Mapping cell-type-specific regulatory genomic variation in Alzheimer's disease pathology.

阿尔茨海默病(AD)是一种慢性神经退行性疾病，影响着全球2600万人，目前尚无治疗方法。尽管在识别阿尔茨海默病的遗传危险因素方面取得了重大进展，但对于涉及的特定致病基因及其在神经病理进展过程中功能如何失调仍存在不确定性。基因组测序只是我们探索了解基因是如何表达和调控的第一步。对基因组功能复杂性的理解增加了对调节变异在健康和疾病中的作用的认识。位于DNA序列之上的是第二层信息(“表观基因组”)，它调节基因何时何地被功能性转录。这些机制在确定人脑中特定细胞类型的基因转录模式方面发挥了关键作用。以前对阿尔茨海默病大脑的基因组分析由于使用了由不同神经细胞类型组成的混合组织而受到限制。由于AD的特点是特定细胞类型的变化(例如，它涉及神经元的广泛丧失和神经胶质细胞的增殖)，因此在基因调控中考虑细胞差异是至关重要的。我们的研究将首次系统地研究调控基因组过程在AD病理中特定细胞类型中的作用。我们的创新提案利用了英国目前正在进行的前所未有的脑库努力，特别是在痴呆症研究(BDR)队列中。我们提出了一种综合基因组学方法，分析了来自AD病理水平低和高水平的捐赠者的皮质核纯化群体。我们的项目有以下主要目的首先，我们将从AD病理水平低和高水平的捐赠者的皮质组织中分离出三种不同细胞类型(神经元、少突胶质细胞和小胶质细胞)的纯化细胞核中的表观基因组调控标记。其次，我们将在更多的样本和数据集中验证与AD病理相关的调控区域。第三，我们将研究与AD相关的遗传变异如何影响特定皮质细胞类型的基因调控。我们的团队处于独特的地位，能够承担这一雄心勃勃的项目，因为我们的开创性工作评估了AD大脑中的表观基因组变异，以及我们在开发跨不同神经细胞类型的调控基因组图谱的新方法方面所扮演的角色。最后，我们是开放科学的热情倡导者，我们将向更广泛的研究社区免费提供所有数据和方法。结合研究中收集的每个捐赠者的大量临床和神经病理学数据，我们将产生一个无与伦比的数据资源，将刺激痴呆症研究，并使对AD涉及的机制路径的理解发生阶段性变化。

Alzheimer's disease (AD) is a chronic neurodegenerative disorder affecting >26 million people worldwide, with no disease-modifying treatments available. Despite major advances in identifying genetic risk factors for AD, there remains uncertainty about the specific causal genes involved and how their function is dysregulated during the progression of neuropathology. Sequencing the genome was only the first step in our quest to understand how genes are expressed and regulated. Increased understanding about the functional complexity of the genome has led to recognition about the role of regulatory variation in health and disease. Sitting above the DNA sequence is a second layer of information (the 'epigenome') that mediates the regulation of when and where genes are functionally transcribed. These mechanisms play a critical role in determining cell-type-specific patterns of gene transcription in the human brain.Previous genomic analyses of AD brain have been limited by their use of 'bulk' tissue, comprising a mix of different neural cell-types. Because AD is characterised by changes in specific cell-types (for example it involves the extensive loss of neurons and the proliferation of glial cells) it is critical to consider cellular differences in gene regulation. Our study will, for the first time, systematically examine the role of regulatory genomic processes in specific cell types in AD pathology.Our innovative proposal leverages the unprecedented brain-banking efforts currently taking place in the UK, specifically within the Brains for Dementia Research (BDR) cohort. We propose an integrative-genomics approach, profiling purified populations of cortical nuclei from donors with low and high levels of AD pathology. Our project has the following key aimsFirst, we will profile markers of epigenomic regulation in purified nuclei from three different cell types (neurons, oligodendrocytes and microglia) isolated from cortex tissue from donors with low and high levels of AD pathology. Second, we will validate regulatory regions associated with AD pathology in additional samples and datasets. Third, we will examine how AD-associated genetic variation influences gene regulation in specific cortical cell-types.Our team is uniquely placed to undertake this ambitious project given our pioneering work assessing epigenomic variation in AD brain and our role in developing novel methods for regulatory genomic profiling across distinct neural cell-types.Finally, we are passionate advocates for Open Science, and we will make all data and methods freely available to the wider research community. In conjunction with the extensive clinical and neuropathological data being collected on each donor included in the study, we will generate an unrivalled data resource that will stimulate dementia research and enable a step-change in understanding of the mechanistic pathways involved in AD.