Integrative nuclear modulation of the Hedgehog transcriptional profile (.2)

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Responding to changing environmental conditions and implementing these changes into the cellular gene expression profile is highly important during many physiological processes. However, in the case of physical cues such as a changing substrate stiffness it is most often not entirely clear how such information is molecularly relayed to critical signaling nodes in order to impact on the cellular transcriptome. Here, we would like to focus on the Hedgehog (Hh)/GLI pathway, an essential signaling system in development and cancer. Our previous work hints to novel protein complexes (Actin-MAL-GLI1 and KDM-GLI1) capable of serving as molecular platforms gathering cellular information and conveying these data to the GLI1 transcription factor. Specifically, we will investigate how external cues such as substrate stiffness or cell-intrinsic information such as cell shape or metabolism impact on the Hh pathway and on Hh-driven physiological processes such as cell differentiation. This will be complemented by a detailed biochemical analysis of the two protein complexes previously identified by us. We believe that such integrative functions of protein complexes are of high significance for non-canonical pathway activation in physiological settings but also in pathological situations such as cancer or fibrosis. Hence, understanding the biology of these signaling complexes is crucial for future therapeutic interventions.