Laurence Arbibe is an INSERM director and a team leader at the INEM since 2014. After a residency in Intensive Care and Anesthesiology, a PhD on the biochemistry of phospholipase A2 (Institut Pasteur, L. Touqui team) and a postdoc in immunology at the Scripps Research Institute (R. Ulevitch lab), she obtained an academic position at the INSERM in P. Sansonetti Lab (Institut Pasteur). She dedicated her career to research and focused on signal transduction pathways driving the innate immune response (Arbibe et al, Nature Immunol, 2000). LA has provided pioneering data showing that a bacterial effector can target epigenetic information carried by host promoter chromatin and thereby takes over the control of a small number of immune genes (Arbibe et al, Nature Immunol 2007). Using bacterial proteins as probes to identify new mechanisms controlling the immune epigenome, the group has accumulated expertise in the field of chromatin regulation of innate immune gene expression. The research is now focused on the mechanisms by which bacterial stress imposed by commensal or pathogenic bacteria can shape chromatin information and eventually destabilize the epigenome and genome in the gut.
Tolerance is a host defense strategy by which a tissue can protect against immune–inflammatory stressors. With the constant assault of antigens and resident microbes, the gut is by essence submitted to environmental stresses. Control of inflammation and tissue repair capacity are equally central for gut tolerance. Epigenetics captures environmental stresses and translate them into specific gene expression patterns. However, little is known on the mechanisms by which gut tolerance is epigenetically regulated and how those mechanisms nurture inflammatory states seen in Inflammatory Bowel Diseases (IBD). Thus, identifying epigenetic regulators sustaining tolerance is mandatory for understanding IBD pathogenesis and should lead to novel therapeutic strategies.
Inflammation and genomic instability can be prevented under gnotobiotic conditions revealing a link between the commensal flora and intestinal diseases. Genotoxins are a family of microbial effectors in pathogenic and commensal bacteria. So far only three types of bacterial genotoxins are identified. To what extend these effectors act as virulence factors during in vivo infections is unclear. Moreover, whether the carcinogenic effect shown in vitro is relevant in vivo during chronic intoxication remains uncertain. Thus, there is a need for identification of new genotoxins and for development of models exploring their implication in infectious diseases and tumorigenesis.
Our studies spotlighted the epigenetic regulator HP1γ as a sensor of acute inflammation in the colon. HP1 is a chromatin-associated transcriptional silencer enriched in heterochromatin, while also silencing inducible genes. HP1 also interacts with Argonautes proteins suggesting functions in small RNA-mediated gene regulation. We showed that HP1 acts as a repressor of inflammatory chemokines while promoting genes involved in stem cell renewal and tissue repair. We will:
- decrypt the functions of HP1 in small RNA-mediated gene regulation
- unravel its functions in anti-inflammation and intestinal regeneration
- develop innovative approaches reinforcing HP1 bioactivity in the intestine
We have shown that some enteropathogens such as Shigella flexneri can inactivate the tumor suppressor gene p53 in the context of genotoxic stress to preserve the life of its own epithelial niche. This example illustrates a mechanism by which bacteria can potentially induce genomic instability. In this context, the identification of bacterial traits that can directly alter the host genome is crucial to understanding how some bacterial species promote cancer.
Our second line of research aims:
- to the identification of new bacterial genotoxins released by both commensal and pathogenic enterobacteria.
- to modelize the long-term impact of this genotoxic stress on the stability of the host genome and epigenome.