© Francesca Luca 2012

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Our Research

Functional Characterization of the Genetic and Environmental Determinants of Complex Traits

Functional variants associated with complex traits tend to fall in non-coding regions and affect regulatory mechanisms that are not yet well characterized. Furthermore, it is generally difficult to determine in which tissues and conditions they may have a functional impact. This is because the effect of a genetic variant on a molecular pathway, and ultimately on the individual’s phenotype, may be modulated by “environmental” factors. We denominate such variants “gene-expression environment-specific quantitative trait nucleotides” GxE-QTNs. Achieving a better understanding of the mechanisms underlying GxE-QTNs is a critical step in understanding the link between genotype and complex phenotype. To identify and characterize GxE-QTNs, we are currently analyzing allele specific gene expression in a panel of 5 relevant tissues (e.g. the vascular endothelium for cardiovascular diseases) under 50 controlled environmental conditions (e.g. glucocorticoids treatment, as a proxy for stress exposure).

Functional Genomics Characterization of Genetic Variation Associated with Cardiovascular Disease

The endothelium is crucial to the modulation of vessel tone and to the control of platelet adhesion and aggregation, two key factors in the initiation and development of atherosclerosis.  Human umbilical vein endothelial cells (HUVECs) are primary cells that have played a major role as a model system for the study of vascular endothelial cell function. Glucocorticoids (GCs) are steroid hormones that mediate the response to stress and are widely used as pharmacological agents. High cortisol levels (the endogenous GC) represent a risk factor for cardiovascular disease (CVD).  GC action is largely mediated by the glucocorticoid receptor (GR), which acts as a transcription factor to regulate gene expression. In vascular endothelial cells, GR activation prevents angiogenesis, a key process in the recovery from infarction.

In the lab we are using a novel approach to analyze and functionally characterize CVD genetic risk variants modulated by stress exposure. Our preliminary studies show that GCs induce a transcriptional response in HUVECs. We are now combining ChIP-seq for the GR with ATAC-seq and RNA-seq on HUVECs to identify allele specific GR binding and expression in response to GC and functionally annotate GC dependent CVD risk variants. Our findings will represent the first comprehensive catalog of genetic variants that interact with stress exposure in determining an individual’s risk for CVD. 

The regulatory landscape and genetic determinants of host-microbiome interactions

Characterization of the human gut microbiome is becoming increasingly important as a means of understanding inter-individual differences in health status and digestive processes. Specific microbiome profiles have been associated with variation in diet composition, but also with physiological and disease status in the host. Despite these promising examples, the cause-effect relationships between the host and the microbiome are still unclear. Recent studies have shown that host genetic variation is an important factor shaping the composition of the microbiome. In addition, functional genomic studies have investigated the transcriptional response and chromatin landscape changes induced by the microbiome in mice. However, we still know very little about the molecular mechanisms controlling host-microbiome interaction, and how variation in host genetic background and gene regulation affects this interaction, especially in humans.

We have recently developed an approach that uses a human cellular model (primary human colonic epithelial cells) and a functional genomics approach to characterize the host regulatory changes determined by interaction with the microbiome in a manner that will elucidate the cause-effect relationships. This approach is effective in identifying host genetic variants that modulate the response to the microbiome, through allele-specific expression (ASE). We have also shown that it can be used to dissect the expression changes induced by the microbiome in genes associated with human complex traits, including colorectal cancer and obesity. We are now applying this approach to study the functional genomics of host-microbiome relationships across different human phenotypes and primate species.