Epigenetic mechanisms in stem cell differentiation and oncogenesis
Diego Pasini, PhD
Department of Experimental Oncology,
European Institute of Oncology,
c/o IFOM-IEO Campus
Via Adamello, 16 - 20139 Milan, Italy
T office: +39 02 94375139
Italian Association for Cancer Research (AIRC)-Start-Up Grant
Italian Ministry of Health (Ministero della Salute)-Young Investigators
Epigenetic regulation of transcription is controlled by different enzymatic activities and several co-factors, which are necessary to "place, read and remove" specific modifications on DNA and histone proteins. Cell fate determination is the basis of organism development. Proper cellular differentiation continuously takes place also in adult organisms and is an essential process that sustains tissues and organs throughout the entire life.
Fig1: Model of PcG mediated transcriptional repression [+zoom]
The goal of our laboratory is to study the transcriptional mechanisms that regulate cell fate during development and differentiation. Many human diseases are the consequence of loss of cellular identity. Cancer is probably the best example since in all tumors, independently of their origin, cells lose their normal identity and acquire features that lead to aberrant growth and or to differentiation defects. For these reasons we also aim to translate our knowledge in the prospective of a pathological situation in order to understand how diseases like cancer can form maintain and develop. Consistent with this, the activity of several "chromatin modifiers" is frequently deregulated in human cancer. More specifically, the lab is interested in studying these mechanisms by focusing on Polycomb Group (PcG) proteins, Histone modifications and DNA binding transcription factors.
PcG proteins are epigenetic factors essential for development that execute their repressive function in 2 distinct multiprotein complexes named Polycomb Repressive Complex (PRC) 1 and 2. PRC1 and PRC2 repress transcription respectively by Ubiquitylating Histone H2A lysine (K) 119 and by tri-methylating (me3) Histone H3K27. Deregulation of both PRC1 and PRC2 activities is a common feature of human tumors strongly suggesting that PcG proteins play an active role in cancer formation. Several aspects of PcG mediated transcriptional regulation are poorly understood. This includes the upstream signaling and the factors that regulate PcG activities, the molecular mechanisms by which H3K27me3 and H2AUbq lead to transcriptional silencing and the mechanisms that specify PcG recruitment to target genes during development.
Fig2: Effects of loss of PRC2 enzymatic activity in embryionic development and ES cell differentiation [+zoom]
Moreover, the role of PcG proteins in cancer formation is also poorly characterized. For example, the PRC2 complex is an attractive target for cancer therapy but the requirement of PcG activities and the mechanisms by which PcGs over-expression contributes to cancer formation are not understood. In addition, the characterization of the role that different Histone modifications have in the regulation of transcription is also an important open question. It is becoming clear that transcriptional control is achieved trough combinations of several different Histone modifications but these mechanisms are not well characterized particularly in the context of cellular differentiation and neoplastic transformation.
Fig3: Overexpression and amplification of the catalitic subunit of the PRC2 complex EZH2 in human tumors [+zoom]
With the use of biochemical, molecular and genetic approaches our lab aim to address some of these questions with the following lines of investigation:
- Mechanisms of PcG mediated transcriptional silencing.
- Role of Histone post-translational modifications in transcriptional control.
- Role of DNA binding transcription factors in stem cell differentiation and cancer.