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: 9123819
• 负责人: Ryan Joseph Gleason
• 金额: $ 5.61万
• 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/9123819
• 关键词: Address; Adhesives; Animal Model; Binding; 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; Life; Mediating; Membrane; Molecular Genetics; Muscular Dystrophies; Organism; Pathway interactions; Positioning Attribute; Post-Translational Protein Processing; Process; 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; stem cell population; 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（由适用提供）：表观遗传现象是指通过细胞分裂遗传的基因表达的变化而不改变潜在的DNA序列。是由DNA甲基化，组蛋白修饰，非编码RNA介导的加工等标记的表观遗传信息，它将带有相同基因组的细胞引导为整个Metazoan生物学中的不同细胞类型。这种表观遗传调节的失败导致干细胞行为异常，这是潜水疾病的基础，包括肌肉营养不良，糖尿病，不育和许多类型的癌症。不对称干细胞分裂中的中心谜是如何保留表观遗传记忆以控制一个子细胞的自我更新，同时允许区分另一个子细胞。最近，我们的实验室发现，在果蝇男性生殖干细胞（GSC）的不对称细胞分裂期间，先前存在的组蛋白3（H3）选择性地分离为GSC，而新合成的H3则富含在不同的子细胞中。这种不对称的组蛋白遗传可以为细胞在确定命运之前向两个子细胞传递不同的表观遗传信息的手段。该建议旨在定义果蝇和秀丽隐杆线虫在具有不同优势的双模型系统中，将分子遗传学和细胞生物学工具的组合结合起来，该建议旨在定义（1）（1）从干细胞壁细胞壁细胞构造的外在信号如何调节固有的固有组蛋白不对称的GSC，（2）确定IS与iSymmetric andistors的遗传性（2）是否存在（2）是否存在（3）在整个发育过程中多个谱系中的不对称细胞分裂，以维持表观遗传记忆。应用果蝇男性GSC模型，研究表明，内在因素和外部线索都调节了GSC的身份和活性。外在机制包括从细分市场发出的信号，细胞外基质和膜结合分子。有趣的是，我们已经证明，从细分市场发出的这些外部信号中的至少一个对于调节不对称组蛋白的遗传是必要的。我们计划进一步表征这些外部途径，这些途径在利基市场中处于独特的位置，以与不对称组蛋白遗传的内在调节剂集成。我们还将利用秀丽隐杆线虫的遗传模型来解决（1）不对称组蛋白的遗传是不同物种之间的组成机制，并且（2）如果这种对干细胞特异性的非对称组蛋白遗传或不对称细胞中使用的更广泛机制以指定明显的细胞命运。秀丽隐杆线虫是一种理想的遗传模型生物体，可以研究不对称的组蛋白遗传，具有独特的实验优势，可以解决这两个问题。拟议的研究应在整个发育过程中发现在不对称细胞分裂期间表观遗传调节的引人入胜的元素，并产生与干细胞生物学，表观遗传学，再生医学，遗传学和非对称细胞分裂有关的潜在变化影响。