GROWTH HORMONE GENE EXPRESSION AND HISTONE ACETYLATION

人生长激素（hGH）基因簇包括垂体和垂体前叶。 胎盘特异性基因对正常生长至关重要， 在发育和成年期间的生理学。hGH的失调 基因簇导致了严重的病理后果， hGH基因在出生后生长，代谢控制， 和妊娠生理学 一组远端hGH调控元件， 称为基因座控制区（LCR），已被确定，并显示， 对垂体中hGH的适当表达至关重要 和胎盘。 然而，这些职能所依据的机制 一般来说，远程元件，特别是LCR元件， 定义了 定义LCR活动的潜在机制是 在hGH LCR的情况下特别重要，因为它与 与其他至少有4种不同组织特异性的基因。 的 LCR的各种元素参与适当的组织特异性 hGH基因簇在垂体和胎盘中的表达， 通过它们的DNA酶I超敏性（HS）鉴定。 垂体 细胞核，hGH LCR中4个调节决定簇的子集， 在远离基因簇的5 '侧翼区检测到 （命名为HSI，II，III，V）和胎盘合体滋养层细胞 在细胞核中，检测到3个调节决定簇的子集（指定为 HSIII，IV，V）. 本提案的重点将是阐明 垂体和胎盘中HS活性的潜在机制 研究组蛋白乙酰化在HS功能/基因中的作用 activation. 目的验证组蛋白乙酰化在 LCR中的关键控制决定因素（HS）将与 hGH基因簇的组织特异性基因激活。 Aim II将 检验CBP/p300组蛋白乙酰化酶介导 组织特异性和靶向的组蛋白超乙酰化. 这些特殊的HS。 这项研究的结果将提供一个新的 深入了解LCR功能的潜在机制以及如何 适当的基因表达谱被建立、调节并 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.