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，已经作为一种 基因表达调控机制的基本层。在皮肤中，几种组蛋白修饰，如 对H3K27me3和HDAC1/2/3等组蛋白脱乙酰酶进行了研究。这些优雅的书房有 不仅为表观遗传机制在皮肤中的重要功能提供了新的见解，而且 建立了皮肤作为一个很好的模型系统来研究时空完好的表观遗传机制- 定义好的组织。然而，我们对皮肤表观遗传机制的了解是不完整的。这个 许多组蛋白标记及其相关修饰酶的功能尚不清楚。其中， 组蛋白4赖氨酸16乙酰化(H4K16Ac)尤其值得注意的是它在调节染色质中的关键作用 压实。结构和生物物理研究表明H4K16Ac在转录中起重要作用 通过影响核小体结构和与染色质结合蛋白的相互作用而激活。 H4K16Ac由myst家族赖氨酸乙酰转移酶MOF(也称为KAT8)催化，该酶是 在苍蝇、老鼠和人类中广泛保守。MOF及其催化的H4K16Ac标记物的功能首次 在果蝇黑腹果蝇身上进行了研究，发现H4K16Ac标记覆盖在雄性X- 染色体和上调转录由中性性剂量补偿两倍。然而， MOF和H4K16Ac的功能并不局限于X染色体基因的剂量补偿。财政部和 H4K16Ac已被证明控制许多涉及胚胎干细胞、肝脏调节的基因 小鼠和人的发育、周细胞发育等。这件事的首要目标是 应用于确定MOF和H4K16Ac在表皮中的转录调控作用 发展。在我们的初步研究中，我们发现MOF的基因缺失会导致严重的 表皮黏附、分化和形态发生缺陷。在本申请中，我们将阐明 MOF/H4K16Ac在表皮发育中的分子机制和细胞功能我们建议 目的：1)探讨MOF在表皮发育中的作用；2)探讨MOF的发病机制。 调控纤毛发生和线粒体功能；3)阐明MOF的表观遗传学机制。 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，我们将提供遗传学、 对哺乳动物皮肤关键表观遗传机制的基因组和分子洞察力 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.