Exploring the role of epigenetic mechanisms in the manifestation of Huntington's disease

探索表观遗传机制在亨廷顿舞蹈病表现中的作用

基本信息

  • 批准号:
    MR/Y014685/1
  • 负责人:
  • 金额:
    $ 133.94万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2024
  • 资助国家:
    英国
  • 起止时间:
    2024 至 无数据
  • 项目状态:
    未结题

项目摘要

Huntington's disease (HD) is a neurodegenerative disease caused by an expansion of typically 40 or more repeats of the DNA code "CAG" in the Huntingtin (HTT) gene. The disease is characterised by movement disturbances, cognitive impairments, and psychiatric symptoms and there is currently no disease-modifying treatment. The size of the CAG repeat is closely associated with the age of symptom onset, with individuals with high numbers of repeats developing the disease at a young age. However, there is variation in the age of symptom onset between individuals with the same CAG repeat length. It is known that the expression of genes relies not only on a person's specific DNA code (their genome) but can also be altered by an extra level of information called the "epigenome". Epigenetic processes are chemical tags added to the DNA or histone proteins that turn genes on and off and can be influenced by external factors. We have recently shown robust alterations in two epigenetic marks (DNA methylation (DNAm) and H3K27ac) in Alzheimer's disease (AD). We have also seen DNAm differences in a pilot study of HD brain. We hypothesise that epigenetic mechanisms contribute to the manifestation of HD and plan to use state-of-the art genomic technology and computational approaches to undertake the most comprehensive study of epigenetic mechanisms in HD brain to date. We have the following complimentary work-packages:WP1: (EPI)GENETIC CHARACTERISATION OF HTT USING LONG-READ SEQUENCINGWe will use cutting-edge long-read sequencing technology to measure the length of the CAG repeat and extent of DNAm across that region of the HTT gene. This will allow us to determine exactly where DNAm is seen in the CAG repeat in HD brain samples. We plan to study two brain regions: the striatum and prefrontal cortex, which are affected at different stages of the disease. It is reported that the CAG repeat length can increase in some cells with age, which is termed somatic mosaicism. One advantage of using long-read sequencing is that we can measure both the CAG repeat length and DNAm on the same molecule, which will allow us to explore this phenomenon in our samples.WP2: DECIPHERING THE EPIGENETIC LANDSCAPE IN HD VIA EWASWe will perform the first genome-scale assessment of epigenetic variation in HD brain samples, profiling DNAm, H3K27ac, chromatin accessibility and genetic variation in the striatum and prefrontal cortex. We will investigate whether DNAm, H3K27ac or areas of open chromatin are seen at specific gene regions in HD. As we have generated similar datasets in other neurodegenerative diseases, we can then examine whether there is any overlap in the epigenetic changes we identify in HD to, for example, AD. Using integrative computational approaches, we will explore the relationship between different layers of epigenetic information. By integrating genetic data, we can identify quantitative trait loci (QTLs), where genetic differences alter the epigenetic marks, and then investigate if these QTLs are enriched in genes we know are affected in HD, and other related disorders. WP3: DETERMINING THE CELLULAR SPECIFICITY OF LOCI USING FANSWe will isolate nuclei from different cell types in the prefrontal cortex using fluorescence-activated nuclei sorting (FANS), including inhibitory (GABA) and excitatory (glutamatergic) neurons that are known to be affected in disease, as well as glial cells such as microglia, oligodendrocytes and astrocytes. We will determine which cell types are responsible for the epigenetic changes we observed in the earlier WP in a subset of the cohort with severe pathology (N=20), moderate pathology (N=20) or no pathology (N=20)WP4: CHARACTERISATION OF HTT TRANSCRIPT ISOFORM DIVERSITY IN HDWe will use long-read sequencing to measure expression of the HTT gene, and other genes we have identified. The advantage of this technology is that we can identify completely novel isoforms, which we have previously done in AD.
亨廷顿舞蹈病(HD)是一种神经退行性疾病,由亨廷顿舞蹈症(HTT)基因中DNA代码“CAG”的扩增引起,通常是40或更多的重复。该病的特点是运动障碍、认知障碍和精神症状,目前没有改善疾病的治疗方法。CAG重复序列的大小与症状发作的年龄密切相关,重复序列数量高的个体在年轻时发病。然而,具有相同CAG重复序列长度的个体在症状发作年龄上存在差异。众所周知,基因的表达不仅依赖于一个人的特定DNA代码(他们的基因组),而且还可以被称为“表观基因组”的额外信息水平所改变。表观遗传过程是添加到DNA或组蛋白上的化学标签,它可以打开和关闭基因,并受外部因素的影响。我们最近发现了阿尔茨海默病(AD)中两个表观遗传标记(DNA甲基化(DNAm)和H3K27ac)的显著改变。我们还在对HD大脑的初步研究中看到了dna的差异。我们假设表观遗传机制有助于HD的表现,并计划使用最先进的基因组技术和计算方法来进行迄今为止HD大脑中最全面的表观遗传机制研究。我们有以下免费的工作包:WP1:(EPI)使用长读测序的HTT遗传特征我们将使用尖端的长读测序技术来测量CAG重复序列的长度和HTT基因区域的dna范围。这将使我们能够准确地确定dna在HD脑样本CAG重复序列中的位置。我们计划研究大脑的两个区域:纹状体和前额皮质,它们在疾病的不同阶段受到影响。据报道,CAG重复序列长度在一些细胞中随着年龄的增长而增加,这被称为体细胞嵌合。使用长读测序的一个优点是我们可以同时测量同一分子上的CAG重复长度和dna,这将使我们能够在我们的样品中探索这种现象。我们将对HD脑样本进行首次基因组尺度的表观遗传变异评估,分析纹状体和前额叶皮层的DNAm、H3K27ac、染色质可及性和遗传变异。我们将研究dna、H3K27ac或开放染色质区域是否存在于HD的特定基因区域。由于我们已经在其他神经退行性疾病中产生了类似的数据集,因此我们可以检查在HD和AD中发现的表观遗传变化是否存在重叠。利用综合计算方法,我们将探索不同层次表观遗传信息之间的关系。通过整合遗传数据,我们可以确定数量性状位点(qtl),遗传差异改变表观遗传标记,然后研究这些qtl是否富集在我们已知的HD和其他相关疾病中受影响的基因中。我们将使用荧光激活核分选(FANS)从前额皮质不同类型的细胞中分离细胞核,包括已知在疾病中受影响的抑制性(GABA)和兴奋性(谷氨酸能)神经元,以及胶质细胞,如小胶质细胞、少突胶质细胞和星形胶质细胞。我们将确定哪些细胞类型负责我们在早期WP中观察到的表观遗传变化,这些变化发生在具有严重病理(N=20),中度病理(N=20)或无病理(N=20)的队列子集中。WP4: hdtt转录物异构体多样性的特征。我们将使用长读测序来测量HTT基因的表达,以及我们已经确定的其他基因。这项技术的优势在于,我们可以识别出完全新颖的异构体,这是我们之前在阿尔茨海默病中所做的。

项目成果

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Katie Lunnon其他文献

Elucidating distinct molecular signatures of Lewy body dementias
阐明路易体痴呆的不同分子特征
  • DOI:
    10.1016/j.nbd.2023.106337
  • 发表时间:
    2023-11-01
  • 期刊:
  • 影响因子:
    5.600
  • 作者:
    Joshua Harvey;Ehsan Pishva;Leonidas Chouliaras;Katie Lunnon
  • 通讯作者:
    Katie Lunnon
Exploring Beyond the DNA Sequence: A Review of Epigenomic Studies of DNA and Histone Modifications in Dementia
  • DOI:
    10.1007/s40142-020-00190-y
  • 发表时间:
    2020-08-03
  • 期刊:
  • 影响因子:
    1.300
  • 作者:
    Lachlan F. MacBean;Adam R. Smith;Katie Lunnon
  • 通讯作者:
    Katie Lunnon
Erratum to: Variation in 5-hydroxymethylcytosine across human cortex and cerebellum
  • DOI:
    10.1186/s13059-016-0958-4
  • 发表时间:
    2016-06-17
  • 期刊:
  • 影响因子:
    9.400
  • 作者:
    Katie Lunnon;Eilis Hannon;Rebecca G.Smith;Emma Dempster;Chloe Wong;Joe Burrage;Claire Troakes;Safa Al-Sarraj;Agnieszka Kepa;Leonard Schalkwyk;Jonathan Mill
  • 通讯作者:
    Jonathan Mill

Katie Lunnon的其他文献

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{{ truncateString('Katie Lunnon', 18)}}的其他基金

Cutting-edge precision profiling of specific cell populations using a Laser Capture Microdissection (LCM) system
使用激光捕获显微切割 (LCM) 系统对特定细胞群进行尖端精确分析
  • 批准号:
    MR/X013413/1
  • 财政年份:
    2022
  • 资助金额:
    $ 133.94万
  • 项目类别:
    Research Grant
Elucidating the role of DNA methylation in the pathophysiology of lewy body diseases.
阐明 DNA 甲基化在路易体疾病病理生理学中的作用。
  • 批准号:
    MR/S011625/1
  • 财政年份:
    2019
  • 资助金额:
    $ 133.94万
  • 项目类别:
    Research Grant
JPND: Targeting epigenetic dysregulation in the brainstem in Alzheimer's Disease (EPI-AD)
JPND:针对阿尔茨海默病脑干的表观遗传失调 (EPI-AD)
  • 批准号:
    MR/N027973/1
  • 财政年份:
    2016
  • 资助金额:
    $ 133.94万
  • 项目类别:
    Research Grant

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