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Elucidating the Role of Enhancer Methylation Variation in Cancer and Developing Enhancer-based Markers and Targets for Precision Medicine

Periodic Reporting for period 3 - ONCOmetENHANCERS (Elucidating the Role of Enhancer Methylation Variation in Cancer and Developing Enhancer-based Markers and Targets for Precision Medicine)

Reporting period: 2020-04-01 to 2021-09-30

Cancer tumors develop when a particular set of genes lose their normal performances. However, up to 80 percent of the patients suffering from common types of cancers, display less than the expected number of mutated genes, even when the genomes of the cancer cells are thoroughly sequenced. Therefore, according to the state of the art knowledge and technologies, these non-mutated cells should have never transformed into cancer. This paradoxical results signify a significant gap in the understanding of the processes leading to cancer development. Despite massive efforts over the last decade to decoded these so called ‘dark matter cancers’, their mechanism remains unexplained.

Cancer is a growing medical problem but its genetic and environmental bases are not clearly understood. In this regards, it belongs to a large group of common human diseases including metabolic, cardiovascular, autoimmune, psychiatric, and cancer illnesses which jointly affect hundreds of millions of people around the globe and their incidence and prevalence are rapidly growing. There is strong epidemiological evidence indicating complex genetic origins of these ailments along with a significant contribution from the environment, but the mechanisms underlying the vast majority of these diseases are still unknown. Our project aims at elucidating whether a particular research hypothesis, namely that variation in the epigenetic marks of gene regulatory components consist the missing mutational events that drive such complex diseases (Figure 1). If our hypothesis will be supported, it may provide a whole new understanding of the mechanism leading to the development of cancer and other diseases, and pave the way for the developing of improved tools for prediction, diagnosis, and treatment of the patients.

We suspect that a particular epigenetic mark called ‘DNA methylation’ tackles the normal communication between the environment and the genetic backgrounds of the patients, and by that cause the disease. The goal of our research is to determine if changes in the DNA methylation of particular components of the gene regulatory machinery, known as ‘cis-acting transcriptional enhancers’, may lead to malfunctioning of cancer driver genes, and by that form a significant part of the cellular mechanism underlie cancer. Therefore, we aim to map and explain the ways by which DNA methylation affect the regulatory circuits of key genes that drive cancer risk, initiation and development.
We are testing the above hypothesis in disease models. Utilizing novel genomic methodologies, which developed by our research group, we are systematically analyzing numerus potential enhancers across disease genomes and explored the effects of genetic and epigenetic mutations and variations at these regulatory elements. Key regulatory elements are then evaluated as biomarkers in actual tumors. Finally, genetic and epigenetic editing are applied to the most promising elements, in order to assess the possibility to reset their deleterious effects.
This project has important implications for the elucidation of the biological basis of cancer, including the comprehensive mapping of enhancer regulatory circuits contributing to cancer risk and development, and elucidating the ways by which they are affected by DNA sequence and methylation mutations. It will also constitute a pioneering exploration of the role of enhancer genetic and epigenetic mutations in ‘dark matter’ tumours lacking coding sequence mutations, thus helping to explain the origin of these tumours. Our study may transform the understanding of the mechanisms underlying disease predisposition and determine the regulatory circuits of key disease genes. We expect that these knowledge will ultimately serve to the development of effective markers for cancer risk, progression, and response for particular drugs and therapeutic protocols.