富亮氨酸胶质瘤失活1抗体脑炎的异常DNA甲基化分析揭示了与预后和临床特征相关的新的甲基化驱动基因。

IF 5.7 2区 医学 Q1 Medicine
Shan Qiao, Quanye Sun, Haiyun Li, Jie Yin, Aihua Wang, Shanchao Zhang
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引用次数: 0

摘要

背景:异常DNA甲基化在神经免疫性疾病的发病过程中很常见,在各种脑炎亚型中具有临床价值。然而,关于DNA甲基化变化对富含亮氨酸的胶质瘤失活1 (LGI1)抗体脑炎发病机制的影响的知识仍然有限。方法:检测LGI1型脑炎患者和健康供者血清中44种细胞因子和10种免疫检查点分子(ICMs)水平,探讨其与临床参数的相关性。采用亚硫酸氢盐还原测序(RRBS)对LGI1型脑炎患者和hd患者外周血单个核细胞(PBMC)进行了全基因组DNA甲基化谱分析,并通过焦磷酸测序验证了甲基化状态。通过小RNA测序获得血清外泌体的MicroRNA谱。在pbmc和培养基中评估miR-2467-5p存在或不存在时靶向细胞因子的表达,并通过荧光素酶测定验证miR-2467-5p与其靶向基因的结合。结果:LGI1型脑炎患者与hd患者在22种细胞因子/趋化因子及6种ICMs上存在显著差异。LGI1型脑炎患者1年随访时PDCD1降低与ICAM1升高可预测预后不良。15个细胞因子/趋化因子和ICMs在启动子和基因体中出现dna甲基化变化,其中5个通过焦磷酸测序证实为甲基化状态,CSF3、CCL2和ICAM1的甲基化水平与其在PBMCs中的表达呈相反相关。通过将RRBS数据与外泌体衍生的microRNA测序相结合,我们发现低甲基化驱动的hsa-miR-2467-5p在LGI1脑炎的血清外泌体和PBMCs中表达升高。机械上,miR-2467-5p通过与CSF3和PDCD1的3'UTR结合,显著诱导CSF3和PDCD1表达降低,CCL15表达增强,但与LGI1脑炎患者外周血CD19 + B细胞比例无显著相关性。结论:我们的研究结果为LGI1脑炎的DNA甲基化变化和血清外泌体microRNA谱提供了令人信服的证据,我们还发现了一些与临床特征相关的新细胞因子,其中一些细胞因子代表了甲基化驱动模式和microRNA调节的表观遗传修饰。我们的研究有助于开发LGI1脑炎表观遗传发病机制的治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Abnormal DNA methylation analysis of leucine-rich glioma-inactivated 1 antibody encephalitis reveals novel methylation-driven genes related to prognostic and clinical features.

Abnormal DNA methylation analysis of leucine-rich glioma-inactivated 1 antibody encephalitis reveals novel methylation-driven genes related to prognostic and clinical features.

Abnormal DNA methylation analysis of leucine-rich glioma-inactivated 1 antibody encephalitis reveals novel methylation-driven genes related to prognostic and clinical features.

Abnormal DNA methylation analysis of leucine-rich glioma-inactivated 1 antibody encephalitis reveals novel methylation-driven genes related to prognostic and clinical features.

Background: Aberrant DNA methylation occurs commonly during pathogenesis of neuroimmunological diseases and is of clinical value in various encephalitis subtypes. However, knowledge of the impact of DNA methylation changes on pathogenesis of leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis remains limited.

Methods: A total of 44 cytokines and 10 immune checkpoint moleculars (ICMs) in the serum of patients with LGI1 encephalitis and healthy donors (HDs) were measured to evaluate the association of them with clinical parameters. Genome-wide DNA methylation profiles were performed in peripheral blood mononuclear cell (PBMC) from LGI1 encephalitis patients and HDs using reduced representation bisulfite sequencing (RRBS) and validated for the methylation status by pyrosequencing. MicroRNA profiles were acquired in serum exosome by small RNA sequencing. Targeted cytokines expression was assessed at the presence or absence of miR-2467-5p in PBMCs and the culture media, and the binding of miR-2467-5p and its targeted genes was validated by luciferase assay.

Results: There existed significant difference in 22 cytokines/chemokines and 6 ICMs between LGI1 encephalitis patients and HDs. Decreased PDCD1 with increased ICAM1 could predict unfavorable prognosis in one-year follow-up for LGI1 encephalitis patients. Fifteen of cytokines/chemokines and ICMs presented DNA-methylated changes in the promoter and gene body using RRBS in which five were verified as methylation status by pyrosequencing, and the methylation level of CSF3, CCL2, and ICAM1 was conversely associated with their expression in PBMCs. By combining RRBS data with exosome-derived microRNA sequencing, we found that hypomethylated-driven hsa-miR-2467-5p presented elevated expression in serum exosomes and PBMCs in LGI1 encephalitis. Mechanically, miR-2467-5p significantly induced reduced expression of CSF3 and PDCD1 by binding with their 3`UTR while enhanced CCL15 expression, but not significantly correlated with peripheral blood CD19 + B cell proportion of LGI1 encephalitis patients.

Conclusions: Our results provided convincing evidence for DNA methylation changes, microRNA profiles in serum exosome for LGI1 encephalitis, and we also identified several novel cytokines related to clinical features in which some represented epigenetic modification of methylated-driven pattern and microRNA modulation. Our study contributed to develop treatment for epigenetic pathogenesis in LGI1 encephalitis.

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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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