Long Range Epigenetic Silencing in Cancer

表观遗传学是一个描述基因表达改变而不改变DNA序列的术语，其过程涉及DNA的化学变化，如DNA甲基化和特定蛋白质的结合。现在已经确定表观遗传学在癌症的发展中起着重要作用，但仍有一个重要的问题有待解决，即表观遗传变化的机制。我们最近的工作揭示了癌症中表观遗传基因沉默的新机制，它可以影响大的染色体区域。我们发现，通过改变癌细胞中与DNA结合的蛋白质模式，甲基化和非甲基化基因都可以沉默。我们的数据还表明，这种沉默可以通过表观遗传药物逆转。这一发现代表了表观遗传控制的新范式，不仅对癌症诊断而且对癌症表观遗传治疗具有重大意义。在这项资助中，我们建议进一步表征和理解涉及长期表观遗传沉默的机制，并确定其在癌症中的患病率。这一建议将揭示癌症中长期表观遗传基因沉默的潜在过程，并将为癌症检测、预后和治疗提供潜在的新靶点。

Epigenetics is a term that describes modification of gene expression without a change to the DNA sequence, through processes that involve chemical changes to the DNA such as DNA methylation and binding of specific proteins. It is now well established that epigenetics plays a major role in cancer development, but one of the important questions still to be resolved is the mechanism that is responsible for epigenetic changes. Our recent work has uncovered a new mechanism of epigenetic gene silencing in cancer that can effect large chromosomal regions. We have found that both methylated and unmethylated genes can be silenced by changes to the pattern of proteins that bind to the DNA in a cancer cell. Our data also indicates that this silencing can be reversed using epigenetic drugs. This finding represents a new paradigm in epigenetic control and has major implications not only on cancer diagnostics but also cancer epigenetic therapy. In this grant we propose to further characterise and understand the mechanism involved in long range epigenetic silencing and to determine its prevalence in cancer. This proposal will shed light onto the process underlying long range epigenetic gene silencing in cancer and will provide potential novel targets for cancer detection, prognosis and therapy.