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A New Histone H3 Modification Regulates Epigenetic Programming and Gene Expression in Breast Cancer

一种新的组蛋白 H3 修饰调节乳腺癌的表观遗传编程和基因表达

基本信息

批准号：
10607954
负责人：
Qing Zhang
金额：
$ 44.37万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-08 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607954
关键词：
ARNT gene Acetylation Affect Antibodies Binding Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast Epithelial Cells C-terminal Cell Proliferation Cells Characteristics Complex Data Detection Dimerization Disease Enzymes Epigenetic Process Event Family member Gene Expression Gene Expression Regulation Genes Genetic Transcription Genomics Growth Inhibitors Histone Code Histone H3 Histones Hydroxylation Hypoxia Hypoxia Inducible Factor In Vitro Lead Lysine Malignant - descriptor Malignant Neoplasms Measures Mediating Metabolism Methylation Mixed-Lineage Leukemia Modeling Modification Molecular Oncogenic Oxygen Phosphorylation Play Post-Translational Protein Processing Procollagen-Proline Dioxygenase Proline Proteins Reader Regulator Genes Reporting Repression Role Signal Transduction Solid Tail Ubiquitination WNT Signaling Pathway Western Blotting Writing angiogenesis beta catenin cancer cell clinically relevant demethylation epigenetic regulation genome-wide histone demethylase histone modification in vivo inhibitor insight malignant breast neoplasm novel promoter recruit triple-negative invasive breast carcinoma tumorigenesis ubiquitin-protein ligase

项目摘要

Project Summary Distinct histone modifications, on N or C-terminal tails, act as a “histone code” to elicit downstream events. Histone subunit post-translational modification (PTM), such as methylation, acetylation and phosphorylation regulates epigenetic regulation and gene expression in diseases such as cancer. Here we identified a new PTM on H3 called hydroxylation on proline 16, which is catalyzed by proline hydroxylase EglN2. Our preliminary data show that EglN2-mediated H3 Pro16-OH leads to increased Lysine (K)-Specific Demethylase 5A (KDM5A) binding corresponding with decreased H3K4me3 in breast cancer. We hypothesize that H3 prolyl hydroxylation mediated by EglN2 recruits KDM5A therefore controlling gene expression important in breast cancer. This is the first study reporting H3 Prolyl hydroxylation and its potential role in epigenetic regulation and gene expression in cancer. In Specific Aim 1, we will determine the effet of H3 prolyl hydroxylation on epigenetic regulation and gene expression on a genome wide scale in breast cancer cells. In Specific Aim 2, we will elucidate the molecular mechanism by which H3 prolyl hydroxylation regulates epigenetic reprogramming by recruiting KDM5A. In Specific Aim 3, we will elucidate the molecular mechanism by which H3 prolyl hydroxylation regulates Wnt/b-Catenin signaling in breast cancer cells. Successful completion of this proposal will characterize a new H3 post-translational modification in its epigenetic regulation and gene expression important in breast cancer.

项目摘要不同的组蛋白修饰，在N或C末端，起到“组蛋白密码”的作用，从而引发下游事件。组蛋白亚单位翻译后修饰，如甲基化、乙酰化和磷酸化调控表观遗传调控和癌症等疾病的基因表达。在这里，我们确定了一种新的PTM 在H3上称为脯氨酸16上的羟基化，它是由Pro羟基酶EglN2催化的。我们的初步数据结果表明，EglN2介导的H3Pro16-OH导致赖氨酸(K)特异性脱甲基酶5A(KDM5A)增加乳腺癌中H3K4me3的结合相应减少。我们假设H3-Pro羟基化在EglN2的介导下，KDM5A招募到了KDM5A，因此控制基因表达在乳腺癌中至关重要。这是首次报道H3脯氨酸羟化及其在表观遗传调控和基因中的潜在作用的研究在癌症中的表达。在特定的目标1中，我们将确定H3丙酰羟化对表观遗传学的影响乳腺癌细胞基因组范围内的调控和基因表达。在具体目标2中，我们将阐明H3脯氨酸羟化调控表观遗传重编程的分子机制招募KDM5A。在具体目标3中，我们将阐明H3脯氨酸羟化的分子机制调节乳腺癌细胞中的Wnt/b-catenin信号转导。这项提案的成功完成将成为一种新的H3翻译后修饰对其表观遗传调控和乳房重要基因表达的影响癌症。