Histone H3 Lysine 56 Acetylation Is Linked to the Core Transcriptional Network in Human Embryonic Stem Cells

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The presence of acetylated histone H3K56 (H3K56ac) in human ES cells (ESCs) correlates positively with the binding of Nanog, Sox2, and Oct4 (NSO) transcription factors at their target gene promoters. However, the function of H3K56ac there has been unclear. We now report that Oct4 interacts with H3K56ac in mouse ESC nuclear extracts and that perturbing H3K56 acetylation decreases Oct4-H3 binding. This interaction is likely to be direct because it can be recapitulated in vitro in an H3K56ac-dependent manner and is functionally important because H3K56ac combines with NSO factors in chromatin immunoprecipitation sequencing to mark the regions associated with pluripotency better than NSO alone. Moreover, reducing H3K56ac by short hairpin Asf1a decreases expression of pluripotency-related markers and increases expression of differentiation-related ones. Therefore, our data suggest that H3K56ac plays a central role in binding to Oct4 to promote the pluripotency of ESCs.

mentioning

confidence: 99%

Acetylated histone H3K56 interacts with Oct4 to promote mouse embryonic stem cell pluripotency

Tan

Xue

Song

et al. 2013

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“…Antifungal drug resistance is a major clinical problem, and few drugs are available to battle Candida infections (21). H3K56 acetylation appears to be much less abundant in mammals than in yeasts (22)(23)(24), and close homologs of Rtt109 are not detected outside of the fungal kingdom (25,26). Therefore, we hypothesized that Rtt109 might provide a unique target for antifungal therapeutics, and we began to investigate the importance of H3K56 acetylation in fungal pathogenicity.…”

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confidence: 99%

Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis

Rosa

Boyartchuk

Zhu

et al. 2010

125

127

Candida albicans is a ubiquitous opportunistic pathogen that is the most prevalent cause of hospital-acquired fungal infections. In mammalian hosts, C. albicans is engulfed by phagocytes that attack the pathogen with DNA-damaging reactive oxygen species (ROS). Acetylation of histone H3 lysine 56 (H3K56) by the fungal-specific histone acetyltransferase Rtt109 is important for yeast model organisms to survive DNA damage and maintain genome integrity. To assess the importance of Rtt109 for C. albicans pathogenicity, we deleted the predicted homolog of Rtt109 in the clinical C. albicans isolate, SC5314. C. albicans rtt109 −/− mutant cells lack acetylated H3K56 (H3K56ac) and are hypersensitive to genotoxic agents. Additionally, rtt109 −/− mutant cells constitutively display increased H2A S129 phosphorylation and elevated DNA repair gene expression, consistent with endogenous DNA damage. Importantly, C. albicans rtt109 −/− cells are significantly less pathogenic in mice and more susceptible to killing by macrophages in vitro than are wild-type cells. Via pharmacological inhibition of the host NADPH oxidase enzyme, we show that the increased sensitivity of rtt109 −/− cells to macrophages depends on the host's ability to generate ROS, providing a mechanistic link between the drug sensitivity, gene expression, and pathogenesis phenotypes. We conclude that Rtt109 is particularly important for fungal pathogenicity, suggesting a unique target for therapeutic antifungal compounds.acetylation | chromatin | fungal pathogenesis | DNA damage resistance | macrophage

“…Rtt109 acetylates lysine 56 on the histone H3 core domain (H3K56), a mark that occurs globally on newly synthesized histones in Saccharomyces cerevisiae and Schizosaccharomyces pombe and is required for genome stability (13,15,(18)(19)(20)(21). H3K56ac was recently detected in humans, where it has been shown to be prominent in multiple cancers and is enriched at genes that are key regulators of stem cell pluripotency (22)(23)(24). H3K56ac is absent in yeast cells lacking Asf1 (asf1Δ mutants), indicating an essential role for Asf1 in the Rtt109-dependent acetylation of H3K56 (11,13,25).…”

mentioning

confidence: 99%

Catalytic activation of histone acetyltransferase Rtt109 by a histone chaperone

Kolonko

Albaugh

Lindner

et al. 2010

Most histone acetyltransferases (HATs) function as multisubunit complexes in which accessory proteins regulate substrate specificity and catalytic efficiency. Rtt109 is a particularly interesting example of a HAT whose specificity and catalytic activity require association with either of two histone chaperones, Vps75 or Asf1. Here, we utilize biochemical, structural, and genetic analyses to provide the detailed molecular mechanism for activation of a HAT (Rtt109) by its activating subunit Vps75. The rate-determining step of the activated complex is the transfer of the acetyl group from acetyl CoA to the acceptor lysine residue. Vps75 stimulates catalysis (>250-fold), not by contributing a catalytic base, but by stabilizing the catalytically active conformation of Rtt109. To provide structural insight into the functional complex, we produced a molecular model of Rtt109-Vps75 based on X-ray diffraction of crystals of the complex. This model reveals distinct negative electrostatic surfaces on an Rtt109 molecule that interface with complementary electropositive ends of a symmetrical Vps75 dimer. Rtt109 variants with interface point substitutions lack the ability to be fully activated by Vps75, and one such variant displayed impaired Vps75-dependent histone acetylation functions in yeast, yet these variants showed no adverse effect on Asf1-dependent Rtt109 activities in vitro and in vivo. Finally, we provide evidence for a molecular model in which a 1∶2 complex of Rtt109-Vps75 acetylates a heterodimer of H3-H4. The activation mechanism of Rtt109-Vps75 provides a valuable framework for understanding the molecular regulation of HATs within multisubunit complexes. p300 | K56 acetylation | K9 acetylation | NAP1