Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ).
Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ).
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全基因组分析通过过氧化物酶体增殖物激活受体-β/δ（PPARβ/δ）定义了不同的转录调节模式。
DOI：
10.1371/journal.pone.0016344
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发表时间：
2011-01-19
期刊：
影响因子：
3.7
通讯作者：
Müller R
中科院分区：
文献类型：
--
作者：
Adhikary T;Kaddatz K;Finkernagel F;Schönbauer A;Meissner W;Scharfe M;Jarek M;Blöcker H;Müller-Brüsselbach S;Müller R
过氧化物酶体增殖物激活受体（Peroxisome proliferator-activated receptor，PPARs）是一类在脂质、葡萄糖和能量稳态、细胞分化、炎症和代谢紊乱中具有重要功能的核受体，是重要的药物靶点。PPARs与类维生素A X受体（RXR）异源二聚化，并可在特异性DNA元件（PPREs）处形成转录激活因子或抑制因子复合物。据信，抑制和激活之间的决定通常由配体介导的开关决定。我们对激动剂处理和PPARβ/δ缺失的人肌成纤维细胞进行了全基因组分析，以验证这一假设，并确定PPARβ/δ介导的基因调控的总体原则。染色质免疫沉淀测序通过对PPARβ/δ、H3 K4 me 3和RNA聚合酶II富集位点的ChIP-Seq分析，结合转录谱分析，能够确定112个真正的PPARβ/δ靶基因，这些靶基因表现出以下三种不同类型的转录反应：（I）PPARβ/δ的配体非依赖性抑制;（II）配体诱导的PPARβ/δ激活和/或去抑制;和（III）通过PPARβ/δ的配体非依赖性激活。这些数据将PPRE介导的抑制确定为通过PPARβ/δ进行转录调节的主要机制，但是，出乎意料地，也表明只有一部分被抑制的基因被配体介导的开关激活。我们的研究结果还表明，特定靶基因的转录反应类型与其相关PPRE的结构及其编码蛋白的生物学功能有关。这些观察结果对于理解调节性PPAR网络和基于PPARβ/δ配体的药物具有重要意义。
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with essential functions in lipid, glucose and energy homeostasis, cell differentiation, inflammation and metabolic disorders, and represent important drug targets. PPARs heterodimerize with retinoid X receptors (RXRs) and can form transcriptional activator or repressor complexes at specific DNA elements (PPREs). It is believed that the decision between repression and activation is generally governed by a ligand-mediated switch. We have performed genomewide analyses of agonist-treated and PPARβ/δ-depleted human myofibroblasts to test this hypothesis and to identify global principles of PPARβ/δ-mediated gene regulation. Chromatin immunoprecipitation sequencing (ChIP-Seq) of PPARβ/δ, H3K4me3 and RNA polymerase II enrichment sites combined with transcriptional profiling enabled the definition of 112 bona fide PPARβ/δ target genes showing either of three distinct types of transcriptional response: (I) ligand-independent repression by PPARβ/δ; (II) ligand-induced activation and/or derepression by PPARβ/δ; and (III) ligand-independent activation by PPARβ/δ. These data identify PPRE-mediated repression as a major mechanism of transcriptional regulation by PPARβ/δ, but, unexpectedly, also show that only a subset of repressed genes are activated by a ligand-mediated switch. Our results also suggest that the type of transcriptional response by a given target gene is connected to the structure of its associated PPRE(s) and the biological function of its encoded protein. These observations have important implications for understanding the regulatory PPAR network and PPARβ/δ ligand-based drugs.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
10.8
作者：
Ali, Faisal;Ali, Nadira S.;Mason, Justin C.
通讯作者：
Mason, Justin C.
影响因子：
64.5
作者：
Jepsen, K;Hermanson, O;Rosenfeld, MG
通讯作者：
Rosenfeld, MG
影响因子：
4.5
作者：
Girroir, Elizabeth E.;Hollingshead, Holly E.;Peters, Jeffrey M.
通讯作者：
Peters, Jeffrey M.
影响因子：
4.8
作者：
Mandard, S;Zandbergen, F;Kersten, S
通讯作者：
Kersten, S