Vrije Universiteit Brussel

 

EPIGEN: INTERPLAY BETWEEN EPIGENETIC MODIFICATION MECHANISMS AND MICRORNAs (GOA78: 2011-2015)

Epigenetic modification of gene expression by interference with histone acetylation (GOA48: 2006-2010)

Funding: Research Council of Vrije Universiteit Brussel (OZR-VUB)

GOA78 (2011-2015)

Jan. 2011:

This project brings together three well-established VUB research teams and welcomes a “VUB newcomer” on the Medical Campus in Jette. They all share a common and active interest in the role of epigenetic modifications in gene expression in health and disease. The ultimate goal of each of the four participating teams is to find novel ways to treat fibroproliferative diseases or cancer and to understand the complex interplay between several major key players.

Two of the four research teams, namely the FAFY team of Prof. Vera Rogiers and the LIVR group of Prof. Leo Van Grunsven had already formal collaborations in the field of molecular hepatology, resulting in common grant applications (FWO, OZR, EU, IAP), a number of collaborative articles in peer-reviewed international scientific journals, chapters in books and several presentations at international congresses and workshops. A previous GOA project had been established that focussed on the mechanisms and phenotypic consequences of histone acetylation/deacetylation in different cell types during normal and pathologic conditions. On the occasion of this previous project (GOA48), a collaboration was formalised between the FAFY and LIVR teams with the HEIM team of Prof. Karin Vanderkerken. This collaboration started at the moment that acetylation of histones emerged as a novel molecular target for therapeutic intervention in multiple myeloma and further underscores the important translational implications of the previous and current GOA (“EPIGEN”), with ramifications beyond hepatic proliferative disorders sensu stricto. Consequently, an intensive and productive collaboration between the three groups was established, resulting in a number of interesting scientific results published in international peer-reviewed journals (including high-impact journals: IF >10), collaborations as research partners within FP6 and FP7 European research projects, consolidation of national and international collaborations, all resulting in additional funding possibilities of the ongoing research at the VUB. The outcome of this previous GOA sets the stage for this renewed GOA project “EPIGEN” that continues to build upon the existing productive collaborations between the FAFY, LIVR and HEIM teams. It is timely now for a fourth group, headed by Prof. Thierry VandenDriessche (Laboratory of Gene Therapy and Regenerative Medicine - GTRM), to join and further strengthen this existing consortium. He was already a lecturer at the VUB Science Campus, but joined the Medical Campus in Jette in 2010. He has a long-standing track record in gene therapy and liver-directed gene transfer and has outstanding expertise in gene transfer technology based on non-viral and viral vectors. For his efforts towards the characterization of “Sleeping Beauty Transposase SB100X”, he and Prof. Marinee Chuah, who also joined the VUB Jette campus, and their collaborators received the 2009 Molecule of the Year Award. Moreover, an innovative technology was established based on associated viral vectors (AAV) vectors for which the 2009 Research in Excellence Award was granted. Obviously, these improved and novel technologies provide added value for the consortium and will be instrumental to help achieve the various scientific objectives. The GTRM team will not only play a key role by bringing innovative technologies on board, but also shares a genuine common scientific interest in addressing the objectives of “EPIGEN” with respect to the identification of the downstream targets of those microRNAs that are involved in hepatocellular carcinoma and the crosstalk/synergistic effects between the different epigenetic mechanisms.

The concept of the current “EPIGEN” GOA research proposal builds upon a number of important observations that were made in the context of our previous successful collaborative GOA48 project and that are partly derived from the current scientific literature. This project focussed specifically on the role of histone acetylation/deacetylation in health and disease. Recent insights revealed that the transcriptional activity of genes involved in the process of cell proliferation, differentiation and apoptosis, largely depends on the accessibility of specific chromatin regions for transcriptional regulators. This, in turn, depends on several distinct epigenetic regulatory mechanisms that include covalent histone modifications, particularly histone (de)acetylation that requires histone acetyltransferases (HAT) and deacetylases (HDAC). In addition, other epigenetic mechanisms based on DNA methylation via DNA methyltransferases (DNMT) seem to be very important [1]. The finding that deregulation or, in some cases, even complete loss of epigenetic control could result in aberrant cell phenotypes leading to diseased states such as cancer [2,3] served as a trailblazer for the discovery and subsequent development of epigenetically-based therapeutics such as HDAC-inhibitors (HDAC-I) and DNMT-inhibitors (DNMT-I) as cancer chemotherapeutics [2,4,5]. Despite the progress made in recent years in the field of epigenetics and disease, there are still many outstanding questions that need to be addressed, particularly in relation to the interaction between different epigenetic processes. ”EPIGEN” focuses on some of these key issues.

References:

1. Szyf M. Epigenetics, DNA methylation, and chromatin modifying drugs. Annu Rev
Pharmacol Toxicol. 2009; 49: 243-63.
2. McCabe MT, Brandes JC, Vertino PMy. Cancer DNA methylation: molecular
mechanisms and clinical implications. Clin Cancer Res. 2009 author; 15: 3927-37.
3. Miremadi A, Oestergaard MZ, Pharoah PDP, Caldas C. Cancer genetics of
epigenetic genes. Hum Mol Genet. 2007; 16: R28-49.
4. Issa JP, Kantarjian HMy. Targeting DNA methylation. Clin Cancer Res. 2009 author;
15: 3938-46.
5. Prince HM, Bishton MJ, Harrison SJy. Clinical studies of histone deacetylase
inhibitors. Clin Cancer Res. 2009 author; 15: 3958-69.

GOA48 (2006-2010)

Jan. 2006:

This project aims at bringing together three established research teams with an active interest in histone deacetylases, and their role in epigenetic modification of gene expression. The ultimate goal of each of the three participating teams is to find novel ways to treat fibroproliferative diseases and cancer.

This project aims at investigating the expression patterns and cell functions of HDACs in three normal cell types and their malignant or pathological counterparts. The team FAFY will study hepatocytes and hepatoma cells. Team CYTO will investigate stellate cells and their activated counterparts, the myofibroblast-like cells, which play a crucial role in development of hepatic fibrosis and cirrhosis. Team IMMI will examine myeloma cells in relationship with their bone marrow microenvironment (in vitro with different types of stromal cells; in vivo in a mouse model).

After characterisation of the cells for their specific HDAC-isoenzyme patterns under healthy and diseased conditions, the effects of specific HDAC-Is will be investigated. As read-outs to assess the effects of HDAC-I, molecular targets, critically involved in differentiation, transdifferentiation, transformation and proliferation will be examined. By using siRNA technology and by overexpressing specific HDACs, new information on the relative contribution of each HDAC to differentiation, transdifferentiation, transformation and proliferation will be obtained. Genes that are modulated by HDACs will be identified. The ultimate goal is (i) to modify the transcriptional activity of these genes in order to restore the homeostatic balance within the cells under investigation. In hepatocytes and hepatoma cells (FAFY), the following applications are envisageable : (i) maintenance of hepatocytes in culture in their differentiated phenotype with a view of using these cells in in vitro toxicological research, (ii) use of these hepatocytes in bio-artificial liver devices, (iii) use for cell transplantation in patients with terminal chronic liver disease, or with acute fulminant hepatitis, (iv) treatment of hepatocellular carcinomas. In stellate cells and myofibroblast-like cells (CYTO), the following applications could be possible : (i) maintenance of quiescent stellate cells in culture with a view to study the cells without spontaneous activation in culture, (ii) use of quiescent stellate cells in co-cultures of hepatocytes for experimental purposes and for use in bio-artificial liver devices, (iii) cell transplantation to repopulate the liver with quiescent stellate cells in the event stellate cells became activated by disease and/or have perished through apoptosis, (iv) use of HDAC-I as therapeutic agents to treat hepatic fibrosis and cirrhosis. In myeloma cells (IMMI), the paramount application resides in the use of HDAC-I as chemotherapeutic agents both as single or combination therapy.

 

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©2006 - 2012 • FAFY/IMMI/CYTO-LIVR • Vrije Universiteit Brussel • Faculteit Geneeskunde & Farmacie • Laarbeeklaan 103 • 1090 Jette • Tel.: 02/477.44.09 • jmlazou@vub.ac.be