MOF-mediated Histone H4 Lysine 16 Acetylation Governs Mitochondrial and Ciliary Functions by Controlling Gene Promoters

Abstract

Histone H4 lysine 16 acetylation (H4K16ac), governed by the histone acetyltransferase (HAT) MOF, orchestrates critical functions in gene expression regulation and chromatin interaction. However, how does MOF and H4K16ac control cellular function and regulate mammalian tissue development remains unclear. Furthermore, whether the function of MOF is mediated by MSL or NSL, two distinct MOF-containing HAT complexes, have not been determined during mammalian development. Here we show that conditional deletion of Mof but not Kansl1, an essential component of the NSL complex, causes severe defects during murine skin development. In the absence of Mof and H4K16ac, basal epithelial progenitors of mammalian skin fail to establish the basement membrane and cell polarity, causing the failure of self-renewal. Furthermore, epidermal differentiation and hair growth are severely compromised, leading to barrier defects and perinatal lethality. Single-cell and bulk RNA-seq, in combination with MOF ChIP-seq, reveal that MOF regulated genes are highly enriched in mitochondria and cilia. Mechanistically, MOF coordinates with RFX2 transcription factor, which preferentially binds to gene promoters, to regulate ciliary and mitochondrial genes. Importantly, genetic deletion of Uqcrq, a nuclear-encoded, essential subunit for electron transport chain (ETC) Complex III, recapitulates the defects of epidermal differentiation and hair follicle growth observed in MOF cKO. Together, this study reveals the requirement of MOF-mediated epigenetic mechanism for mitochondria and cilia, and demonstrates the important function of the MOF/ETC axis for mammalian skin development.