Silvia Monticelli, Group Leader
The research topic of our group concerns the study of transcriptional and post-transcriptional mechanisms of regulation of gene expression in cells of the immune system. The general goal is to extend our knowledge of the mechanisms that regulate immune cell differentiation, proliferation and functions and to disclose networks of interaction between epigenetic modifications, transcription factors, microRNAs (miRNAs) and their targets. Epigenetic modifications include all those sustained changes in transcription programs and cell physiology that do not involve irreversible genetic changes in the DNA. The methylation of the genomic DNA represents an important epigenetic mechanism of regulation of gene expression. The process of DNA methylation must be carefully regulated for example during embryonic development, but it is also important in the immune response to pathogenic or noxious agents. For instance, we recently found that the absence of an enzyme responsible for DNA methylation leads to the hyper-activation of cells of the immune system, which in turn can lead to tissue damage and disease (Leoni C. et al. PNAS 2017). We also determined the dynamics of these modifications in the genomic DNA, and addressed whether DNA demethylation processes linked to T cell activation occur primarily through active or passive processes. We found that activation of human T lymphocytes led to a global reduction of genomic modifications, which was crucial for the proper acquisition of T cell effector functions and that was primarily linked to a proliferation-dependent process of dilution of DNA modifications (Vincenzetti L. et al. European Journal of Immunology 2019; Monticelli S. Trends in Biochemical Sciences 2019).
Other regulatory molecular mechanisms are linked to the cellular expression of miRNAs. MiRNAs are small non-coding RNAs that have emerged as key post-transcriptional regulators in a wide variety of organisms and biological processes, by acting through the modulation of levels of protein expression. Because each miRNA can regulate expression of a distinct set of genes, miRNA expression can shape the repertoire of proteins that are expressed during development, differentiation or disease. Accordingly, genetic ablation of the miRNA machinery, as well as loss or dysregulation of certain individual miRNAs, severely compromises immune development and might lead to disease. In our lab we are studying the role of DNA methylation, transcription factors and miRNAs in the differentiation and function of cells of the immune system, with a special focus on T lymphocytes and mast cells.