Epigenetics demonstration

WP 2 - Epigenetic-proteomic discovery of biomarkers of societal and environmental impacts in patients with NAFLD
The aggregation of risk factors associated with unhealthy societal and environmental contexts represents a cluster of exposures that modify the course of disease trajectories in a specific way.
To test this hypothesis, we will develop a research pipeline combining epigenetics and proteomics to identify circulating (blood) biomarkers in patients with Non-Alcoholic Fatty Liver Disease (NAFLD), a frequent component of multimorbid chronic diseases trajectories associated with intermitted hypoxia, overweight, physical inactivity and overall poor socio-economic contexts. Epigenetics pertain to the identification of chemical modifications on DNA and histones that regulate the dynamics and accessibility of chromatin.

These modifications depend upon the availability of intracellular pools of donor molecules such as methyl and acetyl donors, themselves tightly regulated by the bioenergetics metabolism. The mapping of epigenetic modifications may thus provide a sensitive readout of the impact of complex exposures on gene expression patterns. We will analyze liver biopsies from patients with NAFLD using “omics” approaches to map genes deregulated by epigenetic mechanisms in relation with societal and environmental contexts (integrating methylome and ChipSeq data with transcriptome). Next, candidate genes will be screened by a bioinformatics algorithm to inform on the nature and stability of protein products potentially secreted in the extracellular medium. These candidates will then be detected and quantified in the plasma of patients using a highly specific quantitative proteomics methodology. Finally, robust candidates will be systematically quantified in plasma samples from a large series of NAFLD patients and controls with information on spatial environment, exposure to pollution and socio-economic status. Integrating these data will generate novel information on mechanisms modulating NAFLD in relation with societal and environmental contexts and will identify biomarkers for measuring these effects.


Objectives

  • Annotating environmental and societal exposures of NAFLD patients and integrating them with individual and clinical parameters
  • Omics database of epigenome and transcriptome in NAFLD
  • Candidate plasma biomarkers
  • Simple biomarker assays applicable to large cohorts
  • Integration of Omics, individual, clinical, environmental and societal data in a systemic approach to describe their impact on the progression of NAFLD

Tasks

  • Documenting environmental/social information in a cohort of patients with progressive NAFLD
  • Genome-wide mapping of histone acetylation in relation with gene expression patterns
  • Proteomics translation to plasma-based biomarkers
  • Systematic analysis of biomarkers in a large cohort overweight/OSA patients
     

Leaders

  • Pierre Hainaut (IAB)
  • Virginie Brun (BIG)
  • Saadi Khochbin (IAB)
     

Partners

Initials Full Name
HP2 Hypoxie : Physiopathologie Cardiovasculaire et Respiratoire
LIG Laboratoire d’Informatique de Grenoble
IAB Institut pour l'Avancée des Biosciences
BGE Biologie à Grande Échelle
CHUGA Centre Hospitalo-Universitaire Grenoble Alpes


Published on April 30, 2018