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Genome‐wide tissue‐specific farnesoid X receptor binding in mouse liver and intestine
Author(s) -
Thomas Ann M.,
Hart Steven N.,
Kong Bo,
Fang Jianwen,
Zhong Xiaobo,
Guo Grace L.
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23450
Subject(s) - farnesoid x receptor , nuclear receptor , biology , small heterodimer partner , chromatin immunoprecipitation , transcription factor , liver receptor homolog 1 , microbiology and biotechnology , bile acid , genetics , gene , biochemistry , promoter , gene expression
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. Conclusion: 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. (H EPATOLOGY 2010.)