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首页> 外文期刊>American Journal of Physiology >Regulation of intestinal serotonin transporter expression via epigenetic mechanisms: role of HDAC2
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Regulation of intestinal serotonin transporter expression via epigenetic mechanisms: role of HDAC2

机译：通过表观遗传机制调节肠道5-羟色胺转运蛋白的表达：HDAC2的作用

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The serotonin (5-HT) transporter (SERT) facilitates clearance of extracellular 5-HT by its uptake and internalization. Decreased expression of SERT and consequent high 5-HT levels have been implicated in various diarrheal disorders. Thus, appropriate regulation of SERT is critical for maintenance of 5-HT homeostasis in health and disease. Previous studies demonstrated that SERT is regulated via posttranslational and transcriptional mechanisms. However, the role of epigenetic mechanisms in SERT regulation is not known. Current studies investigated the effects of histone deacetylase (HDAC) inhibition on SERT expression and delineated the mechanisms. Treatment of Caco-2 cells with the pan-HDAC inhibitors butyrate (5 mM) and trichostatin (TSA, 1 muM) decreased SERT mRNA and protein levels. Butyrate- or TSA-induced decrease in SERT was associated with decreased activity of human SERT (hSERT) promoter 1 (upstream of exon la), but not hSERT promoter 2 (upstream of exon 2). Butyrate + TSA did not show an additive effect on SERT expression, indicating that mechanisms involving histone hyperacetylation may be involved. Chromatin im-munoprecipitation assays demonstrated enrichment of the hSERT promoter 1 (flanking nt -250/+2) with tetra-acetylated histone H3 or H4, which was increased (~3-fold) by butyrate. Interestingly, specific inhibition of HDAC2 (but not HDAC1) utilizing small interfering RNA decreased SERT mRNA and protein levels. The decrease in SERT expression by HDAC inhibition was recapitulated in an in vivo model. SERT mRNA levels were decreased in the ileum and colon of mice fed pectin (increased availability of butyrate) compared with controls fed a fiber-free diet (-50-60%). Our results identify a novel role of HDAC2 as a regulator of SERT gene expression in intestinal epithelial cells.
机译：血清素（5-HT）转运蛋白（SERT）通过其摄取和内化作用促进清除细胞外5-HT。 SERT的表达降低和随之而来的5-HT高水平与多种腹泻有关。因此，适当调节SERT对维持健康和疾病中的5-HT稳态至关重要。先前的研究表明，SERT受翻译后和转录机制的调控。但是，表观遗传机制在SERT调控中的作用尚不清楚。当前的研究调查了组蛋白脱乙酰基酶（HDAC）抑制对SERT表达的影响并描述了其机制。用pan-HDAC抑制剂丁酸盐（5 mM）和曲古抑素（TSA，1μM）处理Caco-2细胞可降低SERT mRNA和蛋白水平。丁酸酯或TSA诱导的SERT降低与人类SERT（hSERT）启动子1（外显子1a上游）的活性降低相关，而与hSERT启动子2（外显子2上游）的活性降低相关。丁酸+ TSA对SERT表达未显示累加作用，表明可能参与了涉及组蛋白超乙酰化的机制。染色质免疫沉淀分析表明，hSERT启动子1（nt -250 / + 2侧翼）富集了四乙酰化组蛋白H3或H4，丁酸酯使之增加（〜3倍）。有趣的是，利用小分子干扰RNA特异性抑制HDAC2（而非HDAC1）可降低SERT mRNA和蛋白质水平。在体内模型中概括了由HDAC抑制引起的SERT表达下降。与饲喂无纤维饮食的对照组（-50-60％）相比，饲喂果胶的小鼠的回肠和结肠中的SERT mRNA水平降低（增加了丁酸酯的利用率）。我们的结果确定了HDAC2作为肠道上皮细胞中SERT基因表达的调节剂的新作用。

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