GROWTH HORMONE GENE EXPRESSION AND HISTONE ACETYLATION

人类生长激素(HGH)基因簇包括脑下垂体和 胎盘特有的基因，对正常生长和 发育和成年期的生理学。HGH的不当调控 基因簇会导致严重的病理后果，并说明 HGH基因在出生后生长、代谢控制、 和妊娠生理学。一组远端hGH调节元件， 被称为轨迹控制区(LCR)的基因已被识别并显示为 对于hGH在脑下垂体中的适当表达是必不可少的 还有胎盘。然而，潜在的机制(S)的作用 一般情况下，远程元素，尤其是LCR元素不是很好 已定义。定义LCR活动的基础机制是 HGH LCR特别重要，因为它密切相关 与其他至少有4种不同组织特异性的基因相关联。这个 LCR的各种成分参与了适当的组织特异性 HGH基因簇在垂体和胎盘中的表达 通过他们的DNase I超敏反应(HS)来鉴定。在脑下垂体 核是hGH LCR中4个调控决定因素的子集 在远离基因簇的5‘侧翼区中检测到 (命名为HSI、II、III、V)和胎盘合体滋养细胞 核，3个调控决定因素的子集被检测到(指定为 HSIII、IV、V)。这项提案的重点将是澄清 垂体和胎盘HS活性的机制(S) 组蛋白乙酰化在HS功能/基因中的作用 激活。目的我将验证组蛋白乙酰化在 LCR中的关键控制决定因素(HS)将与 HGH基因簇中的组织特异性基因激活。AIM II将 验证CBP/p300组蛋白乙酰化酶介导 组蛋白的组织特异性和靶向性超乙酰化 这些特定的HS。这项研究的结果将提供一种新颖的 洞察LCR功能的潜在机制(S)及其如何 适当的基因表达谱被建立、调节和 在发育过程中维持在特定的细胞谱系中。

The human growth hormone (hGH) gene cluster encompasses pituitary and placenta specific genes that are essential for normal growth and physiology during development and in adulthood. Misregulation of the hGH gene cluster results in severe pathological consequences and illustrates the importance of the hGH genes in postnatal growth, metabolic control, and gestational physiology. A set of distal hGH regulatory elements, termed the locus control region (LCR), has been identified and shown to be essential for the appropriate expression of the hGH in the pituitary and placenta. However, the mechanism(s) underlying the functions of remote elements in general, and LCR elements in particular, are not well defined. Defining the mechanisms underlying LCR activity is of particular importance in the case of the hGH LCR as it is closely linked to other genes with at least 4 distinct tissue specificities. The various elements of the LCR involved in the appropriate tissue-specific expression of the hGH gene cluster in the pituitary and placenta were identified by their DNase I hypersensitivity (HS). In the pituitary nuclei, a subset of 4 regulatory determinants in the hGH LCR were detected in the 5'-flanking region remote from the gene cluster (designated HSI,II,III,V) and in the placenta syncytiotrophoblastic nuclei, a subset of 3 regulatory determinants were detected (designated HSIII,IV,V). The focus of this proposal will be to elucidate the mechanism(s) underlying HS activity in the pituitary and placenta by investigating the role of histone acetylation in HS function/gene activation. Aim I will test the hypothesis that histone acetylation at critical control determinants (HS) within the LCR will correlate with tissue specific gene activation from the hGH gene cluster. Aim II will test the hypothesis that the CBP/p300 histone acetylase mediates the tissue-specific and targeted hyperacetylation of histone proteins at these specific HS. The outcome of this research will provide a novel insight into the mechanism(s) underlying LCR function and how appropriate gene expression profiles are established, regulated and maintained in specific cell lineages during development.