DNA replication and transcription are two essential processes that share the same chromatin template. The evidence accumulated over the past years, including our work, has unveiled the complex relationship between them and the chromatin structure, essential to maintain genome performance (1-4). To investigate these interdependence, we work at the interface between DNA replication, transcription, chromatin and nuclear organization and combine a range of multidisciplinary state-of-the-art approaches, from multi-omics to super-resolution imaging, chromatin conformation capture, genomic editing and machine learning. By this we aim at gaining a molecular understanding of how the replication-transcription crosstalk modulates chromatin structure in two key cellular processes: cellular plasticity and stress responses. The knowledge generated might be specially relevant in the field of cancer, where cellular de-differentiation and replicative stress induced by transcription dysregulation are hallmarks.