多组测序揭示了与Treatment-Naïve儿童溃疡性结肠炎原发性硬化性胆管炎发展相关的独特基因表达和表观遗传改变

Alejandra Rodriguez-Sosa , Ololade Lawal , Ciaran McDonnell , Luke Grant , John O’Brien , Muhammad Ali , Ian Stephens , Grainne Kirwan , Flavia Genua , Alexander Kel , Anna Dominik , Roisin Stack , Gregory Yochum , Michael McDermot , Glen Doherty , Seamus Hussey , Sudipto Das
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引用次数: 0

摘要

背景和目的原发性硬化性胆管炎(PSC)是一种进行性胆汁淤积性疾病,高达80%的患者同时患有溃疡性结肠炎(PSC- uc)。诊断的困难以及患癌症的风险增加代表了临床挑战。此外,调节该疾病亚型表型的精确分子因子仍然未知。方法应用甲基捕获测序和mRNA测序对3组儿童(treatment-naïve)结肠粘膜活检进行诊断,这些儿童来自儿童和青少年的决定因素和结局研究:UC (n = 10), PSC-UC (n = 10)和健康对照组(n = 10)。结果UC与PSC-UC之间的差异基因表达,PSC-UC患者的基因表达变化明显高于UC。具体来说,这些基因的表达受主要转录调控因子(NLRP3、DLL1)和转录因子(RELA、Myogenin和FOXO1)的调控,这些转录因子被证明只调控PSC-UC患者的炎症反应和免疫相关基因的表达。PSC-UC和UC之间的差异甲基化分析显示有2000个差异甲基化区域,其中很大一部分富集于基因启动子和增强子区域。我们进一步发现PSC-UC和UC的表观遗传年龄没有差异。最后,我们发现KLHL17在PSC-UC患者中低甲基化和上调。我们的研究首次在treatment-naïve儿童患者中发现了不同的基因表达和DNA甲基化改变,以区分UC和PSC-UC的诊断。我们发现在PSC-UC和UC之间观察到的基因表达差异是由复杂的分子机制调节的,其中包括通过转录因子介导的主转录调控因子介导的信号传导。这些发现表明这些分子标记物在UC早期发展阶段作为PSC发展的预测性生物标记物的潜在效用。在更大的患者队列中进一步验证是有必要的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Multiomic Sequencing Reveals Distinctive Gene Expression and Epigenetic Alterations Associated With Primary Sclerosing Cholangitis Development in Treatment-Naïve Pediatric Ulcerative Colitis

Multiomic Sequencing Reveals Distinctive Gene Expression and Epigenetic Alterations Associated With Primary Sclerosing Cholangitis Development in Treatment-Naïve Pediatric Ulcerative Colitis

Background and Aims

Primary sclerosing cholangitis (PSC) is a progressive cholestatic disease with up to 80% of patients also suffering from ulcerative colitis (PSC-UC). The difficulty in the diagnosis along with the increased risk for developing cancer represents a clinical challenge. Furthermore, the precise molecular factors regulating the phenotype of this disease subtype remain unknown.

Methods

We applied methyl-capture sequencing and mRNA sequencing to colonic mucosal biopsies from 3 groups of treatment-naïve children at diagnosis from the Determinants and Outcomes in CHildren and AdolescentS study: UC (n = 10), PSC-UC (n = 10), and healthy controls (n = 10).

Results

Differential gene expression between UC and PSC-UC showed significantly higher gene expression changes in PSC-UC patients when compared to UC. Specifically, expression of these genes was regulated by master transcriptional regulators (NLRP3, DLL1) and transcription factors (RELA, Myogenin, and FOXO1), which are shown to regulate expression of inflammatory response and immune-associated genes in PSC-UC patients exclusively. Differential methylation analysis between PSC-UC and UC demonstrated >2000 differentially methylated regions with a large proportion of them enriched in gene promoter and enhancer regions. We further show no difference in epigenetic age between PSC-UC and UC. Finally, we identify KLHL17 as hypomethylated and upregulated in PSC-UC patients.

Conclusion

Our study, for the first time, identifies distinct gene expression and DNA methylation alterations that differentiate UC from PSC-UC at diagnosis in treatment-naïve pediatric patients. We show the gene expression differences observed between PSC-UC and UC are modulated by intricate molecular mechanisms involving master transcriptional regulator-mediated signaling through transcription factors. These findings suggest the potential utility of these molecular markers as predictive biomarkers for PSC development in UC at an early stage of development. Further validation in larger patient cohorts is warranted.
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来源期刊
Gastro hep advances
Gastro hep advances Gastroenterology
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