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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

基本信息

批准号：
9121791
负责人：
jessica feldman
金额：
$ 5.43万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
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/9121791
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 Genetic Genetic Transcription Genome Genome Stability Genomic Instability Genomics Goals Health Histone Acetylation 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 Techniques Testing Transcript Transcriptional Regulation Untranslated RNA Work Yeasts chromatin remodeling effective therapy genome-wide histone modification human embryonic stem cell in vivo insight member mutant novel pluripotency promoter public health relevance research study stem therapeutic development therapeutic target transcriptome treatment strategy

项目摘要

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.