Determinants for genome-wide epigenomics in metastatic breast cancer

转移性乳腺癌全基因组表观基因组学的决定因素

• 批准号: 7726410
• 负责人: Terumi Kohwi-Shigematsu
• 金额: $ 45.98万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-21 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7726410
• 关键词: Adopted; Binding; Breast Cancer Cell; CD4 Positive T Lymphocytes; Cancerous; Cessation of life; Characteristics; Chromatin; Chromosomes; DNA; DNA Packaging; DNA Sequence; Disease Progression; Disseminated Malignant Neoplasm; Epigenetic Process; Future; Gene Expression Regulation; Gene Mutation; Genes; Genome; Helper-Inducer T-Lymphocyte; Higher Order Chromatin Structure; Human; Human Genome; Individual; Malignant Neoplasms; Maps; Modification; Neoplasm Metastasis; Proteins; Recruitment Activity; Research; Role; Testing; United States; Woman; base; cell type; chromatin modification; epigenomics; genome-wide; histone modification; insight; malignant breast neoplasm; neoplastic cell; outcome forecast; public health relevance; research study; single molecule; thymocyte

DESCRIPTION (provided by applicant): Breast cancer is the most common cancer in women in the United States, causing ~40,000 deaths each year. In the proposed study, we will focus on breast cancer and determine what epigenomic changes cause breast cancer to acquire metastatic activity and how the changes are established. Epigenetic modifications of chromatin are associated with the expression status of individual genes. Here we propose a paradigm-shifting idea that a single molecule involved in global gene regulation underlies the massive epigenetic changes that drive the transformation of a tumor cell to aggressive metastatic tumor cells through binding to a subset of specialized DNA sequence that functions as chromosomal marks. We identified SATB1, a genome organizer in thymocytes, to be a key determinant in breast cancer metastasis by altering expression of ~1000 genes, including many associated with poor prognosis. We will test a hypothesis that SATB1 causes progression of non-aggressive breast cancer to metastatic cancer by establishing genome-wide changes in epigenetic marks through global re- organization of higher-order chromatin structure. We further hypothesize that such re- organization involves SATB1 interaction with highly conserved, specialized DNA sequences called base unpairing regions (BURs), distributed throughout the human genome. These BURs may function as chromosome "marks" to which chromatin modifiers are recruited, thus resulting in specific epigenetic modifications throughout the genome characteristic of aggressive breast cancer. We will adopt a global mapping approach by high-throughput sequencing to map all putative BURs across the human genome and identify those that are bound by SATB1in aggressive breast cancer cells versus those in activated human T helper cells, a non cancerous cell-type where SATB1 is normally expressed. We will subsequently determine genome-wide histone modifications in SATB1-expressing metastatic cancer and SATB1-deficient, non- aggressive breast cancer cells to determine whether aggressive cancer-associated changes in epigenetic marks are centered at SATB1-bound BURs. From the proposed research, we will define the role of BURs in establishing metastatic breast cancer-specific epigenetic marks through interaction with SATB1. These experiments will provide fundamental insight into disease progression that should be useful for developing future therapies. Public Health Relevance: Mounting evidence suggest that cancer is not necessarily a result of accumulated genetic mutations, but may also involve alterations in the epigenome, the modifications on the DNA or the proteins that package the DNA. In fact, recent evidence suggests that these modifications are different between metastatic and non-metastatic breast cancer. We will determine what epigenomic changes underlie metastatic breast cancer and the mechanisms by which these changes are established.

描述（由申请人提供）：乳腺癌是美国女性最常见的癌症，每年造成约40,000人死亡。在拟议的研究中，我们将专注于乳腺癌，并确定哪些表观基因组变化导致乳腺癌获得转移性活动以及如何建立变化。染色质的表观遗传修饰与单个基因的表达状态有关。在这里，我们提出了一个范式转移的想法，即参与全球基因调节的单个分子是巨大的表观遗传变化的基础，该变化促进了肿瘤细胞向侵袭性转移性肿瘤细胞的转化，通过与专门的DNA序列的结合，该序列可作为染色体标记。我们通过改变〜1000个基因的表达，包括许多与预后不良相关的许多基因的表达，从而确定了胸腺癌转移的胸腺癌转移的关键决定因素，这是胸腺癌转移的关键决定因素。我们将检验一个假设，即SATB1通过通过全球高阶染色质结构的全球结构来建立全基因组的表观遗传标记的变化，从而导致非侵略性乳腺癌的转化为转移性癌。我们进一步假设，这种建立涉及SATB1与高度保守的专业DNA序列的相互作用，称为基础不属于不属于的区域（BURS），分布在整个人类基因组中。这些毛刺可能是募集染色质修饰剂的染色体“标记”，从而导致在侵袭性乳腺癌的整个基因组特征中进行特定的表观遗传修饰。我们将通过高通量测序采用全球映射方法，以在人类基因组中绘制所有推定的毛毛，并识别那些受STB1IN侵袭性乳腺癌细胞与激活的人T辅助细胞中的侵略性乳腺癌细胞绑定的囊泡，这是一种非癌细胞型SATB1，其中Satb1通常表达。随后，我们将在表达SATB1的转移性癌和缺乏SATB1的非侵略性乳腺癌细胞中确定全基因组的组蛋白修饰，以确定表观遗传标记的攻击性癌症相关的变化是否以SATB1结合的囊中为中心。从拟议的研究中，我们将通过与SATB1相互作用来定义毛毛的作用在建立转移性乳腺癌特异性表观遗传学标记中的作用。这些实验将提供对疾病进展的基本见解，这对于开发未来的疗法应该有用。公共卫生相关性：越来越多的证据表明，癌症不一定是基因突变累积的结果，但也可能涉及表观基因组的改变，对DNA的修饰或包装DNA的蛋白质的改变。实际上，最近的证据表明，这些修饰在转移性和非转移性乳腺癌之间是不同的。我们将确定哪些表观基因组变化是转移性乳腺癌的基础，以及建立这些变化的机制。