RNA polymerase II CTD modifications and transcriptional dynamics: noise and cell cycle effects.

课程概述：这个由MRC资助的博士培训伙伴关系(DTP)将尖端分子和分析科学与数据分析中的创新计算方法结合在一起，使学生能够解决假设引导的生物医学研究问题。这是一个为期4年的课程，第一年包括一系列的教学模块和两个基于实验室的研究项目，这些项目导致了跨学科生物医学研究的硕士学位。前两个学期包括精选的教学模块，使学生能够在多学科的科学中获得坚实的基础。学生们还参加了由学术和行业专家主持的一系列大师课程，这些专家涉及分子、细胞和组织动力学、微生物学和传染病、应用生物医学技术以及人工智能和数据科学等领域。在第三学期和暑期，学生们在他们选择的实验室里进行两个为期十一周的研究项目。项目：在生物学中，每个活细胞通过在分子水平上的不断变化而与其相邻细胞略有不同。这些分子随机变异(或生物噪声)是当前分子生物学研究中最重要的课题之一。很明显，随机性在许多生物学环境中起着决定性的作用，包括临床上重要的环境，如干细胞分化、艾滋病毒感染、免疫系统或癌症的控制。这一主题在设计复杂的人工基因调控网络时也是高度相关的。这种合成生物学事业在许多不同的领域都有很大的希望，包括能源和食品生产以及提高人类健康，但受到生物噪声的阻碍。如果系统是基于四五个以上的基因设计的，而这些基因本应控制彼此的活动，那么网络的行为就会变得非常嘈杂和不可预测。因此，人们迫切需要更好地理解和控制生物噪声的方法。该项目旨在确定细胞中一种特别嘈杂的过程的分子原因，该过程称为转录，这是信使-RNA的产生。由于目前未知的原因，这一过程的速度波动很大。这导致了同一类型的不同细胞中信使-RNA数量的巨大差异。由于转录在生物学中的核心重要性，了解转录噪声的机制来源和影响是很重要的。从DNA中产生信使-RNA的酶，RNA聚合酶II，有一条影响其行为的长尾。这项研究将集中在阐明所述尾巴的作用，目的是促进对生物波动的起源的理解，并潜在地确定控制和/或调节它们的方法。这将对疾病的分子病因有深入的了解，从长远来看，将有助于开发新一代治疗策略。

Programme overview:This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice. Project:In biology, each living cell is slightly different to its neighbours through constant variations at a molecular level. These molecular random variations (or biological noise) are currently one of the most important topics in molecular biological research. It has become clear that 'randomness' plays decisive roles in many biological contexts, including clinically important settings such as stem cell differentiation, HIV infections, control of the immune system or cancer.This topic is also highly relevant in the design of complex artificial gene regulatory networks. Such synthetic biology undertakings hold great promise for many diverse fields, including energy and food production and the enhancement of human health, but are impeded by biological noise. If systems are designed based on more than four or five genes that are supposed to regulate each other's activity, the behaviour of the network becomes very noisy and unpredictable. Means to better understand and control biological noise are thus greatly sought after.This project aims to identify the molecular causes of a particularly noisy process in the cell called transcription, which is the production of messenger-RNAs. For currently unknown reasons, the rate of this process fluctuates strongly. This gives rise to vastly different messenger-RNA numbers in different cells of the same type. Due to transcription's central importance in biology, it is important to understand the mechanistic origins and effects of transcriptional noise. The enzyme that makes messenger-RNAs from DNA, RNA polymerase II, has a long tail that affects its behaviour. This research will focus on elucidating the role of said tail, with the intention of advancing understanding of the origins of biological fluctuations, and potentially identifying ways to control and/or modulate them. This will yield insights into the molecular causes of diseases and, in the long term, will assist in the development of new generations of treatment strategies.