Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes.
Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes.
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DOI：
10.1007/s00401-023-02583-z
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发表时间：
2023-07
影响因子：
12.7
通讯作者：
Bettencourt, Conceicao
中科院分区：
文献类型：
--
作者：
Fodder, Katherine;Murthy, Megha;Rizzu, Patrizia;Toomey, Christina E. E.;Hasan, Rahat;Humphrey, Jack;Raj, Towfique;Lunnon, Katie;Mill, Jonathan;Heutink, Peter;Lashley, Tammaryn;Bettencourt, Conceicao
关键词：
额颞叶变性 (FTLD) 是一个总称，描述一组临床、遗传和病理上异质性疾病的神经病理学，包括额颞叶痴呆 (FTD) 和进行性核上性麻痹 (PSP)。在主要的FTLD病理亚型中，TDP-43阳性包涵体FTLD（FTLD-TDP）和tau阳性包涵体FTLD（FTLD-tau）最为常见，约占病例的90%。尽管 DNA 甲基化的改变一直与神经退行性疾病（包括阿尔茨海默病和帕金森病）相关，但人们对 FTLD 及其异质亚组和亚型知之甚少。本研究的主要目的是研究 FTLD-TDP 和 FTLD-tau 中的 DNA 甲基化变异。我们使用了来自三个 FTLD 队列（142 例 FTLD 病例和 92 例对照）的额叶皮层全基因组 DNA 甲基化图谱，这些图谱是使用 Illumina 450K 或 EPIC 微阵列生成的。我们对每个队列进行了全表观基因组关联研究 (EWAS)，然后进行荟萃分析，以确定 FTLD 亚组/亚型之间共享的差异甲基化位点。此外，我们使用加权基因相关网络分析来识别与 FTLD 和其他疾病相关性状相关的共甲基化特征。只要有可能，我们还纳入了相关基因/蛋白质表达数据。在考虑了保守的 Bonferroni 多重测试校正后，EWAS 荟萃分析揭示了 FTLD 中的两个差异甲基化位点，一个注释为 OTUD4（5’UTR-shore），另一个注释为 NFATC1（基因体岛）。在这些位点中，OTUD4 在 FTLD 中表现出一致的 mRNA 和蛋白表达上调。此外，在三个独立的共甲基化网络中，包含 OTUD4 的模块针对 EWAS 荟萃分析顶级位点进行了富集，并且与 FTLD 状态密切相关。这些共甲基化模块富集了与泛素系统、RNA/应激颗粒形成和谷氨酸突触信号传导有关的基因。总而言之，我们的研究结果确定了新的 FTLD 相关位点，并支持 DNA 甲基化作为参与 FTLD 相关生物过程失调的机制的作用，突出了治疗开发的新潜在途径。在线版本包含可在 10.1007/s00401-023-02583-z 获取的补充材料。
Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau-positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (142 FTLD cases and 92 controls), generated using the Illumina 450K or EPIC microarrays. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differentially methylated loci across FTLD subgroups/subtypes. In addition, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. After accounting for a conservative Bonferroni multiple testing correction, the EWAS meta-analysis revealed two differentially methylated loci in FTLD, one annotated to OTUD4 (5’UTR-shore) and the other to NFATC1 (gene body-island). Of these loci, OTUD4 showed consistent upregulation of mRNA and protein expression in FTLD. In addition, in the three independent co-methylation networks, OTUD4-containing modules were enriched for EWAS meta-analysis top loci and were strongly associated with the FTLD status. These co-methylation modules were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development. The online version contains supplementary material available at 10.1007/s00401-023-02583-z.
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DOI：
10.1111/bpa.12842
发表时间：
2020-07
期刊：
Brain pathology (Zurich, Switzerland)
影响因子：
--
作者：
Toomey CE;Heywood W;Benson BC;Packham G;Mills K;Lashley T
通讯作者：
Lashley T
影响因子：
3.5
作者：
Dempster EL;Pidsley R;Schalkwyk LC;Owens S;Georgiades A;Kane F;Kalidindi S;Picchioni M;Kravariti E;Toulopoulou T;Murray RM;Mill J
通讯作者：
Mill J
内源性TDP-43而不是FUS，通过G3BP导致应力颗粒组件。
影响因子：
15.1
作者：
Aulas A;Stabile S;Vande Velde C
通讯作者：
Vande Velde C
影响因子：
--
作者：
Botía JA;Vandrovcova J;Forabosco P;Guelfi S;D'Sa K;United Kingdom Brain Expression Consortium;Hardy J;Lewis CM;Ryten M;Weale ME
通讯作者：
Weale ME
影响因子：
39.3
作者：
Müller S
通讯作者：
Müller S