Ottavio Croci

This thesis is divided in three sections; the main project and two appendixes. In the main project we studied YAP, the downstream effector of the Hippo pathway, a transcriptional co-factor that plays a fundamental role in dedifferentiation, cell proliferation and transformation. While its upstream regulation has been extensively studied, its role as transcriptional co-factor is still poorly understood. We show that YAP co-adjuvates the transcriptional responses of the Myc oncogene to promote cell proliferation and transformation. In addition, we show that YAP promotes cell de-differentiation by antagonizing liver-specific transcriptional programs controlled by transcription factor HNF4A, thus providing a mechanism on how YAP can promote de-differentiation of hepatocytes. In the first appendix we investigate the mechanism of BRD4 inhibition, a promising strategy for the treatment of Myc-driven tumors. We demonstrate that the efficacy of this strategy relies on the control of transcriptional elongation mediated by BRD4 on gene promoters, independently of the downregulation of Myc oncogene. Although the inhibition of BRD4 causes its genome-wide displacement from promoters of virtually all expressed genes, the effects on transcription are restricted to a subset of sensitive genes. Our results show how the impairment of elongation genome-wide can affect specific transcriptional programs. In the second appendix we describe a new web application, Chrokit, aimed at analyzing genomic data in a fast and intuitive way. The application is multiplatform and can be run on dedicated servers to maximize computational power and provide accessibility to multiple users simultaneously.