Genome-wide tissue-specific farnesoid X receptor binding in mouse liver and intestine.
Genome-wide tissue-specific farnesoid X receptor binding in mouse liver and intestine.
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DOI：
10.1002/hep.23450
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发表时间：
2010-04
期刊：
影响因子：
--
通讯作者：
Guo GL
中科院分区：
文献类型：
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作者：
Thomas AM;Hart SN;Kong B;Fang J;Zhong XB;Guo GL
法尼醇X受体（Farnesoid X receptor，FXR）是胆汁酸激活的转录因子，属于核受体超家族。FXR在肝和肠中高度表达，并且在这两个器官中由FXR介导的串扰对于维持胆汁酸稳态至关重要。FXR缺乏与许多肝脏和肠道疾病有关。然而，FXR在基因组水平上对转录的调控尚不清楚。本研究通过染色质免疫沉淀结合大规模平行测序（ChIP-seq）分析了用合成FXR配体（GW 4064）处理的小鼠肝脏和肠道中的全基因组FXR结合。结果显示，FXR结合具有很大程度的组织特异性，只有11%的位点在肝脏和肠道之间共享。这些位点广泛分布在基因间、上游、基因内和基因下游，甚至在已知的FXR靶基因中也发现了新的位点。基序分析揭示了一个半核受体结合位点，通常由一些孤儿核受体结合，邻近FXR反应元件，表明可能参与一些孤儿核受体调节FXR功能。此外，途径分析表明，FXR可能广泛参与多种细胞代谢途径。本研究报告了体内全基因组FXR结合，结果清楚地表明了组织特异性FXR/基因相互作用。此外，FXR可能参与调节维持肝脏和肠道稳态的更广泛的生物学途径。
Farnesoid X receptor (FXR) is a bile acid-activated transcription factor belonging to the nuclear receptor superfamily. FXR is highly expressed in liver and intestine and crosstalk mediated by FXR in these two organs is critical in maintaining bile acid homeostasis. FXR deficiency has been implicated in many liver and intestine diseases. However, regulation of transcription by FXR at the genomic level is not known. This study analyzed genome-wide FXR binding in liver and intestine of mice treated with a synthetic FXR ligand (GW4064) by chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq). The results showed a large degree of tissue-specific FXR binding, with only 11% of total sites shared between liver and intestine. The sites were widely distributed between intergenic, upstream, intragenic, and downstream of genes, with novel sites identified within even known FXR target genes. Motif analysis revealed a half nuclear receptor binding site, normally bound by a few orphan nuclear receptors, adjacent to the FXR response elements, indicating possible involvement of some orphan nuclear receptors in modulating FXR function. Furthermore, pathway analysis indicated that FXR may be extensively involved in multiple cellular metabolic pathways. This study reports genome-wide FXR binding in vivo and the results clearly demonstrate tissue-specific FXR/gene interaction. In addition, FXR may be involved in regulating broader biological pathways in maintaining hepatic and intestinal homeostasis.