Skip to 0 minutes and 14 secondsEpigenetic information is heritable information that is not directly coded in the DNA sequence. Epigenetic information is encoded in various different layers of chromatin structure and folding. There are many different layers of this information, including DNA methylation, histone modifications, histone variants, chromatin-binding proteins, nucleosome positioning, and non-coding RNAs. And all these different layers of information can modulate DNA functions, including gene expression, DNA replication, and DNA repair. We know that altered epigenetics contributes to cancer development and progression. The best example of this is probably DNA methylation. In a normal genome, DNA methylation occurs almost exclusively at CpG dinucleotides, that's the filled circles on this slide. But we know that these CpG dinucleotides are unevenly distributed across the genome.
Skip to 1 minute and 11 secondsFor example, repetitive regions of the genome, which make up about over 50% of the genome- these regions tend to be methylated and this contributes to silencing of these regions and also suppression of recombination, which can promote genome instability. On the other hand, other regions of the genome, such a CpG islands within gene promoters- these regions tend to be unmethylated and this is permissive for gene expression, including expression of key tumour suppressor genes, such as P16 and VHL. In a cancer genome, we know that repetitive regions of the genome become unmethylated and this promotes genome recombination and instability, whereas CpG islands can become methylated and this promotes silencing of those key tumour suppressor genes.
Skip to 1 minute and 59 secondsAside from DNA methylation, there are other epigenetic alterations also found in cancer. These include changes in the levels of specific histone modifications, such as methylation and acetylation of specific residues on particular histones and also altered expression of histone-modifying enzymes, such as the Polycomb complex and EZH2. There are also translocation-based fusions of histone-modifying enzymes, such as MLL in leukaemia, and mutations within key chromatin regulatory complexes, such as the SWI/SNF complex. For example, the SNF5 protein, a member of the SWI/SNF complex, is deleted in virtually all childhood malignant rhabdoid tumours and mice engineered to contain mutations in this gene are highly predisposed to cancer. Our understanding of epigenetics can be exploited in the management of cancer.
Skip to 2 minutes and 57 secondsFor example, altered epigenetics can be used in early detection, prognosis, and prediction of cancer response to therapies and altered epigenetics is a target of cancer therapies itself. For example, azacitidine is used to reverse the altered DNA methylation profile in acute myeloid leukaemia and histone deacetylase inhibitors are approved for use in cutaneous T-cell lymphomas. And there are a number of other small molecule inhibitors of epigenetics, which are currently being developed for treatment of cancer. To recap, epigenetic information is heritable information that is not directly coded in the DNA sequence. Epigenetic alterations contribute to development and to progression of cancer and altered epigenetics can be exploited in the early detection and prognosis of cancer.
Skip to 3 minutes and 47 secondsAnd altered epigenetics is, itself, a target of emerging cancer therapies.
Epigenetics and cancer
Professor Peter Adams describes how epigenetics is becoming one of the most exciting areas in cancer research.
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