Dominique HelmlingerCentre de recherche en biologie cellulaire de Montpellier (CRBM) – CNRS / Université de Montpellier
Mes recherches
The overall goals of my research are to determine the principles governing the assembly of chromatin regulatory complexes and to characterize their topology, activities and regulation by signaling cues, using both yeast and cancer cell lines as experimental systems. My interest in chromatin biology stems from my PhD work, performed with Didier Devys and Jean-Louis Mandel at IGBMC (Strasbourg, France), during which I discovered that alterations of chromatin-modifying activities cause neurodegeneration in a polyglutamine disorder. To address more fundamental questions regarding gene regulation, I switched to using yeast as a model system and performed my postdoctoral training with Fred Winston at Harvard Medical School (Boston, USA). There, I studied the contribution of chromatin-modifying complexes to the adaptation of fission yeast to metabolic changes. Then, in my own research group, we identified the mechanisms by which signaling pathways control chromatin complexes in response to nutrient availability. We also characterized a conserved chaperone machinery that promotes the de novo assembly of these large, multimeric complexes. Recently, we implemented nascent transcriptomics, native chromatin profiling, and endogenous inducible degrons in both yeast and human cells, uncovering unexpected roles for chromatin-modifying complexes in transcription regulation.
Mon projet ATIP-Avenir
Regulation of gene expression by co-activator complexes
CoRegEx
How a cell responds to developmental or environmental changes by altering gene expression is a fundamental question. One critical level of regulation is transcription initiation. Transcriptional co-activators are large multiprotein complexes with many distinct activities that play a central role during transcription initiation in eukaryotes. Little is known, however, about how these activities integrate developmental or environmental signals to control gene expression. My work has established one such co-activator, the highly conserved SAGA complex, as an excellent model to address this question. I discovered that, in the fission yeast S. pombe, SAGA regulates the switch from proliferation to differentiation. SAGA uses distinct activities to function either as a repressor or as an activator of differentiation genes, depending on the levels of extracellular nutrients. My objective is to address key issues in transcriptional control by studying the different roles of the SAGA complex, using a combination of genetic, genomic and proteomic approaches. First, I will study which nutrient-sensing signaling pathway causes SAGA to switch from a repressor to an activator and the mechanisms by which distinct SAGA activities regulate the expression of differentiation genes. Second, S. pombe provides the unique opportunity to study the functions of the SAGA subunit Tra1, a key regulator of early embryogenesis and oncogenesis in mammals. I will test the hypothesis that Tra1 plays a central role in coordinating the activity of kinases sensing various cellular stresses and the activity of transcriptional co-activators. These studies will illuminate previously unknown mechanisms for the control of gene expression by signal transduction pathways, by regulating multifunctional co-activators. Given the high conservation of transcriptional mechanisms between S. pombe and mammals, what we learn in yeast will likely be relevant to similar fundamental aspects of gene expression in humans.