The role of Histone H3 lysine 56 acetylation in noncoding transcription and chromatin architecture

组蛋白 H3 赖氨酸 56 乙酰化在非编码转录和染色质结构中的作用

• 批准号: 9415876
• 负责人: jessica feldman
• 金额: $ 0.08万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9415876
• 关键词: Acetylation; Affect; Architecture; Base Pairing; Biochemical; Biological; Biology; Cell Nucleus; Cell physiology; Cells; Chromatin; Chromatin Structure; Chromosome Structures; Complex; Coupled; DNA; DNA Damage; DNA Repair; DNA Sequence; Deacetylation; Deposition; Development; Disease; Embryo; Ensure; Epigenetic Process; Equilibrium; Eukaryota; Eukaryotic Cell; Family; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Genome Stability; Genomic Instability; Genomics; Goals; Health; Histone Acetylation; Histone Deacetylase; Histone H3; Histones; Human; Human Genome; Hybrids; Knowledge; Lysine; Malignant Neoplasms; Measures; Methods; Molecular; Monitor; Nuclear; Nucleosomes; Nucleotides; Outcome; Phenotype; Play; Post-Translational Protein Processing; Predisposition; Prevention; Process; Proteins; RNA; RNA immunoprecipitation sequencing; Reporting; Research; Resolution; Ribonuclease H; Role; Signal Transduction; Sirtuins; Techniques; Testing; Transcript; Transcriptional Regulation; Untranslated RNA; Work; Yeasts; chromatin remodeling; effective therapy; experimental study; genome-wide; genome-wide analysis; histone modification; human embryonic stem cell; in vivo; insight; member; mutant; novel; pluripotency; promoter; public health relevance; stem; therapeutic development; therapeutic target; transcriptome; treatment strategy

 DESCRIPTION (provided by applicant): Although the Human Genome was sequenced to 99.7% completion in 2003, it has become clear that the sequence of DNA alone is not sufficient to explain human health and disease in its entirety. This has led to a new appreciation of the factors outside the DNA sequence itself that regulate cellular processes and outcomes. In eukaryotic cells, the DNA is packaged into arrays of nucleosomes, each of which contains ~146 base pairs of DNA wrapped around an octamer of the core histone proteins. For almost half a century, nucleosomes were thought to be nothing more than building blocks, serving only to package and organize eukaryotic DNA within the nucleus. It is now apparent that histone proteins as well as the associated regulatory machinery are required for all nuclear processes. Chromatin dynamics play a central role in regulating gene expression and are necessary to maintain normal cellular function. Dysregulation of epigenetic signals has been associated with numerous human malignancies. Chromatin-regulating factors are some of the most frequently affected proteins in cancer, and these proteins have emerged as promising therapeutic targets. Many epigenetic regulatory mechanisms, including acetylation of lysine 56 in histone H3 (H3K56Ac), are conserved in eukaryotes. H3K56Ac plays a critical role in replication-dependent histone deposition, nucleosome turnover, DNA repair and in promoting pluripotency of human embryonic stem cells. Alternations in H3K56Ac levels have negative consequences on transcription and genome stability, and elevated levels of H3K56Ac have been measured in several human cancers. Together, the results indicate a regulated balance between acetylation and deacetylation of H3K56 is required for normal cellular function. Recent work suggests H3K56Ac levels are important for regulating noncoding transcription and chromosomal folding in yeast. However, it is unclear whether the effects are replication-dependent or -independent, making it difficult to fully understand the mechanism. The goals of this research are to investigate the role of replication-independent H3K56 acetylation in regulating transcription and chromosomal folding as well as to determine whether aberrant transcription caused by hyperacetylation ultimately leads to DNA damage. State-of-the-art genome-wide analyses of the transcriptome and genome architecture, including native-elongating transcript sequencing and a recently developed chromatin capture technique, termed Micro-C, will be utilized to monitor transcription and chromatin folding at single nucleotide and nucleosome level resolution, respectively. By using novel genome-spanning methods to answer complex biological questions, the results will provide important molecular insight into the cellular functions of H3K56 acetylation as well as the consequences of hyperacetylation, which may have important implications in understanding human malignancies. Furthermore, the results will greatly enhance our knowledge of the interplay between histone PTMs, chromatin remodeling, and chromatin structure as well as their roles in the mechanisms governing transcriptional control.

 描述（由申请人提供）：虽然人类基因组测序在2003年完成了99.7%，但很明显，单靠DNA序列不足以解释人类健康和疾病的全部。这导致了对DNA序列本身之外的因素的新认识，这些因素调节细胞过程和结果。在真核细胞中，DNA被包装成核小体阵列，每个核小体包含约146个碱基对的DNA，包裹在核心组蛋白的八聚体周围。在几乎半个世纪的时间里，核小体被认为只不过是构建模块，仅用于包装和组织细胞核内的真核DNA。现在很明显，组蛋白以及相关的调节机制是所有核过程所必需的。染色质动力学在调节基因表达中起核心作用，并且是维持正常细胞功能所必需的。表观遗传信号的失调与许多人类恶性肿瘤有关。染色质调节因子是癌症中最常受影响的蛋白质，这些蛋白质已成为有前途的治疗靶点。许多表观遗传调控机制，包括组蛋白H3中赖氨酸56的乙酰化（H3 K56 Ac），在真核生物中是保守的。H3 K56 Ac在复制依赖性组蛋白沉积、核小体更新、DNA修复和促进人胚胎干细胞的多能性中起关键作用。H3 K56 Ac水平的改变对转录和基因组稳定性具有负面影响，并且已经在几种人类癌症中测量到H3 K56 Ac水平升高。总之，结果表明H3 K56的乙酰化和脱乙酰化之间的调节平衡是正常细胞功能所需的。最近的工作表明H3 K56 Ac水平对于调节酵母中的非编码转录和染色体折叠是重要的。然而，目前还不清楚这种效应是复制依赖性的还是非复制依赖性的，因此很难完全理解其机制。本研究的目的是研究非复制依赖性H3 K56乙酰化在调节转录和染色体折叠中的作用，以及确定由乙酰化过度引起的异常转录是否最终导致DNA损伤。转录组和基因组结构的最新全基因组分析，包括天然延长转录测序和最近开发的染色质捕获技术，称为Micro-C，将分别用于监测单核苷酸和核小体水平分辨率的转录和染色质折叠。通过使用新的跨基因组方法来回答复杂的生物学问题，这些结果将为H3 K56乙酰化的细胞功能以及超乙酰化的后果提供重要的分子见解，这可能对理解人类恶性肿瘤具有重要意义。此外，这些结果将极大地增强我们对组蛋白PTM、染色质重塑和染色质结构之间的相互作用以及它们在转录控制机制中的作用的认识。