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Deregulation of CTCF in Epigenetic Gene Silencing in Human Cancers

CTCF 在人类癌症表观遗传基因沉默中的失调

基本信息

批准号：
8840898
负责人：
Beverly Marie Emerson
金额：
$ 39.53万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840898
关键词：
Binding Biochemical Biological Models Boundary Elements Breast Cancer cell line Breast Carcinogenesis Breast Epithelial Cells CCCTC-binding factor CDH1 gene CDKN2A gene Cancerous Cell Line Cells Chromatin Chromosome Territory Chromosome abnormality Co-Immunoprecipitations Complex DNA Defect Disease Dissociation Epigenetic Process Epithelial Cells Event Exhibits Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Transcription Genomics Growth Heterochromatin Human Hypermethylation Immunoblotting Lead Malignant Neoplasms Mass Spectrum Analysis Mediating Modeling Modification Molecular Molecular Chaperones Multiple Myeloma Pattern Post-Translational Protein Processing Proteins Regulation Role Staging Structure System T47D Telomere Shortening Tumor Suppressor Genes Variant age related base breast tumorigenesis cancer cell epigenetic regulation gene function genetic information insight malignant breast neoplasm nucleolin programs protein complex public health relevance research study restoration small hairpin RNA uncontrolled cell growth

项目摘要

DESCRIPTION (provided by applicant): Project Summary. Silencing of tumor suppressor genes by epigenetic deregulation is a common occurrence in human malignancies. We find that loss of CTCF-dependent chromatin boundaries, which protects genes from adjacent heterochromatin domains, results in transcriptional inactivation of the p16INK4a tumor suppressor gene, which is a frequent target of epigenetic silencing in many types of human cancers and considered to be an early event in breast carcinogenesis. Loss of CTCF binding also correlates with hypermethylation and silencing of two other tumor suppressor genes, RASSF1A and CDH1, in breast cancer cell lines. CTCF dissociation from the boundary elements of these tumor suppressor genes results from defective poly(ADP-ribosyl)ation of CTCF, which abrogates its proper function. In this proposal, we plan to use primary human mammary epithelial cells (HMECs) to analyze the role of CTCF in molecular aberrations that initiate breast tumorigenesis. In this system, distinct subpopulations of cells emerge from normal HMECs that have overcome barriers to indefinite growth. The first barrier exhibited by "variant" HMECs coincides with p16 gene silencing followed by increasing epigenetic plasticity and chromosomal aberrations similar to those observed in early human breast cancers. Our specific aims are to: characterize native CTCF protein complexes from HMECs and p16-silenced vHMECs using biochemical approaches (Aim 1); examine the basis of defective CTCF PARlation in vHMECs using cell- based (Aim 2) [and biochemical studies (Aim 3)]; and [analyze the role of CTCF protein complexes in p16 gene regulation (Aim 4).] We postulate that destabilization of specific chromosomal boundaries by dysfunctional CTCF complexes may be an initiating event in the genesis of human breast cancers by early inactivation of critical tumor suppressor genes and loss of normal genomic patterns of epigenetic regulation.

描述（由申请人提供）：项目摘要。肿瘤抑制基因的沉默是一种常见的发生在人类恶性肿瘤的表观遗传失调。我们发现，CTCF依赖的染色质边界的损失，保护基因从相邻的异染色质结构域，导致转录失活的p16 INK 4a肿瘤抑制基因，这是一个常见的目标表观遗传沉默在许多类型的人类癌症，被认为是乳腺癌发生的早期事件。CTCF结合的丧失也与乳腺癌细胞系中另外两个肿瘤抑制基因RASSF 1A和CDH 1的高甲基化和沉默相关。CTCF从这些肿瘤抑制基因的边界元件解离是由于CTCF的聚（ADP-核糖基）化缺陷导致的，这废除了其适当的功能。在这个提议中，我们计划使用原代人乳腺上皮细胞（HMEC）来分析CTCF在启动乳腺肿瘤发生的分子畸变中的作用。在这个系统中，不同的细胞亚群从正常的HMEC中出现，这些HMEC已经克服了无限生长的障碍。第一个障碍表现为“变异”HMEC与p16基因沉默相一致，随后增加表观遗传可塑性和染色体畸变，类似于在早期人类乳腺癌中观察到的。我们的具体目标是：使用生物化学方法表征来自HMEC和p16沉默的vHMEC的天然CTCF蛋白复合物（目标1）; 2使用基于细胞的研究（目标2）[和生物化学研究（目标3）]检查vHMEC中有缺陷的CTCF PARlation的基础; 3和[分析CTCF蛋白复合物在p16基因调控中的作用（目标4）]。我们推测，不稳定的特定染色体边界功能失调的CTCF复合物可能是一个起始事件的发生在人类乳腺癌的早期失活的关键肿瘤抑制基因和损失的正常基因组模式的表观遗传调控。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phosphoinositide-mediated oligomerization of a defensin induces cell lysis.

DOI：
10.7554/elife.01808
发表时间：
2014-04-01
期刊：
eLife
影响因子：
7.7
作者：
Poon IKh;Baxter AA;Lay FT;Mills GD;Adda CG;Payne JA;Phan TK;Ryan GF;White JA;Veneer PK;van der Weerden NL;Anderson MA;Kvansakul M;Hulett MD
通讯作者：
Hulett MD

The β-NAD+ salvage pathway and PKC-mediated signaling influence localized PARP-1 activity and CTCF Poly(ADP)ribosylation.

β-NAD 挽救途径和 PKC 介导的信号传导影响局部 PARP-1 活性和 CTCF 聚 (ADP) 核糖基化。