Investigation of novel mechanisms of miRNA-dependent gene expression control

We recently demonstrated a direct role for let-7b/c to regulate KSRP expression, which in turn controls let-7 processing in competition with Lin28, and the turnover rate of the pituitary terminal differentiation marker aGSU leading to an upregulation of its expression. These findings defined a hierarchical mechanism by which during organogenesis the upregulation of specific miRNAs controls the expression of KSRP and the subsequence fine-tuning of the processing for selected miRNAs and decay rate of mRNAs encoding for differentiation markers.Currently, we are using proteomic and high-throughput sequencing approaches coupled with bioinformatics to study the protein/miRNA code to orchestrate the post- transcriptional programme(s) of regulated gene expression.


Investigation of the function of RNY-derived small RNAs in macrophage foam cells

Using deep sequencing, we demonstrated that the ~110 nucleotides (nt) long Ro-associated Y-RNAs (or RNYs), are processed into small ~30 nt sequences in apoptotic and lipid-laden macrophages. The expression of RNY–derived small RNAs (referred as s-RNYs) is significantly upregulated in serum of 263 patients with coronary artery disease compared to 514 controls. These findings were patented (n° WO2015055857 A1) and published in BMC Medicine in 2015. As follow up of this primary discovery, we have investigated the role of s-RNYs in macrophages. Loss and gain of function experiments show that s-RNYs activate both caspase-dependent cell death and NF-kappaB-dependent inflammation in macrophages. We found that s-RNYs activate Toll-like receptor 7 (TLR7).These data indicate that s-RNYs are intrinsic components of the machinery regulating lipid-laden macrophage phenotype and function as mediator of inflammation/apoptosis. We are currently investigating the protein complex associated to s-RNYs to study the direct and specific mechanism(s) of s-RNYs inflammation and cell death in macrophages.

Role of small RNAs in epigenetic inheritance of metabolic pathologies (conducted by Dr. Valerie Grandjean)

Recently, we and others extended the concept of « epigenetic inheritance » to RNA-mediated paternal heredity. We found that mice derived from embryos microinjected with HFD-sperm or -testis RNA, developed metabolic pathologies, such as obesity and diabetes. Interestingly, miR-19b alone was sufficient to mediate the paternal diet-induced heredity, as we demonstrated by microinjecting it into naive one-cell embryo (Figure). To gain insight into the mechanism of epigenetic inheritance, we are now exploring the following specific aims: i) To identify the epigenetic signal accumulated in sperm upon continuous paternal HFD feeding for multiple generations. ii) To perform a parallel between mice and human, a deep-sequencing analysis of the RNA transcriptome of normal and obese men will be performed.