Investigating the mode and mechanism of histone inheritance across species

研究组蛋白跨物种遗传的模式和机制

• 批准号: 9271048
• 负责人: Ryan Joseph Gleason
• 金额: $ 5.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271048
• 关键词: Address; Adhesives; Animal Model; Biological; Biological Models; Biology; Caenorhabditis elegans; Cell Lineage; Cell Maintenance; Cell division; Cell model; Cells; Cellular biology; Cues; DNA Methylation; DNA Sequence; Data; Development; Diabetes Mellitus; Disease; Drosophila genus; Elements; Ensure; Epigenetic Process; Equilibrium; Extracellular Matrix; Extracellular Matrix Proteins; Failure; Gene Expression; Genes; Genetic; Genetic Models; Genome; Goals; Histones; Homeostasis; Human; Image; Infertility; Inherited; Intrinsic factor; Lead; Mediating; Membrane; Memory Loss; Molecular Genetics; Muscular Dystrophies; Organism; Pathway interactions; Population; Positioning Attribute; Post-Translational Protein Processing; Regenerative Medicine; Regulation; Research; S Phase; Signal Pathway; Signal Transduction; Stem cells; Tissues; To specify; Untranslated RNA; adult stem cell; base; cancer type; cell behavior; cell type; daughter cell; epigenetic memory; epigenetic regulation; fascinate; germline stem cells; histone modification; human disease; male; novel; public health relevance; segregation; self-renewal; stem; stem cell biology; stem cell division; stem cell fate; stem cell niche; tool; tumor progression

 DESCRIPTION (provided by applicant): Epigenetic phenomena refer to changes in gene expression inherited through cell divisions without changing the underlying DNA sequences. It is the epigenetic information marked by DNA methylation, histone modifications, non-coded RNA-mediated processing, etc., that direct cells with identical genomes to become distinct cell types throughout metazoan biology. Failure of this epigenetic regulation leads to abnormalities in stem cell behavior, which underlies diverse diseases including muscular dystrophy, diabetes, infertility, and many types of cancers. A central enigma in asymmetric stem cell division is how the epigenetic memory is retained to govern self-renewal of one daughter cell, while permitting differentiation of the other daughter cell. Recently, our lab has discovered that during the asymmetric cell division of Drosophila male germline stem cells (GSC), the preexisting histone 3 (H3) is selectively segregated to the GSCs, whereas newly synthesized H3 are enriched in the differentiating daughter cell. This asymmetric histone inheritance can provide the means for cells to impart distinct epigenetic information to the two daughter cells before their fates are determined. Employing a combination of molecular genetics and cell biology tools in both Drosophila and C. elegans as dual model systems with distinct advantages, this proposal aims to define (1) how the extrinsic signals emanating from the stem cell niche regulate intrinsic histone asymmetry of GSCs, (2) determine whether asymmetric histone inheritance is conserved, and (3) examine whether it is a broader mechanism used in asymmetric cell divisions in multiple lineages throughout development to maintain epigenetic memory. Applying the Drosophila male GSC model, studies have revealed that both intrinsic factors and extrinsic cues regulate GSC identity and activity. The extrinsic mechanisms include signals emanating from the niche, the extracellular matrix, and membrane bound molecules. Intriguingly, we have demonstrated that at least one of these extrinsic signals emanating from the niche are necessary to regulate asymmetric histone inheritance. We plan to further characterize these extrinsic pathways, which are in a unique position within the niche to integrate with intrinsic regulators of asymmetric histone inheritance. We will also exploit a C. elegans genetic model to address (1) whether asymmetric histone inheritance is a conserved mechanism across different species and (2) if this asymmetric histone inheritance specific for stem cells or a broader mechanism used in asymmetrically dividing cells to specify distinct cell fates. C. elegans is an ideal genetic model organism to study asymmetric histone inheritance with distinct experimental advantages to address both of these questions. The proposed study should uncover a fascinating element of epigenetic regulation during asymmetric cell division throughout development and generate a potentially transformative impact relevant to the fields of stem cell biology, epigenetics, regenerative medicine, genetics, and asymmetric cell division.

 描述（由申请人提供）：表观遗传现象是指通过细胞分裂遗传的基因表达变化，而不改变潜在的DNA序列。它是以DNA甲基化、组蛋白修饰、非编码RNA介导的加工等为标志的表观遗传信息，在后生动物的生物学中，它指导具有相同基因组的细胞变成不同的细胞类型。这种表观遗传调控的失败导致干细胞行为异常，这是多种疾病的基础，包括肌肉萎缩症，糖尿病，不育症和许多类型的癌症。干细胞不对称分裂的一个核心谜团是表观遗传记忆如何保留以控制一个子细胞的自我更新，同时允许另一个子细胞分化。最近，我们的实验室发现，在果蝇雄性生殖干细胞（GSC）的不对称细胞分裂过程中，预先存在的组蛋白3（H3）被选择性地分离到GSC中，而新合成的H3则富集在分化的子细胞中。这种不对称的组蛋白遗传可以为细胞提供一种方法，在决定两个子细胞的命运之前，将不同的表观遗传信息传递给它们。采用分子遗传学和细胞生物学工具相结合的果蝇和C。本研究的目的是确定（1）从干细胞小生境发出的外部信号如何调节GSC的内在组蛋白不对称性，（2）确定不对称组蛋白遗传是否保守，（3）检查它是否是在整个发育过程中用于多个谱系的不对称细胞分裂以维持表观遗传记忆的更广泛机制。应用果蝇雄性GSC模型，研究表明，内在因素和外在线索调节GSC的身份和活动。外在机制包括从龛、细胞外基质和膜结合分子发出的信号。有趣的是，我们已经证明，至少有一个从生态位发出的这些外在信号是必要的，以调节不对称组蛋白遗传。我们计划进一步表征这些外在途径，这些途径在生态位内处于独特的位置，与不对称组蛋白遗传的内在调节因子相结合。我们还将使用C。elegans遗传模型，以解决（1）不对称组蛋白遗传是否是不同物种之间的保守机制，以及（2）这种不对称组蛋白遗传是否对干细胞具有特异性，或者在不对称分裂细胞中使用更广泛的机制来指定不同的细胞命运。C.线虫是研究组蛋白不对称遗传的理想模式生物，在解决这两个问题上具有明显的实验优势。拟议的研究应该揭示在整个发育过程中不对称细胞分裂过程中表观遗传调控的迷人元素，并对干细胞生物学，表观遗传学，再生医学，遗传学和不对称细胞分裂领域产生潜在的变革性影响。