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Identification of a binding motif specific to HNF4 by comparative analysis of multiple nuclear receptors.

ABSTRACT: Nuclear receptors (NRs) regulate gene expression by binding specific DNA sequences consisting of AG[G/T]TCA or AGAACA half site motifs in a variety of configurations. However, those motifs/configurations alone do not adequately explain the diversity of NR function in vivo. Here, a systematic examination of DNA binding specificity by protein-binding microarrays (PBMs) of three closely related human NRs--HNF4?, retinoid X receptor alpha (RXR?) and COUPTF2--reveals an HNF4-specific binding motif (H4-SBM), xxxxCAAAGTCCA, as well as a previously unrecognized polarity in the classical DR1 motif (AGGTCAxAGGTCA) for HNF4?, RXR? and COUPTF2 homodimers. ChIP-seq data indicate that the H4-SBM is uniquely bound by HNF4? but not 10 other NRs in vivo, while NRs PXR, FXR?, Rev-Erb? appear to bind adjacent to H4-SBMs. HNF4-specific DNA recognition and transactivation are mediated by residues Asp69 and Arg76 in the DNA-binding domain; this combination of amino acids is unique to HNF4 among all human NRs. Expression profiling and ChIP data predict ? 100 new human HNF4? target genes with an H4-SBM site, including several Co-enzyme A-related genes and genes with links to disease. These results provide important new insights into NR DNA binding.

SUBMITTER: Fang B

PROVIDER: S-EPMC3384313 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Identification of a binding motif specific to HNF4 by comparative analysis of multiple nuclear receptors.

Fang Bin B Mane-Padros Daniel D Bolotin Eugene E Jiang Tao T Sladek Frances M FM

Nucleic acids research 20120301 12

Nuclear receptors (NRs) regulate gene expression by binding specific DNA sequences consisting of AG[G/T]TCA or AGAACA half site motifs in a variety of configurations. However, those motifs/configurations alone do not adequately explain the diversity of NR function in vivo. Here, a systematic examination of DNA binding specificity by protein-binding microarrays (PBMs) of three closely related human NRs--HNF4α, retinoid X receptor alpha (RXRα) and COUPTF2--reveals an HNF4-specific binding motif (H ...[more]

PMID: 22383578

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Identification of a binding motif specific to HNF4 by comparative analysis of multiple nuclear receptors.

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Identification of a binding motif specific to HNF4 by comparative analysis of multiple nuclear receptors.

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