Italo Tempera, PhD
Assistant Professor, Fels Institute for Cancer Research and Molecular Biology
Assistant Professor, Microbiology and Immunology
Department of Microbiology and Immunology
Fels Institute for Cancer Research and Molecular Biology
Dr. Tempera’s research focuses on understanding the functional links between epigenetic domains, chromosome conformation and gene expression in the contest of cancer. Chromatin composition and organization represent an important element in regulating genome function. The analysis of chromosome conformation in yeast and Drosophila promoted the view of the genome as a set of physical domains that correlate with the epigenetic domains, suggesting a strong link between genome structure and genome function.
Our goal is to understand how the chromatin three-dimensional structure affects gene expression and how cancer can alter this process.
In particular we study the role of epigenetic modifications into the mechanism regulating Epstein-Barr virus (EBV) latency since EBV latent infection has been causally linked to a variety of B-cell and epithelial malignancies. EBV is able to establish a life-long latent infection persisting in memory B-lymphocytes as a chromatin-associated multicopy mini-chromosome adopting different gene expression programs that are referred to as latency types. These different latency types are epigenetically stable and correspond to different promoter utilization and depend on the host cell type and the nature of the tumor from which EBV is isolated. Hence, EBV represents a useful system for gaining a new insight into the basic understanding of the role of chromatin architecture in gene expression regulation in mammals. EBV studies are also instrumental in clarifying how cancer manipulates the epigenome for continued neoplastic growth and adaptability.
Chromatin architecture and its implication in gene expression. Recent studies have implicated CTCF in the regulation of high-order chromatin structure. In particular CTCF has been shown to promote and maintain the formation of intra- and inter-chromosomal interactions between different regions of DNA. Furthermore, genome-wide studies mapping CTCF binding profiles on human genome revealed that CTCF colocalized with Cohesin complex. We aim to clarify the importance of CTCF/Cohesin interaction for the chromatin architecture organization and gene expression by analyzing this association on EBV chromosome as well as on the human genome.
Alteration of the three-dimensional structure of chromatin in cancer. An interesting and novel direction that we want to further investigate is the possibility that viruses have evolved to interfere with the mechanisms that regulate chromatin architecture and exploit them to promote and support viral infection. Our research aims to address the question if EBV can manipulate the host chromatin structure to hijack host gene expression and its consequence on carcinogenic risk associated with EBV infection.
Correlation between metabolism and chromosome conformation. Another question that interests our lab is how gene expression responds to changes in the cellular environment. We speculate that, as post-translation modifications of histones are critical for chromatin functions, post-translation modifications of proteins involved in chromatin structure are important for remodeling the three-dimensional organization of the genome. CTCF is a critical factor for the chromatin architecture and it is also subject to different post-translation modifications that are very sensible to changes in the metabolic state of the cell. We intend to use EBV as model to reveal the function of post-translation modifications on CTCF. Our project aims to discover the molecular mechanism that translates fluctuations on metabolites into stable change in chromatin structure. This information will offer a new paradigm for understanding how the epigenome responds to environmental stimuli. By clarifying the effect of post-translation modifications on EBV viral expression we can also provide a new potential therapeutic approach for treating EBV infection and EBV-related malignancies.
NIH Pathway to Independence (PI) Award K99/R00, NIAID 2012-2015