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机制。 细胞命运选择和承诺的机制。由于细胞命运的丧失导致发育障碍， 癌症和不育症，全面了解细胞使用的许多不同机制， 建立和确保其所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 在果蝇的生殖系中，我们发现雌性生殖细胞的身份取决于 睾丸基因的抑制。这项建议建立在我们令人兴奋的，已发表的工作，表明离散的基因- 抑制性H3 K9 me 3染色质的特定块使通常在男性中表达的关键调控基因沉默 生殖系抑制性H3 K9 me 3组蛋白修饰以其在组成性异染色质中的作用而闻名 形成和抑制转座因子，但最近的工作在生物体，从裂变酵母 对人类（包括我们自己）的研究表明，H3 K9 me 3峰也与蛋白质沉默有关， 在其他组织中正常表达的编码基因。虽然这些新兴的研究确定H3 K9 me 3介导的 基因沉默作为保护细胞命运的保守和重要策略，很少有关于如何沉默的信息。 H3 K9 me 3被募集到蛋白质编码基因中。目前还没有关于该机制是否 在一种组织中控制H3 K9 me 3介导的基因沉默的基因表达可推广到其它组织。这些差距限制了 我们对H3 K9 me 3在正常发育中沉默谱系不适当基因的作用的理解， 从而影响我们诊断和治疗疾病的能力。在MIRA申请中提出的研究 将建立在我们在果蝇生殖系的基础工作上，以填补这些知识空白。使用强大的 遗传学方法和令人兴奋的现代技术可在苍蝇，我们希望我们的工作在女性生殖 细胞，以加速发现与H3 K9 me 3介导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。这些研究完成后， 一个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。

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.