We aim to explore chromatin signaling, how its deregulation can lead to pathological states and could be targeted to treat human diseases.
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Jérôme Govin launched his team in 2012 at the Bioscience and Biotechnology Institute of Grenoble (BIG). We have been studying chromatin signaling pathways, histone acetylation and extensively characterizing the biology of acetyl-reader modules, bromodomains (BDs).
In 2018, his team moved to the Department “Signaling Through Chromatin” of the Institute of Advanced Biosciences. It now includes a research program lead by the senior scientist Anouk Emadali with several clinicians of the Hospital of Grenoble. This broadens the research field to the chromatin biology in onco-hematology, with a proficient expertise to address translational questions in epigenetics.
Our team is driven by this central question: understanding cellular fate, which is conditioned by the regulation of gene expression.
We are studying how the genome is organized into chromatin and how histones, their variants and chromatin machineries regulate gene expression.
These mechanisms are very well conserved during evolution, from yeast to human. Thus, we are studying the fundamental mechanisms of chromatin organization in physiological contexts, with yeast and mammalian models, and in pathological contexts, such as infectious diseases and cancer.
Grenoble is an international center of excellence for R&D, recognized by Forbes as the 5th most innovative city in the world in 2013.
With 80,000 jobs in R&D (7.1% of the population, ranking n°1 in France), the science community of Grenoble offers the attractions of an exceptionally dense research plateau, together with a unique supportive atmosphere for investment and business development, within an outstanding location at the foot of the French Alps.
Grenoble hosts top class research organizations such as EMBL, CNRS, Inserm, INRIA, INRAE, CEA and IRSTEA. It benefits from an international high-tech cluster on digital and nano technologies, as well as R&D centers of multinational industrial R&D leaders (STMicroelectronics, Schneider Electric, etc).
Finally, Grenoble benefits from an outstanding quality of life, with a broad diversity of culture and sportive activities. More information on the Giant Genoble website.
Improve clinical care with translational research in epigenetics
As you may know, cell fate is conditioned by the regulation of gene expression. We are deciphering how the organization of the genome regulates transcription. The genome is organized in the form of chromatin, in particular by histones.
Thus, our central question is to understand the concepts, to understand the fundamental mechanisms of chromatin organization.
These mechanisms have been very well conserved during evolution, from yeast to man, and we are studying them in a physiological context, mainly gamete differentiation in mammals and in yeast, and in a pathological context, infectious diseases and cancer.
We have explored different aspects of these mechanisms, combining cell biology, biochemistry, proteomics, structural biology and bioinformatics.
A proteomics-oriented database for histone variants. When working on histone variants, the interpretation of mass spectrometry data relies on public databases which are either not exhaustive or contain many redundant entries. We manually curated >1700 entries to produce a non-redundant list of 83 mouse and 85 human histones, named MS_HistoneDB. This resource is provided in a format that can be directly read by programs used for mass spectrometry data interpretation. Published in 2017 in Epigenetics & Chromatin (Pubmed, DOI).
Systematic quantitative analysis of H2A and H2B variants by targeted proteomics. Classically, the study of histone variants has largely relied on antibody-based assays. We established a mass spectrometry-based analysis to address this challenge, which took advantage of MS_HistoneDB. This strategy was developed on H2A and H2B variants, among which a few differ by a single amino acid. The methodology was then applied to mouse testis extracts and mouse model of male infertility. Published in 2018 in Epigenetics Chromatin (Pubmed, DOI).
Our research program focuses on epigenetics and chromatin in yeast spores. Yeast sporulation is a widely established model to study meiosis. However, post-meiotic events and final spore differentiation remain largely unexplored. Notably, spores have a very distinct chromatin organization, which is highly compacted, yet ready for rapid reactivation when provided with nutrients. How chromatin compaction primes genes for transcription induction is not understood.
Our program explores this apparent paradox and provide new insights into how chromatin organisation impacts transcription regulation. Chromatin signaling has been well conserved through evolution: deciphering such pathways, here in spores, will contribute to better understand the impact of chromatin organisation in human diseases.
Histones during yeast sporulation. We performed systematic mutational and proteomics screens on histones. Among 250 mutations, 75 H2A H2B residues affected sporulation, many of which were localized to the nucleosome lateral surface. In addition, proteomic analysis identified 67 unique histone modifications during sporulation. Published in 2020 in Epigenetics Chromatin (Pubmed, DOI).
BET proteins during yeast sporulation. We characterized the role of Bdf1, a key chromatin regulator, during yeast sporulation. It recognizes chromatin through their two bromodomains (BDs), which specifically recognize histones acetylated on lysine. We showed that Bdf1 BDs are essential for the formation of spores and the meiotic progression. Taken together, our results unveil a new role for Bdf1 BDs as regulators of meiosis-specific genes. Published in 2017 in PLoS Genet (Pubmed, DOI).
Diffuse B Large Cell Lymphoma (DLBCL) is the most common form of B lymphoma. The first-line of treatment, R-CHOP, has significantly improved the prognosis of this cancer. However, 30% of patients present a refractory disease or relapse within 2 years. No efficient alternative therapeutic option is currently available for these patients.
We have demonstrated that overexpression of a novel nuclear protein CYCLON is associated with therapeutic resistance in B-cell lymphomas. Moreover, a clinical evaluation performed in a DLBCL cohort showed that an specific localization of this protein represents a very poor prognostic factor and a potent biomarker to identify high-risk patients.
Altogether, we are currently exploring the different molecular actors participating in CYCLON localization and oncogenic network, to, in the end, improve the clinical management of high-risk DLBCL.
Bromodomain and Extra-Terminal (BET) proteins are epigenetic readers that can control gene expression through their two bromodomains (BDs), BD1 and BD2, which specifically recognize acetylated histone tails and an Extra-Terminal (ET) domain that recruit the transcription machinery. In mammals, this family comprises four proteins (BRD2, BRD3, BRD4 and BRDt). BET BDs possess an unusually spacious ligand binding pocket enabling diacetylated ligands binding in a cooperative fashion, which makes BET readily druggable. BET proteins are conserved in unicellular eukaryotes such as S. cerevisiae, where two homologous genes, Bdf1 and Bdf2, are expressed.
The need for new antifungal drugs. Invasive fungal infections kill an estimated 1.6 million people each year – as many deaths as are caused by tuberculosis or malaria. In the developed world the most common fungal disease among hospitalized patients is invasive candidiasis, which has a mortality rate of ~40%. Among Candida species, C. albicans and C. glabrata rank first and second in isolation frequency, respectively, accounting for ~70% of all systemic candidiasis. These fungi are ubiquitous human commensals: the majority of the population is colonized asymptomatically by one or both species. However, under certain conditions (diabetes, cancer, immunosuppression, treatment with antibiotics, intravenous catheters or long-term hospitalization) they can lead to life-threatening systemic infections. An alarming rise in drug resistant strains, combined with the toxicity, high cost and limited repertoire of available drugs has created an urgent need for new therapeutic agents.
Inhibiting BET bromodomains. BET BDs possess an unusually spacious ligand binding pocket that enables them to bind diacetylated ligands in a cooperative fashion. This wide pocket renders them readily druggable: efforts by academic groups and biopharmaceutical companies have led to the discovery of several potent and selective human BET BD inhibitors. They have been used to validate human BET BD inhibition as a therapeutic strategy for various cancers and other non-infectious diseases.
We have been collaborating with Carlo Petosa (Structural Biology, IBS) and Charles McKenna (Medicinal chemistry, Univ. Southern California, Los Angeles, USA), creating the perfect opportunity to transfer our expertise on Bdf1 BDs to biomedical applications. We upgraded our culture room to L2 level to be able to manipulate pathogenic fungi. By screening chemical libraries, we identified small-molecule compounds that inhibit C. albicans Bdf1 with high selectivity over human BDs. Furthermore, we report a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 BD-inactivating mutation on C. albicans viability. These findings identify CaBdf1 BDs as an antifungal drug target that can be selectively inhibited without antagonizing human BET function.
While BET proteins are considered as general transcription regulators, pharmacological inhibition of BET (BETi) shows therapeutic activity in solid and hematological cancers. Their effects have been attributed to target genes whose expression would be “hypersensitive” to BETi. Therefore, the potential of BETi has been demonstrated in numerous preclinical cancer models, including > 20 clinical trials targeting hematological malignancies.
This project focuses on aggressive hematological cancers, called Diffuse Large B-Cell Lymphoma. The expression of oncogenic drivers has been shown to be related to BRD-dependent regulatory mechanisms. We are currently exploring impact of BETi on chromatin structure and gene expression profiles and evaluate their clinical potential in DLBCL, using model cell lines and primary DLBCL cells. This will allow a better characterization of BET molecular targets in B-Cell lymphoma and to rationalize their clinical use as single agents, or in combination therapies to improve clinical outcome of high-risk DLBCL.
BETi are known inhibitors of the expression of pro-inflammatory cytokines and chemokines in different cellular and preclinical models. A large variety of BETi are currently evaluated in clinical trials, but these molecules are associated with high toxicity. It has very recently been shown that BD2-selective molecules can be very active in limiting the expression of genes associated with the inflammatory response, while presenting a low degree of toxicity. In this context, we are evaluating anti-inflammatory effect BET inhibitors of different chemical scaffold and selectivity in immune cell systems, as well as in preclinical models of inflammation (in ovo and in a rat model of inflammation-induced hepatocellular carcinoma).
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The full list of publications can be found here.
Selection of our major papers