Is the methyltransferase, ASH1L a therapeutic target for endocrine-related cancers?

甲基转移酶 ASH1L 是内分泌相关癌症的治疗靶点吗？

• 批准号: 2594271
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2594271
• 关键词: methyltransferase; ASH1L; therapeutic; target; endocrine

One of the features of aging is the loss of sex hormones and in-turn the change in function of androgen and oestrogen nuclear receptors. Changes in the epigenetic co-regulators of the nuclear receptors during aging are known to play a role in many of the age-related diseases such as dementia, diabetes and cancer. Alternative splicing is a mechanism crucial for proteomic diversity. Recent advancements in the understanding of histone modifications (epigenetic) and RNA methylation (epitranscriptomic) role in alternative splicing regulation, not only in transcriptional and translational regulation has highlighted the need for continued progress in dissecting this complex process. Recently, histone modifications have been identified as guiding the RNA methyltransferase complex to nascent RNA molecules allowing m6A addition co-transcriptionally. This exciting study linked epigenetics playing crucial role in RNA methylation. Further understanding of factors that can influence the epigenetic changes that will lead to changes in RNA methylation in disease needs to be investigated. Additionally, the androgen receptor was shown to play a role in alternative splicing in the presence of androgen. Therefore, this project will investigate how histone modifications influence nuclear receptor transcriptional and alternative splicing regulation utilising prostate and breast cancer cell models. Techniques that will be utilised are RNA inteference, analysis of RNAseq and ATACseq data, cell culture, qPCR, protein detection (immunoblotting and immunohistochemistry), pharmacological inhibitors, phenotypic assays (proliferation, invasion, apoptosis).

衰老的特征之一是性激素的丧失，进而导致雄激素和雌激素核受体功能的改变。已知衰老过程中核受体的表观遗传辅助调节因子的变化在许多与年龄相关的疾病如痴呆、糖尿病和癌症中起作用。选择性剪接是蛋白质组多样性的关键机制。最近的进展，在理解组蛋白修饰（表观遗传）和RNA甲基化（epitranscriptomic）的作用，选择性剪接调控，不仅在转录和翻译调控突出了需要继续进步，解剖这个复杂的过程。最近，组蛋白修饰已被确定为引导RNA甲基转移酶复合物的新生RNA分子，允许m6A添加共转录。这项令人兴奋的研究将表观遗传学与RNA甲基化中的关键作用联系起来。需要进一步研究影响表观遗传变化的因素，这些变化将导致疾病中RNA甲基化的变化。此外，雄激素受体被证明在雄激素存在的情况下在选择性剪接中发挥作用。因此，本项目将利用前列腺癌和乳腺癌细胞模型研究组蛋白修饰如何影响核受体转录和选择性剪接调控。将使用的技术是RNA干扰、RNAseq和ATACseq数据分析、细胞培养、qPCR、蛋白质检测（免疫印迹和免疫组织化学）、药理学抑制剂、表型测定（增殖、侵袭、凋亡）。