Chia Dennis J, Young Jennifer J, Mertens April R, Rotwein Peter
Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97239, USA.
Mol Endocrinol. 2010 Apr;24(4):779-89. doi: 10.1210/me.2009-0430. Epub 2010 Feb 16.
Many of the physiological actions of GH are mediated by IGF-I, a secreted 70-residue peptide whose gene expression is induced by GH in the liver and other tissues via mechanisms that remain incompletely characterized but depend on the transcription factor Stat5b. Here we investigate the chromatin landscape of the IGF-I gene in the liver of pituitary-deficient young adult male rats and assess the impact of a single systemic GH injection. Despite minimal ongoing transcription in the absence of GH, both IGF-I promoters appear to reside in open chromatin environments, at least as inferred from relatively high levels of acetylation of core histones H3 and H4 when compared with adjacent intergenic DNA and from enhanced trimethylation of histone H3 at lysine 4. This landscape of open chromatin may reflect maturation of the liver. Surprisingly, in the absence of hormone, IGF-I promoter 1 appears poised to be activated, as evidenced by the presence of the transcriptional coactivator p300 and recruitment of RNA polymerase (Pol) II into a preinitiation complex. By contrast, chromatin surrounding IGF-I promoter 2 is devoid of both p300 and RNA Pol II. Systemic GH treatment causes an approximately 15-fold increase in transcription from each IGF-I promoter within 60 min of hormone administration, leading to a sustained accumulation of IGF-I mRNA. The coordinated induction of both IGF-I promoters by GH is accompanied by hyperacetylation of histones H3 and H4 in promoter-associated chromatin, a decline in monomethylation at lysine 4 of histone H3, and recruitment of RNA Pol II to IGF-I promoter 2. We conclude that GH actions induce rapid and dramatic changes in hepatic chromatin at the IGF-I locus and activate IGF-I gene transcription in the liver by distinct promoter-specific mechanisms: at promoter 1, GH causes RNA Pol II to be released from a previously recruited paused preinitiation complex, whereas at promoter 2, hormone treatment facilitates recruitment and then activation of RNA Pol II to initiate transcription.
生长激素（GH）的许多生理作用是由胰岛素样生长因子-I（IGF-I）介导的，IGF-I是一种分泌型的含70个氨基酸残基的肽，其基因表达在肝脏和其他组织中由GH通过尚未完全明确的机制诱导产生，但依赖于转录因子Stat5b。在此，我们研究了垂体功能缺陷的年轻成年雄性大鼠肝脏中IGF-I基因的染色质状态，并评估了单次全身注射GH的影响。尽管在没有GH的情况下转录活动极少，但两个IGF-I启动子似乎都处于开放染色质环境中，至少从与相邻基因间DNA相比时核心组蛋白H3和H4的相对高水平乙酰化以及组蛋白H3赖氨酸4位点三甲基化增强可以推断出来。这种开放染色质状态可能反映了肝脏的成熟。令人惊讶的是，在没有激素的情况下，IGF-I启动子1似乎已准备好被激活，转录共激活因子p300的存在以及RNA聚合酶（Pol）II募集到预起始复合物中就是证据。相比之下，围绕IGF-I启动子2的染色质既没有p300也没有RNA Pol II。全身注射GH治疗在激素给药后60分钟内使每个IGF-I启动子的转录增加约15倍，导致IGF-I mRNA持续积累。GH对两个IGF-I启动子的协同诱导伴随着启动子相关染色质中组蛋白H3和H4的超乙酰化、组蛋白H3赖氨酸4位点一甲基化的减少以及RNA Pol II募集到IGF-I启动子2。我们得出结论，GH作用在IGF-I基因座处诱导肝脏染色质快速而显著的变化，并通过不同的启动子特异性机制激活肝脏中的IGF-I基因转录：在启动子1处，GH使RNA Pol II从先前募集的暂停预起始复合物中释放，而在启动子2处，激素处理促进RNA Pol II的募集然后激活以启动转录。
