How do non-coding enhancer RNAs confer genetic risk in amyotrophic lateral sclerosis (ALS)?

肌萎缩侧索硬化症(ALS)是一种侵袭性神经退行性疾病，目前尚无有效治疗方法。已经确定的ALS的遗传原因只能解释观察到的疾病表型的一小部分。这个项目将探索新发现的基因组非编码区的疾病突变如何促进ALS。ALS患者的大规模全基因组测序(WGS)突出了非编码增强子中新突变的重要性。增强子是对细胞系特异性基因表达至关重要的基因调控元件，被转录成称为增强子RNA(ERNAs)的非编码RNA。你将领导一个项目，研究新的非编码ALS突变是否会影响eRNAs的结构，以及这是否会影响表观遗传学染色质修饰和基因表达，从而推动ALS疾病的进展。该项目将在谢菲尔德大学的两个惠康信托资助的小组之间建立一个新的令人兴奋的合作。玻色实验室在努力揭示Erna功能的分子基础方面处于领先地位。库珀-敲门实验室领导了WGS联合项目MINE(www.project tmine.com)的非编码基因组分析，使识别和分析ALS中罕见的遗传关联成为可能。因此，该项目提供了一个在一些最新和发展最快的科学领域工作的独特机会：非编码RNA的分子机制以及非编码疾病突变对复杂疾病的贡献。培训您将接受广泛的、多学科的功能基因组学方法培训。这将包括高通量(细胞内)和定向(体外)确定RNA结构的技术；下一代和纳米孔测序(ChIPseq、NETseq和Long-Read RNAseq)；目标基因组和表观基因组编辑(CRISPR/CRISPRa/i)。重要的是，该项目提供了一个独特的机会，将这些实验方法与生物信息学培训联系起来，包括开发用于预测ALS遗传变异的新的深度学习模型。这项工作将提供对生物学中最相关的问题之一的新理解，对常见人类疾病的疾病机制具有广泛的影响。分子生物学和生物技术系)和乔纳森·库珀博士

Amyotrophic Lateral Sclerosis (ALS) is an aggressive neurodegenerative disease with no effective therapy. The established genetic causes of ALS can only explain a small fraction of the observed disease phenotypes. This project will explore how newly uncovered disease mutations in non-coding regions of the genome contribute to ALS.Large scale whole genome sequencing (WGS) in ALS patients has highlighted the importance of new mutations in non-coding enhancers. Enhancers are gene regulatory elements crucial for cell-lineage specific gene expression, and are transcribed into non-coding RNAs called enhancer RNAs (eRNAs). You will lead a project to investigate whether novel non-coding ALS mutations affect the structure of eRNAs, and whether this affects epigenetic chromatin modifications and gene expression to drive ALS disease progression.The project will establish a new and exciting collaboration between two Wellcome Trust Funded groups at the University of Sheffield. The Bose Lab is at the forefront of efforts to uncover the molecular basis for eRNA function. The Cooper-Knock lab leads analysis of the non-coding genome for WGS consortium Project MinE (www.projectmine.com), enabling identification and analysis of rare genetic associations in ALS. The project therefore provides a unique opportunity to work in some of the newest and fastest moving fields in science: molecular mechanisms of non-coding RNAs and the contribution of non-coding disease mutations to complex diseases.TrainingYou will receive a broad, multidisciplinary training in functional genomics approaches. This will include techniques for both high-throughout (in-cell) and targeted (in vitro) determination of RNA structure; next-generation and Nanopore sequencing (ChIPseq, NETseq and long-read RNAseq); targeted genome and epigenome editing (CRISPR/CRISPRa/i). Importantly, the project offers a unique opportunity to link these experimental approaches at the bench to bioinformatics training, including development of new deep-learning models for predicting genetic variants in ALS. The work will provide a new understanding of one of the most relevant questions in biology, with broad implications for disease mechanisms in common human diseases.CommunityYou will be supervised by Dr Daniel Bose (Dept. of Molecular Biology and Biotechnology) and Dr Johnathan Cooper-Knock