Identification of a binding motif specific to HNF4 by comparative analysis of multiple nuclear receptors.
Identification of a binding motif specific to HNF4 by comparative analysis of multiple nuclear receptors.
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DOI：
10.1093/nar/gks190
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发表时间：
2012-07
影响因子：
14.9
通讯作者：
Sladek FM
中科院分区：
文献类型：
--
作者：
Fang B;Mane-Padros D;Bolotin E;Jiang T;Sladek FM
核受体（Nuclear receptors，NR）通过结合由AG[G/T]TCA或AGAACA半位点基序组成的特异性DNA序列来调节基因表达。然而，这些基序/配置本身不足以解释NR功能的多样性在体内。在这里，通过蛋白结合微阵列（PBM）对三种密切相关的人类NR-HNF 4 α、类维生素A X受体α（RXRα）和COUPTF 2-的DNA结合特异性进行了系统性检查，揭示了HNF 4特异性结合基序（H4-SBM）xxxxCAAAGTCCA，以及HNF 4 α、RXRα和COUPTF 2同源二聚体的经典DR 1基序（AGGTCAxAGGTCA）中先前未识别的极性。ChIP-seq数据表明，H4-SBM在体内仅与HNF 4 α结合，而与其他10种NR不结合，而NR PXR、FXRα、Rev-Erbα似乎与H4-SBM相邻结合。HNF 4特异性DNA识别和反式激活由DNA结合结构域中的残基Asp 69和Arg 76介导;这种氨基酸组合在所有人类NR中对HNF 4是独特的。表达谱和ChIP数据预测了约100个新的具有H4-SBM位点的人类HNF 4 α靶基因，包括几个辅酶A相关基因和与疾病相关的基因。这些结果为NR DNA结合提供了重要的新见解。
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 (H4-SBM), xxxxCAAAGTCCA, as well as a previously unrecognized polarity in the classical DR1 motif (AGGTCAxAGGTCA) for HNF4α, RXRα and COUPTF2 homodimers. ChIP-seq data indicate that the H4-SBM is uniquely bound by HNF4α but not 10 other NRs in vivo, while NRs PXR, FXRα, Rev-Erbα 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 HNF4α 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.
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影响因子：
14.9
作者：
Egener T;Roulet E;Zehnder M;Bucher P;Mermod N
通讯作者：
Mermod N
影响因子：
14.8
作者：
Berger, Michael F.;Bulyk, Martha L.
通讯作者：
Bulyk, Martha L.
影响因子：
14.9
作者：
Cui JY;Gunewardena SS;Rockwell CE;Klaassen CD
通讯作者：
Klaassen CD
影响因子：
23.9
作者：
Heng, Jian-Chien Dominic;Feng, Bo;Ng, Huck-Hui
通讯作者：
Ng, Huck-Hui
DOI：
10.1126/science.1198125
发表时间：
2011-03-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Feng D;Liu T;Sun Z;Bugge A;Mullican SE;Alenghat T;Liu XS;Lazar MA
通讯作者：
Lazar MA