Dynamics of nucleosome positioning and the role of chromatin in myogenesis

真核生物的DNA是通过包裹 一种结构称为染色质的组蛋白。这种衰老会影响基因 含有基因的浓缩染色质区域及其相关的 转录激活因子无法接近的调控元件。的调制 因此，染色质结构是转录调节的关键介质之一。 染色质最基本的单位是核小体，它由大约 146个碱基对的DNA包裹在组蛋白的八聚体上。的精确 将核小体定位在基因组的功能调节区中可以直接 影响附近基因的转录调控。ATP依赖染色质 重塑酶，组蛋白和DNA序列的翻译后修饰 本身都涉及调节核小体在特定位置的定位， 基因组的区域。我们建议调查每一个的作用， 果蝇核小体定位的调控机制 黑腹和人类基因组，并进一步开始阐明 染色质与转录因子在基因调控中的关系。我们将首先 研究染色质重塑酶如何被招募的基本问题， 它们的靶点以及ATP依赖的染色质重塑、组蛋白修饰和 利用培养果蝇研究DNA序列相互作用对核小体定位的影响 细胞从果蝇细胞的这些实验中获得的见解， 应用于人类造血细胞的类似实验， 涉及谱系特化的转录因子网络已经被广泛地 研究了通过整合核小体定位和染色质重塑的数据， 在这些细胞中已经建立的转录因子程序，我将能够研究 染色质和转录因子之间的相互作用，在调节 细胞在发育过程中的转录程序。这些研究将导致更大的 理解负责核小体组织的机制 并进一步阐明染色质在调节 转录。

The DNA of eukaryotic organisms is pacl<aged into the nucleus by wrapping around histone proteins in a structure l<nown as chromatin. This pacl<aging can influence gene regulation with condensed chromatin regions containing genes and their associated regulatory elements that are inaccessible to transcriptional activators. The modulation of chromatin structure is therefore one of the key mediators of transcriptional regulation. The most basic unit of chromatin is the nucleosome, which consists of approximately 146 base pairs of DNA wrapped around an octamer of histone proteins. The precise positioning of nucleosomes in functional regulatory regions of the genome can directly influence the transcriptional regulation of nearby genes. ATP-dependent chromatin remodeling enzymes, post-translational modifications to histones and the DNA sequence itself have all been implicated in regulating the positioning of nucleosomes at specific regions of the genome. We propose to investigate the roles of each of these mechanisms in regulating the positioning of nucleosomes in the Drosophila melanogaster and human genomes and furthermore to begin to elucidate the relationship between chromatin and transcription factors in gene regulation. We will first investigate the basic questions of how chromatin remodeling enzymes are recruited to their targets and how ATP-dependent chromatin remodeling, histone modifications and DNA sequence interact to regulate nucleosome positioning by using cultured Drosophila cells. The insights obtained from these experiments in Drosophila cells will then be applied to analogous experiments in human hematopoietic cells, a system for which the network of transcription factors involved in lineage specification has been extensively studied. By integrating data on nucleosome positioning and chromatin remodeling with the already established transcription factor programs in these cells, I will be able to study the interactions between chromatin and transcription factors in regulating the transcriptional programs of cells during development. These studies will lead to a greater understanding of the mechanisms responsible for the organization of nucleosomes across the genome and further elucidate the role of chromatin in the regulation of transcription.