Jean-Francois Couture
Assistant Professor

Degrees:

B.Sc. Microbiology, Universite Laval 1998
Ph.D. Physiology and Endocrinology, Universite Laval, 2003
Post-doctoral Research Biological Chemistry, University of Michigan, 2007

Research Interests:

Genetic information is packaged into a chromatin polymer which must be opened to increase the accessibility of gene regulatory factors, or compacted to restrict the access of the transcriptional machinery to target genes. The nucleosome, the basic repeating unit of the chromatin, is composed of approximately 150 base pairs of DNA wound around a histone octamer composed of two copies each of the core histones H2A, H2B, H3, and H4. Nucleosomes are dynamic complexes that undergo several post-transcriptional modifications such as acetylation, methylation, phosphorylation, ubiquitylation and sumoylation. These modifications control chromatin remodelling during transcription, mitosis, DNA repair and replication and act individually, sequentially and/or in combination to constitute an epigenetically heritable fingerprint. My laboratory is using structural biology as well as several other biochemical techniques to tackle the most fundamental problems regarding the organisation of the chromatin and the roles of proteins regulating its structure. We have three main projects in the laboratory: Understanding the mechanism of action of 1) histone modifying enzymes (HMEs), 2) polypeptide cofactors regulating HMEs activities and 3) histone deposition.

1) Structural analysis of histone modifying enzymes

Covalent modifications of histones control several cellular processes through the architectural reorganization of the chromatin or the recruitment of effector proteins. These modifications include methylation and demethylimination of arginine side chains, methylation and demethylation as well as acetylation/deacetylation of lysine side chains and phosphorylation/dephosphorylation of threonine and serine side chains. Our work primarily focuses on the elucidation of cancer-related histone modifying enzymes. This will help in the establishment of new therapeutic avenues to treat diseases such as leukemia, colon, prostate and breast cancers.

2) Roles and mechanisms of action of HMEs regulators

Many histone modifying enzymes are regulated through an intricate network of protein-protein interactions which inhibit or stimulate their enzymatic activities in a locus- and/or cell-cycle-dependant manner. To provide a clear picture of the interactions responsible for this stimulatory or inhibitory mechanism, our group is using standard biochemical techniques to isolate and characterize HME complexes. We are also using domain deletions as well as point mutations to identify the protein domains responsible in the formation of these polypeptide complexes. The ultimate goal of this work is to solve the structure of these different proteins alone or in complex with their respective HMEs. This will 1) provide several answers on how histone modifying enzymes are regulated by other polypeptides and 2) identify the molecular determinants in HMEs recognition.

3) Histone deposition

During S phase, the entire genome is duplicated and concomitantly, histone expression increases. The daunting task of accurately depositing histones following the replication forks relies on a family of proteins named histone chaperones. These acidic proteins recognize, bind and deposit specific histones onto DNA maintaining the integrity of the architectural organization of the chromatin. One of the most fundamental questions regarding histone deposition is how histone chaperones mediate the binding as well as the deposition of these basic proteins. To understand this paradox, we are currently investigating the binding properties of several histone chaperones in vitro. Combined with structural biology, this work will provide valuable insights into the role of histone chaperones.