© Elisa Bergamin

Elisa BergaminInstitut de génétique et de biologie moléculaire et cellulaire (IGBMC) - CNRS / Inserm / Université de Strasbourg

ATIP-Avenir
mSWI/SNF: Structure and function in health and disease
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Mes recherches

I initially trained in pharmacological chemistry at the University of Studies of Padua in Italy. After, I joined the PhD program in Structural Biology at the Skirball Institute of Biomolecular Medicine, which is part of New York University School of Medicine in New York, USA. In the laboratory of Stevan R. Hubbard, I trained as a protein crystallographer and studied the structure and function of important signalling molecules. First, she solved the crystal structure of SOCS3, an intracellular inhibitor of JAK-STAT signalling misexpressed in a variety of cancer (Bergamin et al. Structure, 2006). Second, the crystal structure of the adaptor protein DOK7 unraveled the unique mechanism by which it activates the MUSK tyrosine kinase receptor from the cytosolic side (Bergamin et al. Molecular Cell, 2010).

After obtaining her Ph.D., I continued my training as a postdoctoral fellow at the Ottawa Institute of Systems Biology, at the University of Ottawa, Canada, in the laboratory of Jean-François Couture. There, I became interested in chromatin enzymes that control cellular functions by epigenetic mechanisms. She worked on the protein ATXR5, a histone methyltransferase that silences heterochromatic loci by monomethylating histone H3 on lysine K27 (H3K27). The crystal structure of ATRX5 allowed her to determine the mechanism by which this protein distinguishes between the two highly related histones (Jacob*, Bergamin* et al. Science, 2014; Bergamin et al. Nucleic Acids Research, 2017). Lastly, following the resolution revolution, I joined as postdoctoral fellow the lab of the Nobel laureate Günter Blobel at Rockefeller University in New York to learn cryo-electron microscopy. I became a member of  the Functional genomics and cancer department at the IGBMC in January 2018. My team is interested into studying structural and functional basis of chromatin remodeling. Thank you to the ATIP-AVENIR grant my team can conduct structural and functional studies on the mammalian SWI/SNF and expanded with the addition of a postdoc. This had a tremendous impact on the progress of the research.

 

 

Mon projet ATIP-Avenir

mSWI/SNF: Structure and function in health and disease

In eukaryotes, DNA is made to fit inside the cell nucleus through a high degree of compaction that is enabled by assembly into chromatin. Processes such as DNA damage repair and transcription require localized changes in chromatin compaction. Cells have multiple molecular strategies to control this. In one, multi-protein chromatin remodelling complexes use the energy from ATP hydrolysis to alter DNA compaction. Among them, the mSWI/SNF complex is of special interest because:

-Although the complex has been studied for many years in yeast, the precise topology of the human complex is not fully known;

-A number of proteins were recently discovered as core components unique to the human complex, but therole they play within mSWI/SNF is unknown;

-Several subunits, including the novel core components, are coded by genes mutated or mis-expressed in many forms of cancer;

-The impact of these cancer-associated mutations on mSWI/SNF assembly and function, and on the cancerous phenotype, is mostly unknown.

The goal of my research is to gain insight on the structure and function of mSWI/SNF, without neglecting the novel subunits, and understanding the impact of cancer-derived aberrations. We will use protein crystallography, cryo-EM and proteomics to accomplish the following aims:

-Determine the molecular function and 3D structure of the novel mSWI/SNF subunits;

-Determine the overall structure of the human mSWI/SNF complex by cryo-EM;

-Establish a map of direct protein-protein interactions within mSWI/SNF;

-Locate interaction points in mSWI/SNF that are mutated in cancer cells, and determine the effect on complex assembly and activity;

The proposed work represents the starting point towards our long term goal to design pharmacological inhibitors for mutant mSWI/SNF complexes. Therefore, this research proposal is important and valuable because in addition to generating important new knowledge on the fundamental processes that regulate chromatin structure in human cells, it has the potential to help developing new cancer therapeutic approaches.