ANALYSIS OF CHROMATIN REMODELING IN MAMMARY GLAND DEVELOPMENT USING TILING ARRAYS

使用平铺阵列分析乳腺发育中的染色质重塑

• 批准号: 7936036
• 负责人: Monique Rijnkels
• 金额: $ 3.55万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936036
• 关键词: Acetylation; Adult; Affect; Antibodies; Attention; Binding; Binding Sites; Biological Assay; Biological Models; Cell Culture Techniques; Cells; Child; Chromatin; Chromatin Structure; Complex; DNA Methylation; DNA Packaging; Data; Development; Developmental Process; Endocrine; Epigenetic Process; Epithelial Cells; Exhibits; Foundations; Gene Expression; Gene Expression Regulation; Genes; Genome; Genomics; Gland; Goals; Growth; Growth and Development function; Histone H3; Histones; Hormones; Hypersensitivity; Knowledge; Lactation; Literature; Mammals; Mammary Gland Parenchyma; Mammary gland; Memory; Milk; Milk Proteins; Molecular Conformation; Molecular Profiling; Mothers; Mus; Newborn Infant; Oligonucleotides; Organogenesis; Pathway interactions; Pattern; Play; Polymerase; Precipitation; Pregnancy; Process; Puberty; RNA Polymerase II; Regulation; Regulatory Element; Research; Role; Solid; Source; Staging; System; Techniques; Technology; Tissue-Specific Gene Expression; Tissues; Transact; Transcription Initiation; Transcriptional Regulation; Work; autocrine; base; chromatin remodeling; frontier; genome-wide; histone modification; mammary gland development; neonate; new technology; nutrition; paracrine; promoter; public health relevance

DESCRIPTION (provided by applicant): The interplay between chromatin structure and transcriptional regulators has an important role in gene regulation throughout development and differentiation. Because the mammary gland develops mostly postnatally and the hormones of puberty and pregnancy tightly regulate its tissue specific gene expression, it makes an excellent model system to study the mechanisms by which chromatin remodeling regulates developmental processes in general. The long-term goal of this research is to determine the role chromatin remodeling plays in the maturation of the mammary gland and regulation of lactation, and identify the pertinent regions in the genome that function as regulatory elements in these processes. Numerous studies have identified the factors involved in transcriptional regulation of mammary specific genes during development. However, the mechanisms by which these genes are regulated globally, at the level of chromatin conformation (epigenetically), to define development and differentiation of the gland have received much less attention. We hypothesize that chromatin remodeling occurs in the mammary gland during development and differentiation, and is an integral part of the regulation of the tissue-specific expression patterns that convey the cellular memory needed for the gland's maturation. A global approach to this problem is now possible with the recent development of ChIP-chip, a new technology combining Chromatin Immuno-precipitation (ChIP) and high-throughput oligonucleotide-tiling arrays (chip). We will use ChIP-chip to establish tissue- and developmental stage-specific patterns of histone modifications (Aim 1a) and RNA-polymerase-II (Aim 1b), in non-mammary, non-locating and lactating mammary gland tissue of the mouse. As milk protein genes are expressed in functionally differentiated mammary epithelial cells, our studies will focus on the genomic domains encompassing these genes, and other developmentally regulated genes. These studies will bring about new knowledge of the factors and pathways regulating mammary gland development and lactation, opening new frontiers in the manipulation of these processes to benefit mother and child. In addition, they will provide a foundation for understanding epigenetic changes that determine differentiation and organogenesis of specific tissues. Public Health Relevance Statement: Milk is the primary source of nutrition for neonates it provides all the essential components for healthy growth and development of newborns of all mammalian species. However, our knowledge of the factors involved in establishing and maintaining lactation is far from complete. In particular the role DNA packaging plays is not well established. In this study we will investigate the DNA packaging in the developing mammary gland at a genome wide scale. These studies will provide a foundation for understanding the mechanisms that determine differentiation and organogenesis of specific tissues.

描述（由申请人提供）：染色质结构和转录调节因子之间的相互作用在整个发育和分化的基因调控中具有重要作用。由于乳腺主要在出生后发育，并且青春期和妊娠的激素严格调节其组织特异性基因表达，因此它是研究染色质重塑总体上调节发育过程的机制的绝佳模型系统。这项研究的长期目标是确定染色质重塑在乳腺成熟和泌乳调节中所起的作用，并确定基因组中在这些过程中充当调节元件的相关区域。许多研究已经确定了发育过程中参与乳腺特异性基因转录调控的因素。然而，这些基因在染色质构象（表观遗传学）水平上进行全局调节以定义腺体发育和分化的机制却很少受到关注。我们假设染色质重塑发生在乳腺发育和分化过程中，并且是组织特异性表达模式调节的一个组成部分，该表达模式传达腺体成熟所需的细胞记忆。随着 ChIP 芯片的最新发展，现在可以在全球范围内解决这个问题，ChIP 芯片是一种结合染色质免疫沉淀 (ChIP) 和高通量寡核苷酸平铺阵列（芯片）的新技术。我们将使用 ChIP 芯片在小鼠的非乳腺、非定位和哺乳期乳腺组织中建立组蛋白修饰 (Aim 1a) 和 RNA 聚合酶-II (Aim 1b) 的组织和发育阶段特异性模式。由于乳蛋白基因在功能分化的乳腺上皮细胞中表达，我们的研究将集中于包含这些基因和其他发育调控基因的基因组结构域。这些研究将带来有关调节乳腺发育和哺乳的因素和途径的新知识，为操纵这些过程以造福母亲和儿童开辟新领域。此外，它们还将为理解决定特定组织分化和器官发生的表观遗传变化奠定基础。 公共卫生相关性声明：牛奶是新生儿营养的主要来源，它为所有哺乳动物物种的新生儿提供健康生长和发育的所有必需成分。然而，我们对建立和维持泌乳所涉及的因素的了解还远远不够。尤其是 DNA 包装所发挥的作用尚不明确。在这项研究中，我们将在全基因组范围内研究发育中乳腺的 DNA 包装。这些研究将为理解决定特定组织分化和器官发生的机制提供基础。

项目成果

From genes to milk: genomic organization and epigenetic regulation of the mammary transcriptome.

• DOI: 10.1371/journal.pone.0075030
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lemay DG;Pollard KS;Martin WF;Freeman Zadrowski C;Hernandez J;Korf I;German JB;Rijnkels M
• 通讯作者: Rijnkels M

The epigenetic landscape of mammary gland development and functional differentiation.

• DOI: 10.1007/s10911-010-9170-4
• 发表时间: 2010-03
• 期刊: JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA
• 影响因子: 2.5
• 作者: Rijnkels, Monique;Kabotyanski, Elena;Montazer-Torbati, Mohamad B.;Beauvais, C. Hue;Vassetzky, Yegor;Rosen, Jeffrey M.;Devinoy, Eve
• 通讯作者: Devinoy, Eve