The role of DNA Methylation, Chromatin Remodelling and Histone Modification in Syndromic and Non-Syndromic Congenital Heart Disease.

先天性心脏病（CHD）是出生时心脏结构的变化。作为最常见的出生缺陷，英国每年有超过4，500名婴儿出生时患有CHD。CHD可能对儿童造成重大影响，通常需要专家治疗或手术，并可能与寿命缩短有关。我们知道，如果家族中的其他人也受到影响，CHD更常见，但这种常见疾病的确切遗传原因仍然不清楚。基因是身体如何生长和发育的指令。它们由我们身体细胞中的DNA组成。细胞内的DNA使用称为组蛋白的蛋白质包装：这些蛋白质可以通过化学基团（如“甲基化”）标记，这可以改变基因在身体每个细胞中的“打开”和“关闭”方式。有一些证据表明，所谓的“表观遗传”变化，如组蛋白甲基化，可以导致一定比例的冠心病病例。为了研究这一假设，我们获得了来自10万基因组计划招募的近600个CHD家庭的非常详细的基因检测数据（全基因组测序数据）。此外，在以前的研究中，我们确定了一些家庭，其中不止一个人患有冠心病。我们计划在这些家庭中进行进一步，更详细的基因检测，以更好地了解CHD的病因。一旦我们确定了CHD的新原因，我们将使用疾病的细胞模型来证实我们的发现。该项目的第二部分将涉及一种名为KMT 2D的特定蛋白质的研究，该蛋白质也参与组蛋白甲基化。我们发现，这种蛋白质与一种新的综合征有关，这种综合征以CHD为重要特征。我们现在想研究这种蛋白质的遗传变化或“突变”如何导致如此严重的疾病，以及这与CHD的联系。我们将通过在干细胞中使用新的“基因编辑”工具来做到这一点，我们将用它来制作患者神经细胞的模型。然后，我们将研究这些细胞模型的具体特征，以及突变如何影响它们。这将使我们能够更好地了解KMT 2D的工作原理，并将其与CHD联系起来。PI是一位经验丰富的临床遗传学家，对CHD特别感兴趣，并且是CHD相关详细遗传数据分析的博士。因此，候选人具有拟议项目所需的经验和技能。PI将加入一个由CO-I领导的经验丰富的研究小组，该小组在该领域具有成功的成功记录。他们使用最先进的技术，如新的基因编辑工具和新型细胞模型，来研究人类疾病的遗传基础。候选人和研究小组得到了大学和医院信托基金的大力支持。自2013年以来，他们一直在项目上合作，可以为该项目带来互补的技能和经验，以解决临床和研究合作伙伴的重要问题。发现CHD的新遗传原因并了解CHD与“组蛋白甲基化”之间的联系将增加对形成胎儿心脏的详细过程以及疾病可能影响的方式的科学理解。这将有助于决定冠心病的药物或手术治疗，因为我们怀疑患有不同遗传原因的冠心病患者可能对药物或手术有不同的反应。由于我们正在研究的特定蛋白质组是重要的药物靶点，我们的科学研究可能对发现新药至关重要。该项目位于利兹，将在未来5年内新建一所儿童医院，为最先进的患者护理、研究、培训和创新创造一个中心。

Congenital Heart Disease (CHD) is a change to the structure of the heart at birth. As the commonest birth defect, over 4,500 babies per year in the UK are born with CHD. CHD can cause a significant effect on a child, often needing specialist treatments or surgery, and can be associated with a shortened life-span. We know that CHD is more common if someone else in the family is also affected, but the exact genetic causes of this common condition are still not well understood. Genes are instructions to the body on how to grow and develop. They are made up of DNA in our body's cells. DNA inside cells is packaged using proteins called histones: these can be tagged by chemical groups (such as "methylation"), that can change how a gene is turned "on" and "off" in each cell of the body. There is some evidence to suggest that so-called "epigenetic" changes, such as histone methylation, can cause a proportion of CHD cases. To investigate this hypothesis, we have gained access to very detailed genetic testing data (Whole Genome Sequencing data) from nearly 600 families with CHD recruited to the 100,000 Genomes Project. Also, in a previous study, we identified a number of families where more than one individual had CHD. We plan to conduct further, more detailed genetic testing in these families, to understand better the cause of CHD. Once we have identified new causes of CHD, we will use cell models of disease to confirm our findings. The second part of the project will involve investigation of a specific protein, called KMT2D, which is also involved in histone methylation. We showed that this protein is associated with a new syndrome that has CHD as an important feature. We now want to investigate how a genetic change or "mutation" in this protein causes such severe disease, and how this links to CHD. We will do this by using new "gene-editing" tools in stem cells, which we will use to make a model of patient nerve cells. We will then investigate specific characteristics of these cell models, and how the mutations affect them. This will allow us to understand better how KMT2D works and to link this to CHD.The PI is an experienced Clinical Geneticist with a particular interest in CHD and a PhD in detailed genetic data analysis in relation to CHD. The candidate therefore has the experience and skills needed for the proposed project. The PI will join an experienced research group, led by the CO-I, with a proven track record of success in this field. They work with state-of-the-art technology, such as new gene-editing tools and novel cellular models, to investigate the genetic basis of human disease. The candidate and research group have strong support from the University and Hospital Trust. They have worked together on projects since 2013 and can bring complementary skills and experience to this project to tackle an important question for both the clinical and research partners. Finding new genetic causes of CHD and understanding the link between CHD and "histone methylation" will increase scientific understanding of the detailed processes involved in forming a fetal heart, and the ways in which this may be affected in disease. This will help in deciding upon medical or surgical managements for CHD, since we suspect that patients with different genetic causes of CHD may respond differently to medicines or surgery. Because the specific group of proteins we are studying are important drug targets, our scientific studies may be of key importance to discovering new drugs. This project is ideally placed in Leeds, where a new Children's Hospital is to be built over the next 5 years, to create a hub for state-of-the-art patient care, research, training and innovation.