Farnesoid X Receptor Activation Mediates Head-to-Tail Chromatin Looping in the Nr0b2 Gene Encoding Small Heterodimer Partner
Farnesoid X Receptor Activation Mediates Head-to-Tail Chromatin Looping in the Nr0b2 Gene Encoding Small Heterodimer Partner
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DOI：
10.1210/me.2010-0014
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发表时间：
2010-07-01
影响因子：
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通讯作者：
Guo, Grace L.
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文献类型：
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作者：
Li, Guodong;Thomas, Ann M.;Guo, Grace L.
小异源二聚体伴侣（small heterodimer partner，SHP）是一种独特的核受体，它只与配体结合而不与DNA结合，可与多种转录因子相互作用，抑制转录因子的功能。然而，SHP表达的调节还没有得到很好的理解。SHP在肝脏中高度表达，先前的研究表明法尼醇X受体（FXR）通过与编码SHP的Nr 0 b2基因启动子中的FXR反应元件（FXRRE）结合来高度诱导SHP。FXR-SHP途径在维持胆汁酸和脂肪酸稳态中至关重要。在通过染色质免疫沉淀（ChIP）结合大规模平行测序（ChIP-seq）进行全基因组FXR结合后，在Nr 0 b2基因的3 '-增强子区域发现了一种新的FXRRE。这种由一个核苷酸分隔的下游反向重复序列在整个哺乳动物物种中是高度保守的。我们假设这个下游FXRRE是功能性的，并且可以通过与近端启动子FRXRE相互作用来介导头-尾染色质环，以增加SHP转录效率。在目前的研究中，ChIP-定量PCR检测显示FXR与小鼠肝脏中的该下游FXRRE强烈结合。下游FXRRE对于荧光素酶基因转录激活以及缺失和定点诱变所揭示的FXR介导的转录激活是重要的。染色质构象捕获法检测染色质成环，结果证实位于Nr 0 b2启动子和下游增强子的两个FXRRE相互作用形成了一个首尾相连的染色质环。到目前为止，在肝脏中还没有报道过头-尾染色质环。总之，我们的研究结果表明，FXR的激活有效地诱导SHP转录的机制是通过头到尾染色质环。（分子内分泌学24：1404-1412，2010）
As a unique nuclear receptor with only ligand-binding but no DNA-binding domain, small heterodimer partner (SHP) interacts with many transcription factors to inhibit their function. However, the regulation of SHP expression is not well understood. SHP is highly expressed in the liver, and previous studies have shown farnesoid X receptor (FXR) highly induces SHP by binding to a FXR response element (FXRRE) in the promoter of the Nr0b2 gene, which encodes SHP. The FXR-SHP pathway is critical in maintaining bile acid and fatty acid homeostasis. After genome-wide FXR binding by chromatin immunoprecipitation (ChIP) coupled to massively parallel sequencing (ChIP-seq), a novel FXRRE was found in the 3'-enhancer region of the Nr0b2 gene. This downstream inverted repeat separated by one nucleotide is highly conserved throughout mammalian species. We hypothesized that this downstream FXRRE is functional and may mediate a head-to-tail chromatin looping by interacting with the proximal promoter FRXRE to increase SHP transcription efficiency. In the current study, a ChIP-quantitative PCR assay revealed FXR strongly bound to this downstream FXRRE in mouse livers. The downstream FXRRE is important for FXR-mediated transcriptional activation revealed by luciferase gene transcription activation, as well as by deletion and site-directed mutagenesis. The chromatin conformation capture assay was used to detect chromatin looping, and the result confirmed the two FXRREs located in the Nr0b2 promoter and downstream enhancer interacted to form a head-to-tail chromatin loop. To date, the head-to-tail chromatin looping has not been reported in the liver. In conclusion, our results suggest a mechanism by which activation of FXR efficiently induces SHP transcription is through head-to-tail chromatin looping. (Molecular Endocrinology 24: 1404-1412, 2010)