Role of non-coding RNA in ageing-dependent epigenetic changes in blood cancer

老龄化是癌症的一个主要风险因素，对血液病癌症的疾病进展和治疗结果有重大影响。虽然衰老有遗传成分，但似乎这种风险的大部分是由表观遗传机制2调节的。癌症和衰老有一些表观遗传学特征，包括异常的组蛋白修饰和DNA甲基化3。我们预测，表观遗传标记中与年龄相关的变化是由催化这些修饰的酶的行为变化引起的。之前实验室的工作研究了CCDC26，这是一种从一个富含癌症相关突变的区域转录而来的长非编码RNA 4。这种lncRNA被发现与DNMT1相互作用并调节DNMT1，DNMT1是负责维持体细胞DNA甲基化模式的酶。它在慢性粒细胞白血病(CML)细胞系K562中高度表达，在那里它是正确定位DNMT1到细胞核所必需的。因此，在K562细胞中，CRISPR-Cas9敲除这种lncRNA会导致全局DNA低甲基化和DNA不稳定，导致生长速度减慢和细胞凋亡增加。这揭示了一种ncRNAs可以调节表观遗传变化从而导致致癌效应的机制。本项目旨在扩大这项研究的范围，研究CCDC26等ncRNAs在癌症相关表观遗传变化中的作用，特别是与衰老有关的变化。项目监督团队拥有从分子和细胞生物学到计算生物学和基因组学的专业知识，因此可以支持这项研究的多学科方法。与临床医生合作将保持翻译的重点，并允许在临床上下文中解释结果1。Appelbaum，F.R.等人。年龄和急性髓系白血病。血液107,3481-3485(2006)2.陈晓明，李晓波，等.长寿与衰老的表观遗传机制研究.166,822-839(2016).3.Aunan，J.R.，Cho，W.C.和Soreide，K.《衰老和癌症的生物学：共享和不同分子特征的简要概述》。老龄化的疾病。8,628-642(2017)。Jones，R.等人。一个长的基因间非编码RNA调节DNA甲基转移酶-1的核定位。《科学》24,102273(2021年)。

Ageing is a major risk factor in cancer, and has a significant impact on disease progression and treatment outcomes in haematological cancers1. Although ageing has a genetic component, it appears that the majority of this risk is mediated by epigenetic mechanisms2. Cancer and ageing share some epigenetic hallmarks, including aberrant histone modifications and DNA methylation3. We predict that age-associated changes in epigenetic marks are caused by changes in the behaviour of the enzymes that catalyse these modifications.Previous work in the lab investigated CCDC26, a long non-coding RNA which is transcribed from a region rich in cancer-associated mutations4. This lncRNA was found to interact with and regulate DNMT1, the enzyme responsible for maintaining DNA methylation patterns in somatic cells. It is highly expressed in the chronic myeloid leukemia (CML) cell line, K562, where it is required for correct localisation of DNMT1 to the nucleus. CRISPR-Cas9 knockout of this lncRNA in K562 cells therefore leads to global DNA hypomethylation and DNA instability, causing reduced growth rates and increased apoptosis. This reveals a mechanism by which ncRNAs can modulate epigenetic changes, resulting in oncogenic effects.This project aims to expand on this research, investigating the role of ncRNAs such as CCDC26 in cancer-associated epigenetic changes, particularly those linked to ageing. The project supervisory team have expertise ranging from molecular and cellular biology to computational biology and genomics, and therefore can support a multidisciplinary approach to this research. Working with clinicians will maintain a translational focus, and allow for interpretation of results in a clinical context.1. Appelbaum, F. R. et al. Age and acute myeloid leukemia. Blood 107, 3481-3485 (2006).2. Sen, P., Shah, P. P., Nativio, R. & Berger, S. L. Epigenetic Mechanisms of Longevity and Aging. Cell 166, 822-839 (2016).3. Aunan, J. R., Cho, W. C. & Soreide, K. The Biology of Aging and Cancer: A Brief Overview of Shared and Divergent Molecular Hallmarks. Aging Dis. 8, 628-642 (2017).4. Jones, R. et al. A long intergenic non-coding RNA regulates nuclear localization of DNA methyl transferase-1. iScience 24, 102273 (2021).