H3K9me3-based gene silencing and cellular identity

Salz实验室研究的首要目标是了解调控逻辑和分子 细胞命运、选择和承诺背后的机制。随着细胞命运的丧失导致发育障碍， 癌症和不孕不育，全面了解细胞用来 建立和确保他们选择的命运是至关重要的。我们目前的工作集中在女性/男性的命运选择上 在果蝇的生殖系中，我们发现雌性生殖细胞的身份取决于永久的 对睾丸基因的抑制。这一提议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- 特定的抑制性H3K9me3染色质阻断了男性正常表达的关键调控基因 生殖系。抑制性H3K9me3组蛋白修饰因其在结构性异染色质中的作用而广为人知 转座子的形成和抑制，但最近在从分裂酵母到生物体的工作 对人类(包括我们自己)的研究表明，H3K9me3峰也与蛋白质的沉默有关- 编码基因通常在其他组织中表达。尽管这些新出现的研究发现H3K9me3介导的 基因沉默作为确保细胞命运的一种保守而重要的策略，关于它是如何 H3K9me3被招募到蛋白质编码基因。目前还没有关于这种机制是否存在的信息 在一个组织中控制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‘S在沉默正常发育家族不适当基因中的作用的理解 因此影响了我们诊断和治疗疾病的能力。在这项Mira应用中提出的研究 将在我们对果蝇种系的基础性工作的基础上，填补这些知识空白。使用强大的 基因方法和令人兴奋的现代技术在飞行中可用，我们期待着我们在女性生殖细胞方面的工作 细胞加速发现与H3K9me3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 细胞使用类似的沉默机制。完成后，这些研究将提供基本的见解。 变成最不为人所知的控制细胞命运、选择和承诺的表观遗传机制之一。

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.