cAMP prevents glucose-mediated modifications of histone H3 and recruitment of the RNA polymerase II holoenzyme to the L-PK gene promoter.
cAMP prevents glucose-mediated modifications of histone H3 and recruitment of the RNA polymerase II holoenzyme to the L-PK gene promoter.
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DOI：
10.1016/j.jmb.2009.07.053
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发表时间：
2009-09-25
影响因子：
5.6
通讯作者：
Scott DK
中科院分区：
文献类型：
--
作者：
Burke SJ;Collier JJ;Scott DK
葡萄糖和cAMP通过控制含有碳水化合物反应元件结合蛋白（ChREBP）和L-PK启动子上的共激活物CREB结合蛋白（CBP）的复合物的形成来调节L型丙酮酸激酶（L-PK）基因的表达。然而，翻译后组蛋白修饰对葡萄糖和cAMP对L-PK基因的相反作用的作用是未知的。使用高度葡萄糖敏感的832/13大鼠胰岛素瘤细胞系，我们证明了葡萄糖调节L-PK基因启动子处的各种组蛋白残基的乙酰化和甲基化。这些葡萄糖依赖性组蛋白修饰与L-PK基因启动子上RNA聚合酶II（Pol II）的募集和磷酸化增加相关。相反，cAMP激动剂forskolin通过降低启动子上组蛋白H3和H4的乙酰化，降低编码区上H3-K4的甲基化和增加编码区上H3-K9的甲基化来阻止葡萄糖介导的L-PK基因的表达。cAMP诱导的这些变化最终导致磷酸化Pol II向L-PK基因启动子的葡萄糖依赖性募集减少。此外，干扰ChREBP和CBP在L-PK启动子上的葡萄糖依赖性组装的策略，例如：1）增加细胞内cAMP水平; 2）ChREBP的显性负性形式的过表达;或3）siRNA介导的CBP丰度抑制均改变了L-PK启动子上组蛋白的乙酰化和甲基化，其减少Pol II募集并随后抑制L-PK基因的转录激活。我们的结论是，葡萄糖和cAMP的影响介导的组蛋白的表观遗传调制的一部分。
Glucose and cAMP reciprocally regulate expression of the L-type pyruvate kinase (L-PK) gene by controlling the formation of a complex containing Carbohydrate Response Element Binding Protein (ChREBP) and the coactivator CREB Binding Protein (CBP) on the L-PK promoter. However, the role of post-translational histone modifications on the opposing effects of glucose and cAMP on the L-PK gene are unknown. Using the highly glucose-sensitive 832/13 rat insulinoma cell line, we demonstrated that glucose regulates acetylation and methylation of various histone residues at the L-PK gene promoter. These glucose-dependent histone modifications correlated with an increase in the recruitment and phosphorylation of RNA Polymerase II (Pol II) on the L-PK gene promoter. Conversely, the cAMP agonist forskolin prevented glucose-mediated expression of the L-PK gene by decreasing the acetylation of histones H3 and H4 on the promoter, decreasing the methylation of H3-K4 on the coding region and increasing the methylation of H3-K9 on the coding region. These changes induced by cAMP culminated with a decrease in the glucose-dependent recruitment of phosphorylated Pol II to the L-PK gene promoter. Furthermore, maneuvers that interfere with the glucose-dependent assembly of ChREBP and CBP on the L-PK promoter, such as: 1) increasing intracellular cAMP levels; 2) overexpression of a dominant-negative form of ChREBP; or 3) siRNA-mediated suppression of CBP abundance all altered the acetylation and methylation of histones on the L-PK promoter, which decreased Pol II recruitment and subsequently inhibited transcriptional activation of the L-PK gene. We conclude that the effects of glucose and cAMP are mediated in part by epigenetic modulation of histones.
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影响因子：
14.9
作者：
Ma L;Sham YY;Walters KJ;Towle HC
通讯作者：
Towle HC
影响因子：
56.9
作者：
Nakayam, J;Rice, JC;Grewal, SIS
通讯作者：
Grewal, SIS
影响因子：
4.8
作者：
Ma, L;Tsatsos, NG;Towle, HC
通讯作者：
Towle, HC
DOI：
10.1111/j.1432-1033.1992.tb17013.x
发表时间：
1992-07-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
BOQUET, D;VAULONT, S;RAYMONDJEAN, M
通讯作者：
RAYMONDJEAN, M
影响因子：
5.3
作者：
KOLODZIEJ, PA;WOYCHIK, N;YOUNG, RA
通讯作者：
YOUNG, RA