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

衰老是癌症的主要风险因素，对血液系统癌症的疾病进展和治疗结果有显著影响1。虽然衰老具有遗传成分，但似乎大多数这种风险是由表观遗传机制介导的2。癌症和衰老有一些共同的表观遗传特征，包括异常的组蛋白修饰和DNA甲基化。我们预测，与年龄相关的表观遗传标记的变化是由催化这些修饰的酶的行为变化引起的。实验室以前的工作研究了CCDC 26，一种长的非编码RNA，从富含癌症相关突变的区域转录4。发现这种lncRNA与DNMT 1相互作用并调节DNMT 1，DNMT 1是负责维持体细胞中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DNMT 1正确定位到细胞核所必需的。因此，在K562细胞中敲除这种lncRNA的CRISPR-Cas9导致整体DNA低甲基化和DNA不稳定性，导致生长速率降低和细胞凋亡增加。这揭示了ncRNA可以调节表观遗传变化的机制，从而导致致癌效应。本项目旨在扩大这一研究，调查ncRNA如CCDC 26在癌症相关表观遗传变化中的作用，特别是与衰老相关的表观遗传变化。项目管理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重点，并允许在临床背景下解释结果。Appelbaum，F. R.等，Age and acute myeloid leukemia. Blood 107，3481-3485（2006）。森，P。，Shah，P. P.，纳蒂维奥河& Berger，S. L.长寿和衰老的表观遗传机制。Cell 166，822-839（2016）。Aunan，J.R.，Cho，W. C. & Soreide，K.衰老和癌症的生物学：共享和分歧分子标志的简要概述。Aging Dis. 8，628-642（2017）。琼斯河，巴西-地A long intergenic non-coding RNA regulates nuclear localization of DNA methyl transferase-1. iScience 24，102273（2021）.

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).