Coactivator-associated arginine methyltransferase-1 enhances nuclear factor-κB-mediated gene transcription through methylation of histone H3 at arginine 17
Coactivator-associated arginine methyltransferase-1 enhances nuclear factor-κB-mediated gene transcription through methylation of histone H3 at arginine 17
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DOI：
10.1210/me.2005-0365
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发表时间：
2006-07-01
影响因子：
--
通讯作者：
Natarajan, Rama
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文献类型：
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作者：
Miao, Feng;Li, ShuLian;Natarajan, Rama
已知辅激活因子相关精氨酸甲基转移酶-1 (CARM1) 通过与辅激活因子 p160 和 cAMP 反应元件结合蛋白结合蛋白 (CBP) 的相互作用以及组蛋白 H3 在精氨酸 17 (H3-R17) 的甲基化来增强核受体的转录激活。在这里，我们证明 CARM1 可以作为转录因子核因子 kappa B (NF-kappa B) 的共激活子，并以 CBP (p300) 依赖性方式增强 NF-kappa B 活性。通过与靶向敲低 CARM1 的特定短发夹 RNA 共转染，293T 细胞中的这种增强作用被消除。染色质免疫沉淀证明 CARM1 在体内招募到 NF-kappa B p65 调节基因的启动子以及 CBP 和类固醇受体辅激活因子 1。这伴随着组蛋白 H3-R17 甲基化以及 H3-K9 和 H3-K14 乙酰化的增加，以及 H3-瓜氨酸的减少。使用抗 p65 抗体进行免疫沉淀显示 CARM1 与 NF-κ B p65 发生物理相互作用。此外，我们通过观察用 TNF-α 或 S100b（晚期糖基化终产物受体的配体）刺激 THP-1 单核细胞时发生的类似事件来证明其生理意义，这两者都与糖尿病并发症相关，并且也是单核细胞中已知的 NF-κ B 和炎症基因的诱导剂。这些结果表明，CARM1 通过 H3-R17 甲基化参与 NF-kappa B 介导的转录，并支持 CARM1 的非核受体相关功能。他们还首次证明，CARM1 占据、组蛋白 H3-R17 甲基化和瓜氨酸化在单核细胞炎症基因的启动子处受到调节，从而表明组蛋白精氨酸修饰在炎症疾病中的新作用。
Coactivator-associated arginine methyltransferase-1 (CARM1) is known to enhance transcriptional activation by nuclear receptors through interactions with the coactivators p160 and cAMP response element binding protein-binding protein (CBP) and methylation of histone H3 at arginine 17 (H3-R17). Here, we show that CARM1 can act as a coactivator for the transcription factor nuclear factor-kappa B (NF-kappa B) and enhance NF-kappa B activity in a CBP (p300)-dependent manner. This enhancement in 293T cells was abolished by cotransfection with a specific short hairpin RNA targeted to knockdown CARM1. Chromatin immunoprecipitation demonstrated CARM1 recruitment in vivo to the promoters of NF-kappa B p65-regulated genes along with CBP and steroid receptor coactivator-1. This was accompanied by an increase in histone H3-R17 methylation as well as H3-K9 and H3-K14 acetylation, and a decrease in H3-citrulline. Immunoprecipitation with anti-p65 antibody revealed that CARM1 physically interacts with NF-kappa B p65. Furthermore, we demonstrated the physiological significance by observing that similar events occurred when THP-1 monocytic cells were stimulated with TNF-alpha or with S100b, a ligand for the receptor of advanced glycation end products, both of which are associated with diabetic complications and also known inducers of NF-kappa B and inflammatory genes in monocytes. These results demonstrate that CARM1 participates in NF-kappa B-mediated transcription through H3-R17 methylation and support a nonnuclear receptor-associated function for CARM1. They also demonstrate for the first time that CARM1 occupancy, histone H3-R17 methylation, and citrullination are regulated at the promoters of inflammatory genes in monocytes, thereby suggesting a novel role for histone arginine modifications in inflammatory diseases.