Subnuclear Targeting and Architectural Epigenetics in Cancer Cells

癌细胞的亚核靶向和结构表观遗传学

• 批准号: 8052324
• 负责人: Gary S. Stein
• 金额: $ 30.86万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052324
• 关键词: Acetylation; Acute Myelocytic Leukemia; Architecture; Biochemical; Biological; Breast Cancer Cell; Cell Fate Control; Cell Nucleus; Cell division; Cells; Chimeric Proteins; Chromatin; Chromatin Structure; Chromosomes; Chromosomes, Human, Pair 1; Collaborations; Commit; DNA Methylation; DNA Polymerase I; DNA Polymerase II; DNA Sequence; Dimensions; Environment; Epigenetic Process; Etiology; Event; Exhibits; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genomics; Histones; Instruction; Interphase; Link; Malignant Neoplasms; Mediating; Methods; Microscopy; Mitosis; Mitotic; Mitotic Chromosome; Modification; Molecular; Normal Cell; Nuclear; Nuclear Structure; Oncogenic; Phenotype; Post-Translational Protein Processing; Proteins; Proteomics; Regulation; Regulator Genes; Research Personnel; Role; Shapes; Signal Transduction; Somatic Cell; Structure; cancer cell; cancer stem cell; malignant breast neoplasm; metaplastic cell transformation; novel; programs; promoter; t(8; 21)(q22; q22); trafficking; transcription factor; tumorigenesis

Cancer cells exhibit alterations in parameters of nuclear architecture that control cell fate and compromise control of cell groyvth. Our Program has established new biological paradigms by showing that gene regulatory factors integrate cell signaling at chromatin microenvironments ('subnuclear foci') and support epigenetic mechanisms through association with mitotic chromosomes. In collaboration with other Program Project investigators. Project 1 will now establish new dimensions in gene regulation by defining perturbations in architecturally linked regulatory mechanisms during interphase and mitosis in AML and breast cancer cells. Our central hypothesis is that (i) subnuclear targeting of transcription factors to gene regulatory foci during interphase and (ii) the association of transcription factors wifh their target genes in mitotic chromosomes are fundamental to the retention of biological states of normal and cancer cells. Therefore, we will use IF microscopy, biochemical, genomic and proteomic approaches (i) to characterize modificafions in architectural epigenetics and molecular pathological consequences of expressing the translocation-related t(8;21) AML-ETO fusion protein (Aim 1), (ii) to analyze genes that are transcriptionally and spatially controlled by Runx2 in chromatin micro-environments ('subnuclear foci') during interphase in breast cancer ceils (Aim 2), and (iii) to examine Runx2 mediated architectural epigenetics in breast cancer cells by characterization of Runx2 and cognate gene regulatory factors that associate with mitotic chromosomes (Aim 3). By investigating the functional role of Runx2 in establishing chromatin micro- environments ('subnuclear foci') during interphase and architectural epigenetics in cancer cells during mitosis, we will challenge traditional biochemical views of gene regulation by defining the pathological linkages between modifications in nuclear architecture and gene expression that are fundamental to the molecular etiology of tumorigenesis. RELEVANCE (See instructions): Changes in the overall shape and structure ofthe nucleus are pathological hallmarks of cancer cells that are linked to cellular transformation. This study will use state-of-the-art methods to characterize how targeting of oncogenic transcription factors to specific subnuclear structures and mitotic chromosomes supports gene regulation as components of a novel epigenetic mechanism ('architectural epigenetics').

癌细胞表现出控制细胞命运和妥协的核结构参数的改变