Transcriptional regulation by epigenetic factors

表观遗传因素的转录调控

• 批准号: 9060950
• 负责人: ALEXANDER M MAZO
• 金额: $ 31万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9060950
• 关键词: Accounting; Address; Adult; Biological; Cell Cycle; Cell Cycle Stage; Cell Differentiation process; Cell Proliferation; Cells; Chromatin; Chromatin Modeling; Chromatin Structure; DNA; DNA Replication Timing; DNA biosynthesis; Data; Development; Drosophila genus; Embryo; Epigenetic Process; Foundations; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Germ Cells; Goals; Health; Histones; Malignant - descriptor; Mediating; Methods; Modeling; Molecular; Molecular Conformation; Mothers; Mus; Nucleosomes; Phase; Process; Proteins; RNA; Recruitment Activity; Repression; Research; Signal Transduction; Solid; Somatic Cell; Stem cells; Testing; Time; Transcriptional Regulation; Undifferentiated; Work; base; blastomere structure; chromatin protein; chromatin remodeling; daughter cell; design; embryonic stem cell; histone modification; insight; programs; stem cell differentiation; tool; transcription factor

DESCRIPTION (provided by applicant): Epigenetic inheritance of transcriptional programs is essential for cell proliferation, cell differentiation and malignant transformation. Molecularly, epigenetic inheritance of transcriptional programs relies in large part on conservation of chromatin structure through disruptive cell cycle phases. Despite the biological importance of this phenomenon, the details of the molecular mechanisms of epigenetic inheritance are elusive, mostly because of the lack of appropriate experimental approaches. We developed new experimental paradigms, and found that many chromosomal proteins are associated with DNA during replication. However, methylated histones are accumulated on nascent DNA with significant delay. Our preliminary results suggest that following DNA replication, undifferentiated cells, including mouse embryonic stem cells (mESCs), accumulate methylated histones and resume transcription more slowly than differentiated cells of the same origin. We hypothesize that this may create a narrow time window at the time of DNA replication, with a uniquely open chromatin configuration lacking histone modifications and lacking transcription that is very susceptible to receiving signals for differentiation. We will test this hypothesis by examining th accumulation of different modified histone residues, histone-modifying and chromatin remodeling proteins following DNA replication during differentiation of mouse ESCs. We will also examine when transcription resumes in these cells, and when components of the transcriptional machinery are recruited to nascent DNA. Finally, we will test a hypothesis that the short period of time just after DNA replication, when chromatin is not modified, provides a window of opportunity for acquiring signals for differentiation through association of the newly induced transcription factors. This may account for a higher plasticity of undifferentiated states in acquiring new transcriptional programs. Overall, this proposal will greatly contribute to the ke epigenetic issues during cell differentiation.

描述（由申请人提供）：转录程序的表观遗传遗传对于细胞增殖，细胞分化和恶性转化至关重要。从分子上讲，转录程序的表观遗传遗传在很大程度上依赖于通过破坏性细胞周期阶段对染色质结构的保存。尽管这种现象具有生物学重要性，但表观遗传遗传的分子机制的细节是难以捉摸的，这主要是因为缺乏适当的实验方法。我们开发了新的实验范式，发现许多染色体蛋白在复制过程中都与DNA相关。但是，甲基化的组蛋白在新生的DNA上积聚，并显着延迟。我们的初步结果表明，DNA复制后，未分化 包括小鼠胚胎干细胞（MESC）在内的细胞比相同起源的分化细胞更慢地积累了甲基化组蛋白和恢复转录。我们假设这可能会在DNA复制时创建一个狭窄的时间窗口，而独特的开放式染色质构型缺乏组蛋白修饰，并且缺乏转录，这非常容易接收具有分化信号的信号。 我们将通过检查不同修饰的组蛋白残基的积累，在小鼠ESC分化期间DNA复制后进行组蛋白修饰和染色质重塑蛋白来检验该假设。我们还将检查这些细胞中的转录何时恢复，以及募集转录机械的成分何时募集到新生的DNA。最后，我们将检验一个假设，即DNA复制后的短时间（未经修饰染色质时）为通过新诱导的转录因子的关联而获取信号的机会窗口提供了机会窗口。这可能是在获取新的转录程序中未分化状态的较高可塑性。总体而言，该提案将在细胞分化过程中极大地有助于表观遗传问题。