Synchronous recruitment of epigenetic modifiers to endotoxin synergistically activated Tnf-α gene in acute kidney injury.
Synchronous recruitment of epigenetic modifiers to endotoxin synergistically activated Tnf-α gene in acute kidney injury.
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DOI：
10.1371/journal.pone.0070322
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Denisenko O
中科院分区：
文献类型：
--
作者：
Bomsztyk K;Flanagin S;Mar D;Mikula M;Johnson A;Zager R;Denisenko O
作为急性肾损伤的结果，近端肾小管上皮细胞对内毒素(脂多糖)的高反应是通过过度产生肾脏肿瘤坏死因子-α。这种内毒素的高反应性是由转录调节的。控制这些反应的表观遗传途径尚不清楚。本研究应用多重染色质免疫沉淀平台(MATRIX CHIP)，探讨小鼠急性肾损伤模型单侧肾缺血/再灌注(I/R)模型内毒素高反应性的表观遗传机制。I/R后暴露内毒素导致转录增强，表现为核糖核酸聚合酶II(POL II)在肿瘤坏死因子-α基因处的高反应性募集。在该位点，LPS而不是I/R增加了POLII C末端结构域(CTD)phsho-serine2&5的水平，并诱导了转录抑制组蛋白H4磷酸化-丝氨酸-1的去磷酸化。相反，I/R而不是内毒素增加了肿瘤坏死因子-α基因转录许可的组蛋白磷酸化(H3磷酸化丝氨酸-10，H3.3磷酸化丝氨酸-31)。与这些观察结果相一致的是，I/R而不是内毒素增加了肿瘤坏死因子-α基因座上同源激酶(ERK1/2、Msk1/2和Aurora A)的活性。组蛋白磷酸化和乙酰化的串扰协同作用于活跃的基因表达。I/R和内毒素可促进组蛋白乙酰化。(H3K9/14Ac、H4K5/8/12/16Ac、H2KA5Ac、H2BK4/7Ac)。一些组蛋白乙酰转移酶(PCAF和MOF)的水平在I/R后升高，但不受LPS的影响，而另一些则由I/R或LPS诱导，并表现出内毒素高反应模式(GCN5、CBP和p300)。接头蛋白14-3-3将组蛋白磷酸化与乙酰化偶联，并将染色质修饰物/转录延伸因子与靶基因连接。I/R和内毒素均增加肿瘤坏死因子-γ基因14-3-3和几种染色质/转录修饰物(BRD4、BRG1、HP-1α和IKKα)的水平，均表现出与POL II相似的内毒素高反应性募集模式。我们的结果表明，I/R和内毒素不同地触发了与肿瘤坏死因子-α基因相互作用的磷酸化(POL II和组蛋白)和乙酰化(组蛋白)表观遗传途径，从而在AKI中产生内毒素高反应。
As a consequence of acute kidney injury (AKI), proximal tubular cells hyperrespond to endotoxin (lipopolysaccharide, LPS) by exaggerated renal Tnf-α Production. This LPS hyperresponsiveness is transcriptionally mediated. The epigenetic pathways that control these responses are unknown. We applied multiplex chromatin immunoprecipitation platform (Matrix ChIP) to explore epigenetic pathways that underlie endotoxin hyperresponsiveness in the setting of preceding unilateral renal ischemia/reperfusion (I/R) in mouse AKI model. Endotoxin exposure after I/R resulted in enhanced transcription, manifested by hyperresponsive recruitment of RNA polymerase II (Pol II) at the Tnf-α gene. At this locus, LPS but not I/R increased levels of Pol II C-terminal domain (CTD) phosho-serine2 &5 and induced dephosphorylation of the transcription-repressive histone H4 phospho-serine-1. In contrast, I/R but not LPS increased the transcription-permissive histone phosphorylation (H3 phospho-serine-10, H3.3 phospho-serine-31) at the Tnf-α gene. In agreement with these observations, I/R but not LPS increased activity of cognate kinases (Erk1/2, Msk1/2 and Aurora A) at the Tnf-α locus. Cross-talk of histone phosphorylation and acetylation synergize to active gene expression. I/R and LPS increased histone acetylation. (H3K9/14Ac, H4K5/8/12/16Ac, H2KA5Ac, H2BK4/7Ac). Levels of some histone acetyltransferases at this gene (PCAF and MOF) were increased by I/R but not by LPS, while others were induced by either I/R or LPS and exhibited endotoxin hyperresponsive patterns (GCN5, CBP and p300). The adaptor protein 14-3-3 couples histone phosphorylation with acetylation, and tethers chromatin modifiers/transcription elongation factors to target genes. Both I/R and LPS increased levels of 14-3-3 and several chromatin/transcription modifiers (BRD4, BRG1, HP-1γ and IKKα) at the Tnf-α gene, all exhibiting endotoxin hyperresponsive recruitment patterns similar to Pol II. Our results suggest that I/R and LPS differentially trigger phosphorylation (Pol II and histone) and acetylation (histone) epigenetic pathways that interact at the Tnf-α gene to generate endotoxin hyperresponse in AKI.
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DOI：
10.1097/01.asn.0000064946.94590.46
发表时间：
2003-06-01
影响因子：
13.6
作者：
Kelly, KJ
通讯作者：
Kelly, KJ
影响因子：
10.5
作者：
Kwon, So Hee;Florens, Laurence;Workman, Jerry L.
通讯作者：
Workman, Jerry L.
影响因子：
14.9
作者：
Drobic B;Pérez-Cadahía B;Yu J;Kung SK;Davie JR
通讯作者：
Davie JR
影响因子：
4.5
作者：
Lavigne M;Eskeland R;Azebi S;Saint-André V;Jang SM;Batsché E;Fan HY;Kingston RE;Imhof A;Muchardt C
通讯作者：
Muchardt C
DOI：
10.1073/pnas.91.2.812
发表时间：
1994-01-18
影响因子：
11.1
作者：
KELLY, KJ;WILLIAMS, WW;BONVENTRE, JV
通讯作者：
BONVENTRE, JV