Investigate MOF regulated epigenetic mechanisms of skin development

研究 MOF 调节皮肤发育的表观遗传机制

基本信息

批准号：
10467552
负责人：
Rui Yi
金额：
$ 45.22万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-03 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467552
关键词：
Acetylation Acetyltransferase Adhesions Affect Aging Binding Proteins Biochemical Biological Models Biology Cell Lineage Cell physiology Cells Chromatin Cilia Code Collaborations Computational Biology Data Defect Development Disease Dosage Compensation (Genetics)Drosophila genus Drosophila melanogaster Embryo Enhancers Enzymes Epigenetic Process Epithelial Epithelial Cells Family Gene Dosage Gene Expression Genes Genetic Genetic Transcription Genetic study Genomics Goals HDAC1 gene Histologic Histone Code Histone Deacetylase Histone H4 Histones Homeostasis Human Immunofluorescence Immunologic Knowledge Lysine Mammals Mediating Mitochondria Molecular Morphogenesis Mus Nucleosomes Organelles Pericytes Phenotype Play Regulation Resolution Role Saccharomycetales Signal Transduction Skin Structure Tail Tissues Transcriptional Activation Transcriptional Regulation X Chromosome biophysical analysis cilium biogenesis conditional knockout embryonic stem cell epigenetic regulation fly genomic tools histone modification insight keratinocyte liver development male mitochondrial metabolism mouse genetics mouse model novel promoter sex single cell analysis skin organogenesis spatiotemporal tool transcription factor transcriptome transcriptomics

项目摘要

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.

项目概要表观遗传机制，特别是由组蛋白修饰介导的机制，已成为一种基因表达控制机制的重要层。在皮肤中，一些组蛋白修饰，例如 H3K27me3 和组蛋白脱乙酰酶如 HDAC1/2/3 已被研究。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，而且建立皮肤作为一个优秀的模型系统来研究时空良好的表观遗传机制定义的组织。然而，我们对皮肤表观遗传机制的理解并不完整。这许多组蛋白标记及其相关修饰酶的功能尚不清楚。他们之中，组蛋白 4 赖氨酸 16 乙酰化 (H4K16Ac) 因其在调节染色质中的关键作用而特别引人注目压实。结构和生物物理学研究表明 H4K16Ac 在转录中发挥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。 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、小鼠和人类中广泛保守。 MOF及其催化的H4K16Ac标记的功能是第一在果蝇 Drosophila melanogaster 中进行研究，发现 H4K16Ac 标记覆盖雄性 X- 染色体并通过两倍中间性剂量补偿来提高转录。然而， MOF和H4K16Ac的功能不限于X染色体基因的剂量补偿。金属有机框架和 H4K16Ac 已被证明可以控制许多参与胚胎干细胞、肝脏调节的基因小鼠和人类的发育、周细胞发育等。本次活动的总体目标是应用是确定 MOF 和 H4K16Ac 介导的转录控制在表皮中的作用发展。在我们的初步研究中，我们发现 MOF 的基因缺失会导致严重的表皮粘附、分化和形态发生的缺陷。在此应用程序中，我们将阐明 MOF/H4K16Ac 在表皮发育过程中的分子机制和细胞功能。我们建议 1) 研究MOF在表皮发育中的作用； 2）确定MOF的作用机制控制纤毛发生和线粒体功能； 3）阐明MOF-的表观遗传机制介导的基因表达控制。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、对控制哺乳动物皮肤的关键表观遗传机制的基因组和分子见解发展。