H3K9me3-based gene silencing and cellular identity

基于 H3K9me3 的基因沉默和细胞身份

• 批准号: 10548567
• 负责人: HELEN Karen SALZ
• 金额: $ 42.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-02 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548567
• 关键词: Acceleration; Brain; Cells; Chromatin; Code; DNA Transposable Elements; Development; Diagnosis; Disease; Drosophila genus; Epigenetic Process; Female; Fission Yeast; Gene Silencing; Genes; Germ Cells; Goals; Heterochromatin; Human; Infertility; Knowledge; Logic; Malignant Neoplasms; Mediating; Modernization; Molecular; Organism; Proteins; Publishing; Regulator Genes; Repression; Research; Role; Secure; Somatic Cell; Technology; Testis; Tissues; Work; developmental disease; fly; genetic approach; histone modification; human disease; insight; male; novel strategies; recruit

The overarching goal of the research in the Salz lab is to understand the regulatory logic and molecular mechanisms underlying cell fate choice and commitment. As loss of cell fate leads to developmental disorders, cancer, and infertility, a comprehensive understanding of the many different mechanisms used by cells to establish and secure their chosen fate is essential. Our current work is focused on the female/male fate choice in the Drosophila germline, where we have found that female germ cell identity depends on the permanent repression of testes genes. This proposal builds on our exciting, published work showing that discrete gene- specific blocks of repressive H3K9me3 chromatin silences key regulatory genes normally expressed in the male germline. The repressive H3K9me3 histone modification is best known for its role in constitutive heterochromatin formation and the repression of transposable elements, but recent work in organisms ranging from fission yeast to humans (including our own) reveals that H3K9me3 peaks are also associated with the silencing of protein- coding genes normally expressed in other tissues. Although these emerging studies identify H3K9me3-mediated gene silencing as a conserved and vital strategy for securing cell fate, there is very little information about how H3K9me3 is recruited to protein-coding genes. And there is no information about whether the mechanism governing H3K9me3-mediated gene silencing in one tissue is generalizable to other tissues. These gaps limit our understanding of H3K9me3's role in silencing lineage inappropriate genes in normal development and may therefore impinge on our ability to diagnose and treat disease. The research proposed in this MIRA application will build on our foundational work in the Drosophila germline to fill these gaps in knowledge. Using the powerful genetic approaches and exciting modern technologies available in the fly, we expect our work in female germ cells to accelerate the discovery of new genes and molecular mechanisms relevant to H3K9me3-medidated gene silencing. Our new studies in the larval brain will extend these findings by determining whether somatic cells use an analogous silencing mechanism. When complete, these studies will provide fundamental insights into one of the least understood epigenetic mechanisms governing cell fate choice and commitment.

Salz 实验室研究的首要目标是了解调控逻辑和分子机制。 细胞命运选择和承诺的机制。由于细胞命运的丧失会导致发育障碍， 癌症和不孕症，全面了解细胞使用的许多不同机制 建立并确保他们选择的命运至关重要。我们目前的工作重点是女性/男性的命运选择 在果蝇种系中，我们发现雌性生殖细胞的身份取决于永久的 睾丸基因的抑制。该提案建立在我们令人兴奋的已发表工作的基础上，该工作表明离散基因- 抑制性 H3K9me3 染色质的特定区块会沉默通常在男性中表达的关键调控基因 种系。抑制性 H3K9me3 组蛋白修饰因其在组成型异染色质中的作用而闻名 转座因子的形成和抑制，但最近在裂殖酵母等生物体中的研究 对人类（包括我们自己）的研究表明，H3K9me3 峰也与蛋白质沉默有关 编码基因通常在其他组织中表达。尽管这些新兴研究确定了 H3K9me3 介导的 基因沉默作为确保细胞命运的保守且重要的策略，但关于如何进行基因沉默的信息很少 H3K9me3 被招募到蛋白质编码基因中。并且没有关于该机制是否有效的信息 在一种组织中控制 H3K9me3 介导的基因沉默可以推广到其他组织。这些差距限制了 我们对 H3K9me3 在正常发育中沉默谱系不适当基因中的作用的理解可能是 因此影响了我们诊断和治疗疾病的能力。 MIRA 申请中提出的研究 将以我们在果蝇种系方面的基础工作为基础，以填补这些知识空白。使用强大的 遗传方法和令人兴奋的现代技术可在果蝇中使用，我们期待我们在雌性生殖方面的工作 细胞加速发现与 H3K9me3 介导相关的新基因和分子机制 基因沉默。我们对幼虫大脑的新研究将通过确定体细胞是否 细胞使用类似的沉默机制。完成后，这些研究将提供基本见解 进入人们最不了解的控制细胞命运选择和承诺的表观遗传机制之一。