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K (Lysine) Acetyltransferase 8 (KAT8, also known as MOF or MYST1) is a HAT protein that is conserved among multiple species. It is a histone acetyltransferase belonging to the MYST family (Moz- Ybf2/Sas3-Sas2-Tip60) that contains a conserved acetyl- CoA-binding motif, a zinc finger domain and a chromo domain. It is reported that KAT8 is expressed in many types of tissues, including the ovary. KAT8 affects gene expression in multiple biological processes, and it implicated in several biological processes including DNA replication, DNA repair, cell cycle and tumorgenesis.
In Drosophila, KAT8 is a key component of the X chromosome dosage compensation complex, which is essential for balancing the expression of X-linked gene between male and female. It has been found that KAT8 not only maintains self-renewal and pluripotency of mouse embryonic stem cells (ESCs), but also facilitates the generation of induced pluripotent stem cells in human, suggesting KAT8 may be related to the establishment of both totipotency and pluripotent lineage in embryos. In Kat8 knockout mouse ESCs, levels of several critical transcription factors, such as Oct4, Nanog and Sox2 are significantly decreased and these genes are directly targeted by KAT8. KAT8 is also involved in metabolism by binding to mitochondrial DNAs and regulating their expression. Serious mitochondrial degeneration, high-energy consumption, as well as defective oxidative phosphorylation could be observed after Kat8 deletion in mouse cardiomyocytes, which indicates that KAT8 plays an important role in connecting epigenetics with metabolism.
Mice lacking KAT8 in oocytes are infertile with smaller ovarian size. This indicates that KAT8 is necessary for oocyte and follicle development. Increased reactive oxygen species (ROS) levels are observed in Kat8 knockout oocytes. In other words, low level of the ROS is essential for the normal oocyte and follicle development (Figure 1).Some studies have identified KAT8 as the first HAT with an essential role in mouse follicle development and female fertility.
Figure 1. Working model of how oocyte and follicle development is regulated by KAT8.
In fact, KAT8 contains a chromodomain for DNA binding and a C-terminal HAT domain for histone acetylation.It is reported that maternal histone acetyltransferase KAT8 is required for porcine preimplantation embryo development. Knockdown of KAT8 significantly reduced the blastocyst formation rate and total cell number per blastocyst. These results demonstrate that maternal KAT8 is indispensable for porcine early embryo development potentially through maintaining the proliferation of the first two lineages and genome integrity.
In addition, KAT8 acetylates histone substrates via two complexes, male-specific lethal (MSL) and non- specific-lethal (NSL). Though the NSL complex can acetylate histone H4 at lysines 5 and 8, the major histone substrate for KAT8 is histone H4 lysine 16 (H4K16). KAT8 also acetylates non-histone substrate, such as p53 at lysine 150. Acetylated p53 promotes the expression of several pro-apoptotic factors, such as PUMA and BAX. Besides, KAT8 can regulate its own activity by acetylating itself at lysine 274. Recent studies have shown that KAT8 is also associated with the SET1/MLL histone methyltransferase containing WDR5 and several other proteins in a multiprotein complex that catalyzes both histone acetylation and methylation. Additionally, KAT8-containing KANSL complex-mediated histone H4K16Ac promotes dimethylation at histone H3K4 by interacting with SET/MLL complexes.KAT8 and histone H4K16Ac regulate gene activation by cooperating with or affecting other histone modifications.