, and p53 ChIP-seq, before and after p53 induction. In the comparison between cell types, we delineated marked correlations between gene expression and spatial genome organization and identified hundreds of active enhancer-promoter loops associated with the expression of cell-type marker genes. In contrast, within each cell type, no such links were observed for expression changes induced by p53 activation, even for enhancers and promoters activated by p53 binding. Our analysis points to a fundamental difference between chromatin interactions that define cell identity and those that are established in response to cellular stress. Our results on p53-induced transcriptional responses support the recently proposed TF activity gradient model, which speculated a contact-independent mechanism for enhancer-promoter communication.