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。在人类恶性肿瘤中，通过表观遗传学失调对肿瘤抑制基因的沉默是一种常见。我们发现，CTCF依赖性染色质边界的丧失保护基因免受邻近异染色质结构域的影响，导致P16INK4A肿瘤抑制基因的转录失活的转录失活，这是许多类型的人类的表观遗传沉默的常见靶标，并且被认为是早期的人类癌症。乳腺癌发生的事件。 CTCF结合的丧失还与乳腺癌细胞系中另外两个肿瘤抑制基因RASSF1A和CDH1的高甲基化和沉默有关。 CTCF与这些肿瘤抑制基因的边界元素的分离是由CTCF的聚（ADP-核糖基）缺陷引起的，该肿瘤元素消除了其适当的功能。在此提案中，我们计划使用原发性人类乳腺上皮细胞（HMEC）来分析CTCF在启动乳腺肿瘤发生的分子畸变中的作用。在该系统中，细胞的不同亚群来自正常的HMEC，这些HMEC克服了无限期生长的障碍。 “变体” HMEC表现出的第一个障碍与p16基因沉默相吻合，然后增加表观遗传可塑性和与早期人类乳腺癌相似的表观遗传可塑性和染色体畸变。我们的具体目的是：使用生化方法表征来自HMEC和P16脱毛VHMEC的天然CTCF蛋白复合物（AIM 1）；使用基于细胞的（AIM 2）[和生化研究（AIM 3）]检查VHMEC中CTCF解析有缺陷的基础； [分析CTCF蛋白复合物在p16基因调节中的作用（AIM 4）。]我们假设，通过功能障碍的CTCF复合物对特定的染色体边界的不稳定可能是通过早期灭绝关键肿瘤抑制者的早期失活而引发的事件。基因和表观遗传调节正常基因组模式的丧失。

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。