Diego Pasini
Diego Pasini
affiliation: IEO - Istituto Europeo di Oncologia
research area(s): Cancer Biology, Stem Cells And Regenerative Medicine
Course: Molecular Medicine: Molecular Oncology and Computational Biology
University/Istitution: Università di Milano, UNIMI-SEMM
Epigenetic mechanisms in stem cell differentiation and oncogenesis

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.

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.

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.

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.
1)Pasini, D., Cloos, P.A.C., Walfridsson, J., Olsson, L., Bukowski, J.P., Johansen, J.V., Bak, M., Tommerup, N., Rappsilber. J., Helin, K. 2010.
JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells.
Nature. Jan 14. [Epub ahead of print]
2)Leeb, M., Pasini, D., Novatchkova, N., Jaritz, M., Helin, K., and Wutz, A. 2010.
Polycomb complexes act redundantly to repress genomic repeats and genes.
Genes Dev. 24 265-276
3)Pasini, D., Bracken, A.P., Agger K., Christensen J., Cloos P.A.C., Hansen K.H., and Helin, K. 2008.
Regulation of stem cell differentiation by histone methyltransferases and demethylases.
Cold Spring Harb Symp Quant Biol. [Epub ahead of print].
4)Hansen, K.H., Bracken, A.P., Pasini, D., Dietrich, N., Monrad, A., and Helin, K. 2008.
A mechanism for transmission of the H3K27me3 epigenetic mark during DNA replication.
Nature Cell Biology. 10(11):1291-300.
5)Riising, E.M., Boggio, R., Chiocca, S., Helin, K., and Pasini, D. 2008.
The Polycomb Repressive Complex 2 is target by SUMO modifications in vivo.
PLoS ONE. 16:3(7):e2704
6)Lindroth, A.M., Park, J.Y., McLean, C.M.D., G.A., Bernstein, J.M., Herman, H.P., Pasini, D., Miró, X., Donohoe, M.E., Lee, J.T.H., K., and Soloway, P.D. 2008.
Antagonism between DNA and H3K27 methylation at the imprinted Rasgrf1 locus.
PloS Genetics 4(8):e1000145.
7)Herranz, N., Pasini, D., Diaz, V.M., Franci, C., Gutierrez, A., Dave, N., Escriva, M., Hernandez-Munoz, I., Di Croce, L., Helin, K., Garcia de Herreros, A., and Peiro, S. 2008.
Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor.
Mol Cell Biol. 28(15):4772-81.
8)Pasini, D., Hansen, K.H., Christensen, J., Agger, K., Cloos, P.A., and Helin, K. 2008.
Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-Repressive Complex 2.
Genes Dev 22(10): 1345-1355.
9)Agger, K., Cloos, P.A.C., Christensen, J., Pasini, D, Rose, S., Rappsilber, J., Issaeva, I., Canaani, E., Salcini, A.E., and Helin, K. 2007.
UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.
Nature 449(7163):731-4.
10)Villa, R., Pasini, D., Gutierrez, A., Morey, L., Occhionorelli, M., Viré, E., Nomdedeu, J.F., Jenuwein, T., Pelicci, P.G., Minucci, S., Fuks, F., Helin, K., and Di Croce, L. 2007.
Role of the Polycomb repressive complex 2 in acute promyelocytic leukemia.
Cancer Cell 11(6):513-25.
11)Pasini, D., Bracken, A.P., Hansen, J.B., Capillo, M., and Helin, K. 2007.
The Polycomb Group protein Suz12 is required for Embryonic Stem Cell differentiation.
Mol Cell Biol 27(10):3769-79
12)Christensen, J., Agger, K., Cloos, P.A., Pasini, D., Rose, S., Sennels, L., Rappsilber, J., Hansen, K.H., Salcini, A.E., and Helin, K. 2007.
RBP2 Belongs to a Family of Demethylases, Specific for Tri-and Dimethylated Lysine 4 on Histone 3.
Cell 128(6): 1063-1076.
13)Bracken, A.P., Kleine-Kohlbrecher, D., Dietrich, N., Pasini, D., Gargiulo, G., Beekman, C., Theilgaard-Monch, K., Minucci, S., Porse, B.T., Marine, J.C., Hansen, K.H., and Helin, K. 2007.
The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells.
Genes Dev 21(5): 525-530.
14)Bracken, A.P., Dietrich, N., Pasini, D., Hansen, K.H., and Helin, K. 2006.
Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions.
Genes Dev 20(9): 1123-1136.
15)Lazzerini Denchi, E., Attwooll, C., Pasini, D., and Helin, K. 2005.
Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland.
Mol Cell Biol 25(7): 2660-2672.
16)Pasini, D., Bracken, A.P., Jensen, M.R., Lazzerini Denchi, E., and Helin, K. 2004.
Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity.
Embo J 23(20): 4061-4071.
17)Pasini, D., Bracken, A.P., and Helin, K. 2004.
Polycomb group proteins in cell cycle progression and cancer.
Cell Cycle 3(4): 396-400
Project Title:
Identification of genes involved in transcriptional repression by PcG proteins