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

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变化。众所周知，在衰老过程中，核受体的表观遗传协同调节因子的变化在许多与年龄相关的疾病中发挥了作用，如痴呆症、糖尿病和癌症。选择性剪接是蛋白质组多样性的关键机制。最近在理解组蛋白修饰(表观遗传)和RNA甲基化(表观转录)在选择性剪接调控中的作用方面的进展，不仅在转录和翻译调控中，而且突出了在解剖这一复杂过程方面继续取得进展的必要性。最近，组蛋白的修饰被发现可以引导RNA甲基转移酶复合体进入新生的RNA分子，从而允许m6A在共转录方面的加成。这项令人兴奋的研究表明，表观遗传学在RNA甲基化中起着关键作用。需要进一步了解影响表观遗传变化的因素，这些因素将导致疾病中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，该项目将利用前列腺癌和乳腺癌细胞模型来研究组蛋白修饰如何影响核受体转录和选择性剪接调节。将使用的技术包括RNA干扰、RNAseq和ATACseq数据的分析、细胞培养、qPCR、蛋白质检测(免疫印迹和免疫组织化学)、药理抑制剂、表型分析(增殖、侵袭、凋亡)。

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).