Abstract
The meeting ‘Cell signal-omics 2011: integrated cellular pathology – systems biology of human disease‘ held on 26–28 January 2011 in Luxembourg, was organized by Recherches Scientifiques Luxembourg (RSL) under the auspices of the European Research Institute for Integrated Cellular Pathology. The meeting took place in the New Conference Center Kirchberg with the support of the Fonds National de la Recherche (FNR, Luxembourg). This event gathered 48 renowned international speakers and more than 350 participants and 18 trade exhibitors.
The term epigenetics is allied with the appearance of changes in gene expression (i.e. genome function) leading to phenotypic modifications caused by mechanisms other than changes supported in the primary DNA sequence. Epigenetics encompasses three main interconnected mechanisms of regulation: DNA methylation, histone modifications and RNAi (i.e., ncRNA), which together play a fundamental role in the interpretation of genetic information. Mounting evidence has suggested that in addition to genetic aberrations, epigenetic processes play a major role in disease development, especially in cancer. In this respect, environmental factors and dietary behaviors (e.g., alcohol, tobacco, radiation, environmental pollutants and a high-calorie diet) may greatly affect epigenetic mechanisms and therefore play a critical role in the context of tumor initiation for most cancers. In the past few years, the scientific community has consistently expressed an increasing interest for investigating epigenetic alterations associated with carcinogenesis and how these associations may be used to fight cancer.
For this year‘s episode, the meeting ‘Cell signal-omics 2011‘ held in Luxembourg, offered three days of interesting and inspiring talks and posters to participants. Although this meeting was not directly dedicated to epigenetics, we were fortunate enough to hear some of the latest research in epigenetics based and related research topics from many leading scientists. These topics covered all facets of the epigenetic field regarding their role in various processes in health and disease states from a fundamental to a more applied aspect.
New insights into epigenetic regulation of gene expression
Attendees were presented with an overview of the epigenetic field by the presentation of Luciano Di Croce (Barcelona, Spain) who spoke on the elucidation of novel mechanisms of transcriptional control related to polycomb-mediated transcriptional silencing of tumor suppressor genes (TSGs). Di Croce‘s group demonstrated that the transcription factor zuotin-related factor 1 (ZRF1) is specifically recruited to the monoubiquinated histone H2A through a ubiquitin-interacting domain that is located in the evolutionarily conserved zuotin domain. ZRF1 competes with the polycomb repressive complex 1 (PRC1) protein, Ring1B, and promotes, as demonstrated by genome-wide analysis, the transcription of a large set of polycomb-targeted genes such as the Homeobox (HoX) family. Furthermore, using a model of mouse embryonic stem cells (mESCs) induced to differentiate, Di Croce‘s team observed that ZRF1 is not involved in cell proliferation, but is required for the proper differentiation of mESCs. These data suggest that ZRF1 plays a key role in cell fate decisions and may have important role in cancer.
▪ Clinical relevance of DNA methylation
In the first part of his talk, François Fuks (Free University of Brussels, Belgium), reviewed how DNA methylation is involved in highly regulated physiological processes as well as in disease development, such as carcinogenesis, which is commonly associated with TSG silencing. Regarding carcinogenesis, the critical point appears to be how DNA methylation patterns are established and maintained, which seems to correspond to a nonrandom distribution targeting specific genes. To emphasize this critical aspect, Fuks‘ group has demonstrated that beside the aberrant expression and recruitment of DNA methyltransferases (DNMTs) frequently observed in tumors, their activities and chromatin localization is regulated by post-translational modifications leading to the modulation of DNA methylation at specific sequences. Indeed, phosphorylation of DNMT3a by casein kinase II reduces its activity and decreases global genomic DNA methylation. In the second part of his talk, Fuks presented a more comprehensive picture of breast cancer biology by attempting to answer the question of what is the contribution of the DNA methylome to the complexity of this disease? Using patient samples, his group acquired methylomic data with the infinium methylation assay (Illumina) and transcriptomic data. Thereby, identifying new epigenetic signatures that could be used as biomarkers in breast cancer. A similar study was presented in a poster by Sriraksa‘s group in which they addressed genome-wide DNA methylation changes in cholangiocarcinoma (CCA) using HumanMethylation27 BeadChips (Infinium). They demonstrated an enrichment of hypermethylated CpG sites associated with HoX genes as well as PRC2, EED, SUZ12 and H3K27 targets associated with hypomethylation of NOS and OCT4 targets in CCA. Epigenetic aberrations of these genes might provide new biomarkers or therapeutic targets for CCA. In addition, the poster from Brieger‘s group revealed the relevance of DNA hypermethylation in radiation resistance and suggested that the reactivation of relevant TSGs by DNA demethylating agents might be beneficial in overcoming irradiation resistance. Indeed, this group demonstrated that 5-azacytidin-induced DNA demethyltion and re-expression of hypermethylated in cancer (HIC1) TSG, which is frequently found hypermethylated in head and neck squamous cell carcinoma (HNSCC), results in an impaired migration potential, increased apoptosis rate and decreased rate of cell survival leading to an increased radiosensitivity of HNSCC. These types of studies are paving the way for future investigations on how DNA methylation contributes to carcinogenesis and how methylomic data can be used for the development of new anticancer therapies.
▪ Differential effects of HDAC inhibitors
Besides DNA hypo/demethylating agents, numerous promising molecules exhibiting histone deacetylase (HDAC) inhibitory activities are under investigation for epigenetic anticancer therapies. Michael Bots (Peter MacCallum Cancer Centre, Melbourne, Australia) examined the anti-tumor activity of HDAC inhibitors (HDACi) in an interesting mouse model of acute myeloid leukemia (AML) driven by the fusion protein AML1/ETO9a. This fusion protein is frequently observed in AML, where it mediates the aberrant recruitment of HDAC-containing repressor complexes participating to leukemogenesis. Using this model, Dr Bots‘ group gained important insights regarding the mechanism of HDACis-induced anti-tumor response and demonstrated that HDACi such as panobinostat are a rational choice for the treatment of human AML driven by the expression of AML1/ETO. Data indicates that this potent anticancer activity could be related to the induction of differentiation rather than the induction of cell death. The differential and tissue-specific effects commonly observed with HDACis are probably dependent on tumor-specific HDAC isoform expression profiles. Interestingly, in a poster presented by Park‘s group demonstrated in a poster that some isoforms (e.g., HDAC 1, 6 and 8) are critically involved in invasion and MMP-9 expression in breast cancer. Thus, HDAC expression profiles could be used as potential biomarkers for tumorigenesis and in developing more targeted and personalized therapies. In a poster, Chateauvieux‘s group. demonstrated using transcriptomic analyses and differentiation-inducible leukemia models and hematopoietic stem/progenitor CD34+ cells combine to profiling and cell phenotyping approaches, that another HDACi, valproic acid, perturbs hematopoietic homeostasis in the myeloid compartment by inhibiting erythroid differentiation and promoting the myelomonocytic pathway. This alteration may lead to a potential failure of erythropoiesis in patients with cancer or chronic inflammatory diseases with a well-described propensity to anemia.
▪ Epigenetics controls differentiation & autophagy processes
We followed up on the subject of differentiation with Roberto Gambari‘s (Ferrara University, Italy) presentation on the control of this process by miRNAs. His talk was related to the mTOR pathway, which might be associated with erythroid differentiation, as the mTOR inhibitor rapamycin is able to induce erythroid differentiation in a cell model. The same group presented a poster including promising data concerning the use of peptide nucleic acids (PNAs), normally used in antisense therapies, to modulate the biological activity of miRNAs. These results could open up new therapeutic opportunities in the control of diseases associated with miRNA alterations.
Guido Kroemer (INSERM, Villejuif, France) examined the controversial role of autophagy in cell death. Initially, autophagy was regarded as a process of cellular self-destruction leading to cell death. However, Kroemer‘s group demonstrated that autophagy is mostly a cytoprotective event. Interestingly, they found that autophagy-inducing pharmacological agents such as the sirtuin activator, resveratrol, and the histone acetyltransferase (HAT) inhibitor spermidine, enhanced life span in an autophagy-dependent fashion. Similarly, overexpression of the NAD+-dependent class III HDAC sirtuin 1 induces autophagy and increases life span. Accordingly, by performing quantitative acetylproteomic analysis using stable-isotope labeling by amino acids in cell culture (SILAC) technology, they revealed the existence of acetyl proteome modifications associated to pharmacologically induced autophagy. These results are of particular interest regarding the pharmacology of anticancer therapies.
Significant advances have been made in the elucidation of epigenetic processes, as well as in the translation of this knowledge to the clinic in the form of prognostic biomarkers and targeted therapies with epigenetic drugs. Nevertheless, to unravel disease complexity, the field of the cancer epigenome is evolving from a traditional single-gene analysis approach to a more global approach. Accordingly, new technologies such as next-generation sequencing and omics are needed to support large cohort studies. In addition, an improved interplay between the various scientific fields is mandatory to integrate increasing datasets and to provide a more comprehensive global picture of specific diseases. Nonetheless, regardless of technological and financial limits, epigenetic research searching for biomarkers in order to understand, predict and treat of cancer has substantial potential for public health benefits.
Forthcoming meetings
Redox regulation – Natural compounds as regulators of inflammation signaling (RedCat satellite meeting to Natural Compounds 2012): 23–25 January 2012.
Natural compounds 2012 – Regulators of cell signaling pathways and novel therapeutic tools: 26–28 January 2012.
Acknowledgements
The authors would like to thank “Recherches Scientifiques Luxembourg ASBL” who organized the meeting. The Fonds National de la Recherche, Luxembourg, Kuwait Petroleum SA (Luxembourg), The Fondation de Recherche “Cancer et Sang” (Luxembourg), Computer Home (Luxembourg) and Canon (Luxembourg) are thanked for additional support. Finally all members of the organization team are thanked for their great organization.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.