RORγ directly regulates the circadian expression of clock genes and downstream targets in vivo.
RORγ directly regulates the circadian expression of clock genes and downstream targets in vivo.
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DOI：
10.1093/nar/gks630
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发表时间：
2012-09-01
影响因子：
14.9
通讯作者：
Jetten AM
中科院分区：
文献类型：
--
作者：
Takeda Y;Jothi R;Birault V;Jetten AM
在这项研究中，我们证明了维甲酸相关孤儿受体(ROR) γ或α在小鼠中表达的缺乏显著降低了Cry1、Bmal1、E4bp4、Rev-Erbα和Per2在ROR同型和组织选择性方式下的峰值表达水平，而不影响其节律性表达的阶段。对RORγ/RORα双敲除小鼠的分析表明，在某些组织中，RORγ和RORα在调节时钟基因表达方面表现出一定程度的冗余。报告基因分析表明，RORγ能够通过Cry1、Bmal1、Rev-Erbα和E4bp4等含有RORγ的调控区域诱导报告基因活性。Rev-Erbα的共表达或新的ROR拮抗剂的加入抑制了这种激活。ChIP-Seq和ChIP-Quantitative real-time polymerase chain reaction （QPCR）分析表明，在体内，RORγ通过这些ROREs直接调控这些基因，并以Zeitgeber time （ZT）依赖的方式调控这些基因。RORs的转录激活与组蛋白乙酰化和染色质可及性的变化有关。时钟蛋白对rorγ - 1的节律性表达可能导致rorγ - 1靶基因的节律性表达。RORγ结合位点的存在及其在RORγ−/−肝脏中的下调表明，Avpr1a的节律性表达依赖于RORγ，这与RORγ1在时钟机制及其对代谢基因的调节之间提供联系的概念一致。
In this study, we demonstrate that the lack of retinoic acid-related orphan receptor (ROR) γ or α expression in mice significantly reduced the peak expression level of Cry1, Bmal1, E4bp4, Rev-Erbα and Per2 in an ROR isotype- and tissue-selective manner without affecting the phase of their rhythmic expression. Analysis of RORγ/RORα double knockout mice indicated that in certain tissues RORγ and RORα exhibited a certain degree of redundancy in regulating clock gene expression. Reporter gene analysis showed that RORγ was able to induce reporter gene activity through the RORE-containing regulatory regions of Cry1, Bmal1, Rev-Erbα and E4bp4. Co-expression of Rev-Erbα or addition of a novel ROR antagonist repressed this activation. ChIP-Seq and ChIP–Quantitative real-time polymerase chain reaction (QPCR) analysis demonstrated that in vivo RORγ regulate these genes directly and in a Zeitgeber time (ZT)-dependent manner through these ROREs. This transcriptional activation by RORs was associated with changes in histone acetylation and chromatin accessibility. The rhythmic expression of RORγ1 by clock proteins may lead to the rhythmic expression of RORγ1 target genes. The presence of RORγ binding sites and its down-regulation in RORγ−/− liver suggest that the rhythmic expression of Avpr1a depends on RORγ consistent with the concept that RORγ1 provides a link between the clock machinery and its regulation of metabolic genes.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
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作者：
Lau, Patrick;Fitzsimmons, Rebecca L.;Muscat, George E. O.
通讯作者：
Muscat, George E. O.
DOI：
10.1073/pnas.0902425106
发表时间：
2009-10-13
影响因子：
11.1
作者：
Jia, Li;Oh, Edwin C. T.;Forrest, Douglas
通讯作者：
Forrest, Douglas
DOI：
10.1621/nrs.07003
发表时间：
2009
期刊：
Nuclear receptor signaling
影响因子：
--
作者：
Jetten AM
通讯作者：
Jetten AM
影响因子：
4.6
作者：
Kang, Hong Soon;Okamoto, Kyoko;Jetten, Anton M.
通讯作者：
Jetten, Anton M.