Investigate MOF regulated epigenetic mechanisms of skin development

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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.