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首页> 外文期刊>Cellular Signalling >LncRNA XIST modulates 5-hydroxytrytophan-induced visceral hypersensitivity by epigenetic silencing of the SERT gene in mice with diarrhea-predominant IBS
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LncRNA XIST modulates 5-hydroxytrytophan-induced visceral hypersensitivity by epigenetic silencing of the SERT gene in mice with diarrhea-predominant IBS

机译：LNCRNA XIST通过腹泻偏移IBS中的小鼠的SERT基因的表观遗传沉默调节5-羟基羟基甘蔗诱导的内感敏感性

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摘要

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a prevalent gastrointestinal disorder with a high incidence in children. The role of long non-coding RNAs (lncRNAs) in gastrointestinal diseases has been previously highlighted. Nevertheless, the underlying regulatory mechanism of lncRNA X inactivate-specific transcript (XIST) in IBS-D requires further studies. Thus, the present study was conducted with the main objective of elucidating the underlying mechanism of lncRNA XIST in visceral hypersensitivity in IBS-D. An in vivo mouse model of IBS-D was constructed via rectal perfusion of acetic acid. Next, in order to evaluate the effect of lncRNA XIST on the development of visceral hypersensitivity in IBS-D, different vector plasmids were injected into mice along with rectal mucosal epithelial cells, followed by the measurement of abdominal withdrawal reflex (AWR) score, counts of peristaltic wave, abdominal wall contraction and defecation particles. Furthermore, luciferase reporter assay, FISH, RIP and ChIP assays were conducted to determine the interactions between lncRNA XIST and SERT. Subsequently, MS-PCR was adopted to test the methylation level of SERT promoter. 5-hydroxytrytophan (HT) content in rectal tissues was detected using immunohistochemistry. The IBS-D mouse models presented with a high expression of lncRNA XIST along with low expression of SERT. LncRNA XIST was observed to recruit methylase DNMT1, DNMT3A and DNMT3B to promote SERT promoter methylation, reducing its expression. Restoration of lncRNA XIST resulted in increased AWR score, counts of peristaltic wave, abdominal wall contraction and defecation particles along with stimulated 5-HT expression and SERT methylation level, while downregulation of lncRNA XIST reversed these effects. In conclusion, the key findings from our study indicated that lncRNA XIST acts as a regulator in 5-HT-induced visceral hypersensitivity in mice with IBS-D, providing a new insight into the regulatory effect of lncRNA XIST and its epigenetic diagnostic and therapeutic properties in IBS-D.
机译：腹泻主要肠易激综合征（IBS-D）是一种普遍存在的胃肠疾病，儿童发病率很高。先前突出了长期非编码RNA（LNCRNA）在胃肠疾病中的作用。然而，IBS-D中LNCRNA X特异性转录物（XIST）的潜在调节机制需要进一步研究。因此，目前的研究是主要目的，阐明IBS-D中内脏过敏的LNCRNA Xist的潜在机制。 IBS-D的体内小鼠模型通过乙酸直肠灌注构建。接下来，为了评估LNCRNA XIST对IBS-D中内脏过敏的影响，将不同的载体质粒注射到小鼠中以及直肠粘膜上皮细胞，然后测量腹部戒断（AWR）得分，计数蠕动波，腹壁收缩和排便颗粒。此外，进行了荧光素酶报告器测定，鱼，RIP和芯片测定以确定LNCRNA XIST和SERT之间的相互作用。随后，采用MS-PCR来测试SERT启动子的甲基化水平。使用免疫组织化学检测直肠组织中的5-羟基羟基甘蔗（HT）含量。 IBS-D小鼠模型具有高表达LNCRNA XIST以及SERT的低表达。观察到LNCRNA XIST募集甲基酶DNMT1，DNMT3A和DNMT3B以促进SERT启动子甲基化，降低其表达。恢复LNCRNA Xist导致AWR得分增加，蠕动波，腹壁收缩和排放颗粒的计数以及刺激的5-HT表达和Sert甲基化水平，而LNCRNA XIST的下调逆转这些效果。总之，我们研究的主要发现表明，LNCRNA XIST在具有IBS-D的小鼠中作为5-HT诱导的阴道敏感性的调节剂，提供了对LNCRNA XIST的调节效果及其表观遗传诊断和治疗性能的新见解在IBS-D中。

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