Investigate MOF regulated epigenetic mechanisms of skin development

项目摘要 表观遗传机制，特别是由组蛋白修饰介导的机制，已经成为一种新的遗传机制。 基因表达调控机制的关键层。在皮肤中，几种组蛋白修饰，如 已经研究了H3 K27 me 3和组蛋白脱乙酰酶如HDAC 1/2/3。这些优雅的研究 不仅为皮肤表观遗传机制的重要功能提供了新的见解， 建立了皮肤作为一个很好的模型系统，以研究表观遗传机制，在时空良好， 定义的组织。然而，我们对皮肤表观遗传机制的理解是不完整的。的 许多组蛋白标记及其相关修饰酶的功能是未知的。其中， 组蛋白4赖氨酸16乙酰化（H4 K16 Ac）在调节染色质中的关键作用特别值得注意 压实结构和生物物理研究表明H4 K16 Ac在转录中起着重要作用 通过影响核小体结构和与染色质结合蛋白的相互作用来激活。 H4 K16 Ac由MYST家族赖氨酸乙酰转移酶M0 F（也称为KAT 8）催化，其是 在苍蝇、小鼠和人类中广泛保守。MOF及其催化的H4 K16 Ac标记的功能首先是 在果蝇黑腹果蝇（Drosophila melanogaster）中进行了研究，发现H4 K16 Ac标记覆盖在雄性X染色体上， 染色体并通过两倍的中等性剂量补偿来提高转录。但 MOF和H4 K16 Ac的功能不限于X染色体基因用于剂量补偿。MOF和 H4 K16 Ac已被证明控制许多参与胚胎干细胞、肝细胞和肝细胞的调控的基因。 发育，周细胞发育以及小鼠和人类中的许多其他发育。这个项目的首要目标是 应用是确定MOF和H4 K16 Ac介导的转录控制在表皮细胞中的作用， 发展在我们的初步研究中，我们发现MOF的基因缺失导致严重的 表皮粘附、分化和形态发生缺陷。在本申请中，我们将阐明 MOF/H4 K16 Ac在表皮发育过程中的分子机制和细胞功能。我们提出 1）研究MOF在表皮发育中的作用; 2）确定MOF在表皮发育中的机制。 控制纤毛发生和线粒体功能;和3）阐明MOF的表观遗传机制- 介导的基因表达调控。结合我们在小鼠遗传学、转录和 表观遗传调控，上皮生物学，基因组学和计算生物学，我们将提供遗传， 对哺乳动物皮肤关键表观遗传机制的基因组和分子见解 发展

Project Summary Epigenetic mechanisms, in particular the ones mediated by Histone modifications, have emerged as an essential layer of gene expression control mechanism. In the skin, several Histone modifications such as H3K27me3 and Histone deacetylase such as HDAC1/2/3 have been studied. These elegant studies have not only provided novel insights into important functions of epigenetic mechanisms in the skin but also established skin as an excellent model system to study epigenetic mechanisms in a spatiotemporally well- defined tissue. However, our understanding of epigenetic mechanisms in the skin is incomplete. The functions of numerous Histone marks and their associated modifying enzymes are unknown. Among them, Histone 4 Lysine16 acetylation (H4K16Ac) is particularly notable for its key role in regulating chromatin compaction. Structural and biophysical studies indicate that H4K16Ac plays an essential role in transcription activation by influencing both nucleosome structure and interaction with chromatin-binding proteins. H4K16Ac is catalyzed by the MYST-family lysine acetyltransferase MOF (also known as KAT8), which is broadly conserved in fly, mouse and human. The function of MOF and its catalyzed H4K16Ac mark is first studied in the fruit fly Drosophila melanogaster, where H4K16Ac mark is found to coat the male X- chromosome and elevate transcription by two-fold tomediate sex dosage compensation. However, the function of MOF and H4K16Ac is not limited to X-chromosome genes for dosage compensation. MOF and H4K16Ac have been shown to control many genes involved in the regulation of embryonic stem cells, liver development, pericyte development among many others in mouse and human. The overarching goal of this application is to determine the role of MOF and H4K16Ac mediated transcriptional control in epidermal development. During our preliminary study, we have discovered that genetic deletion of MOF causes severe defects in epidermal adhesion, differentiation and morphogenesis. In thisapplication, we will elucidate molecular mechanisms and cellular functions of MOF/H4K16Ac during epidermal development. We propose to 1) investigate the role of MOF in epidermal development; 2) Determine the mechanism of MOF in governing ciliogenesis and mitochondrial functions; and 3) Elucidate the epigenetic mechanism of MOF- mediated gene expression control. Combining our expertise in mouse genetics, transcriptional and epigenetic regulation, epithelial biology, genomics and computational biology, we will provide genetic, genomic and molecular insights into a critical epigenetic mechanism governing mammalian skin development.