Research over the past three decades has firmly established lysine acetyltransferases (KATs) as central players in regulating transcription. Recent advances in genomic sequencing, metabolomics, animal models and mass spectrometry technologies have uncovered unexpected new roles for KATs at the nexus between the environment and transcriptional regulation. Thousands of reversible acetylation sites have been mapped in the proteome that respond dynamically to the cellular milieu and maintain major processes such as metabolism, autophagy and stress response. Concurrently, researchers are continuously uncovering how deregulation of KAT activity drives disease, including cancer and developmental syndromes characterized by severe intellectual disability. These novel findings are reshaping our view of KATs away from mere modulators of chromatin to detectors of the cellular environment and integrators of diverse signalling pathways with the ability to modify cellular phenotype.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Wang, Z. et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138, 1019–1031 (2009).
Kleff, S., Andrulis, E. D., Anderson, C. W. & Sternglanz, R. Identification of a gene encoding a yeast histone H4 acetyltransferase. J. Biol. Chem. 270, 24674–24677 (1995).
Brownell, J. E. et al. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84, 843–851 (1996).
Kuo, M. H. et al. Transcription-linked acetylation by Gcn5p of histones H3 and H4 at specific lysines. Nature 383, 269–272 (1996).
Chelmicki, T. et al. MOF-associated complexes ensure stem cell identity and Xist repression. eLife 3, e02024 (2014).
Visel, A. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009).
Ravens, S., Yu, C., Ye, T., Stierle, M. & Tora, L. Tip60 complex binds to active Pol II promoters and a subset of enhancers and co-regulates the c-Myc network in mouse embryonic stem cells. Epigenetics Chromatin 8, 45 (2015).
Doyon, Y. et al. ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol. Cell 21, 51–64 (2006).
Smith, E. R. et al. A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16. Mol. Cell. Biol. 25, 9175–9188 (2005).
Mendjan, S. et al. Nuclear pore components are involved in the transcriptional regulation of dosage compensation in Drosophila. Mol. Cell 21, 811–823 (2006).
Martinez, E., Kundu, T. K., Fu, J. & Roeder, R. G. A human SPT3-TAFII31-GCN5-L acetylase complex distinct from transcription factor IID. J. Biol. Chem. 273, 23781–23785 (1998).
Wang, Y. L., Faiola, F., Xu, M., Pan, S. & Martinez, E. Human ATAC Is a GCN5/PCAF-containing acetylase complex with a novel NC2-like histone fold module that interacts with the TATA-binding protein. J. Biol. Chem. 283, 33808–33815 (2008).
Sadoul, K., Wang, J., Diagouraga, B. & Khochbin, S. The tale of protein lysine acetylation in the cytoplasm. J. Biomed. Biotechnol. 2011, 970382 (2011).
Kori, Y. et al. Proteome-wide acetylation dynamics in human cells. Sci. Rep. 7, 10296 (2017).
Dai, J., Bercury, K. K., Jin, W. & Macklin, W. B. Olig1 acetylation and nuclear export mediate oligodendrocyte development. J. Neurosci. 35, 15875–15893 (2015).
Faiola, F. et al. Max is acetylated by p300 at several nuclear localization residues. Biochem. J. 403, 397–407 (2007).
di Bari, M. G. et al. c-Abl acetylation by histone acetyltransferases regulates its nuclear-cytoplasmic localization. EMBO Rep. 7, 727–733 (2006).
Zhao, S. et al. Regulation of cellular metabolism by protein lysine acetylation. Science 327, 1000–1004 (2010).
Barlev, N. A. et al. Acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases. Mol. Cell 8, 1243–1254 (2001).
Kim, J. H., Saraf, A., Florens, L., Washburn, M. & Workman, J. L. Gcn5 regulates the dissociation of SWI/SNF from chromatin by acetylation of Swi2/Snf2. Genes Dev. 24, 2766–2771 (2010).
Wan, W. et al. mTORC1 phosphorylates acetyltransferase p300 to regulate autophagy and lipogenesis. Mol. Cell 68, 323–335 (2017). This study reports that the inhibitor of autophagy, mTORC1, directly phosphorylates p300 at its C-terminus. Phosphorylated p300 inhibits autophagy while promoting the transcriptional networks required for lipogenesis through activation of the transcription factor SREBP-1c.
Thompson, P. R. et al. Regulation of the p300 HAT domain via a novel activation loop. Nat. Struct. Mol. Biol. 11, 308–315 (2004).
Lu, L. et al. Modulations of hMOF autoacetylation by SIRT1 regulate hMOF recruitment and activities on the chromatin. Cell Res. 21, 1182–1195 (2011).
Yi, J. et al. Regulation of histone acetyltransferase TIP60 function by histone deacetylase 3. J. Biol. Chem. 289, 33878–33886 (2014).
Zhong, J. et al. TET1 modulates H4K16 acetylation by controlling auto-acetylation of hMOF to affect gene regulation and DNA repair function. Nucleic Acids Res. 45, 672–684 (2017).
Moussaieff, A. et al. Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab. 21, 392–402 (2015).
Mews, P. et al. Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature 546, 381–386 (2017). The authors report that the ASCC2 enzyme, which generates acetyl-CoA from acetate, becomes nuclear during neuronal differentiation and is required for proper histone acetylation at gene loci corresponding to neuronal genes. Accordingly, Ascc2 depletion from the mouse hippocampus leads to defects in memory and learning.
Chen, C. et al. Cytosolic acetyl-CoA promotes histone acetylation predominantly at H3K27 in Arabidopsis. Nat. Plants 3, 814–824 (2017).
Wilde, J. J., Siegenthaler, J. A., Dent, S. Y. & Niswander, L. A. Diencephalic size is restricted by a novel interplay between GCN5 acetyltransferase activity and retinoic acid signaling. J. Neurosci. 37, 2565–2579 (2017). This study reveals that GCN5 interacts directly with RAR-α, RAR-β and TACC1 at specific genomic retinoic acid response elements in neuroectodermal cells. In response to retinoic acid, GCN5 acetylates TACC1, leading to its expulsion from chromatin and subsequent gene activation. The absence of GCN5 catalytic activity in vivo leads to defects in brain patterning, a process regulated by retinoic acid.
Voss, A. K., Collin, C., Dixon, M. P. & Thomas, T. Moz and retinoic acid coordinately regulate H3K9 acetylation, Hox gene expression, and segment identity. Dev. Cell 17, 674–686 (2009).
Sheikh, B. N. et al. MOF maintains transcriptional programs regulating cellular stress response. Oncogene 35, 2698–2710 (2016).
Sutendra, G. et al. A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation. Cell 158, 84–97 (2014).
Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).
Sheikh, B. N. Crafting the brain — role of histone acetyltransferases in neural development and disease. Cell Tissue Res. 356, 553–573 (2014).
Gil, J., Ramirez-Torres, A. & Encarnacion-Guevara, S. Lysine acetylation and cancer: a proteomics perspective. J. Proteomics 150, 297–309 (2017).
Shogren-Knaak, M. et al. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006).
Zhang, R., Erler, J. & Langowski, J. Histone acetylation regulates chromatin accessibility: role of H4K16 in inter-nucleosome interaction. Biophys. J. 112, 450–459 (2017).
Hong, L., Schroth, G. P., Matthews, H. R., Yau, P. & Bradbury, E. M. Studies of the DNA binding properties of histone H4 amino terminus — thermal denaturation studies reveal that acetylation markedly reduces the binding constant of the H4 “tail” to DNA. J. Biol. Chem. 268, 305–314 (1993).
Stasevich, T. J. et al. Regulation of RNA polymerase II activation by histone acetylation in single living cells. Nature 516, 272–275 (2014).
Kanno, T. et al. Selective recognition of acetylated histones by bromodomain proteins visualized in living cells. Mol. Cell 13, 33–43 (2004).
Col, E. et al. Bromodomain factors of BET family are new essential actors of pericentric heterochromatin transcriptional activation in response to heat shock. Sci. Rep. 7, 5418 (2017).
Fujisawa, T. & Filippakopoulos, P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat. Rev. Mol. Cell Biol. 18, 246–262 (2017).
Zaini, M. A. et al. A p300 and SIRT1 regulated acetylation switch of C/EBPalpha controls mitochondrial function. Cell Rep. 22, 497–511 (2018). This paper reports on the balance of C/EBPα acetylation levels mediated by p300 and the KDAC SIRT1. In the presence of high glucose, p300 acetylates C/EBPα whereas deacetylation of C/EBPα under low glucose conditions by SIRT1 promotes C/EBPα transcriptional activity at genes required for mitochondrial respiration.
Daitoku, H. et al. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc. Natl Acad. Sci. USA 101, 10042–10047 (2004).
Rokudai, S. et al. MOZ increases p53 acetylation and premature senescence through its complex formation with PML. Proc. Natl Acad. Sci. USA 110, 3895–3900 (2013).
Wang, S. J. et al. Acetylation is crucial for p53-mediated ferroptosis and tumor suppression. Cell Rep. 17, 366–373 (2016).
Sykes, S. M. et al. Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol. Cell 24, 841–851 (2006).
Rajagopal, N. et al. Distinct and predictive histone lysine acetylation patterns at promoters, enhancers, and gene bodies. G3 4, 2051–2063 (2014).
Wang, Z. et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat. Genet. 40, 897–903 (2008).
Ravens, S. et al. Mof-associated complexes have overlapping and unique roles in regulating pluripotency in embryonic stem cells and during differentiation. eLife 3, e02104 (2014).
Govind, C. K., Zhang, F., Qiu, H., Hofmeyer, K. & Hinnebusch, A. G. Gcn5 promotes acetylation, eviction, and methylation of nucleosomes in transcribed coding regions. Mol. Cell 25, 31–42 (2007).
Voss, A. K. et al. MOZ regulates the Tbx1 locus, and Moz mutation partially phenocopies DiGeorge syndrome. Dev. Cell 23, 652–663 (2012).
Sheikh, B. N. et al. MOZ regulates B cell progenitors and, consequently, Moz haploinsufficiency dramatically retards MYC-induced lymphoma development. Blood 125, 1910–1921 (2015).
Negre, N. et al. A cis-regulatory map of the Drosophila genome. Nature 471, 527–531 (2011).
Li, B. et al. Combined action of PHD and chromo domains directs the Rpd3S HDAC to transcribed chromatin. Science 316, 1050–1054 (2007).
Li, B. et al. Infrequently transcribed long genes depend on the Set2/Rpd3S pathway for accurate transcription. Genes Dev. 21, 1422–1430 (2007).
Pattenden, S. G., Gogol, M. M. & Workman, J. L. Features of cryptic promoters and their varied reliance on bromodomain-containing factors. PLOS ONE 5, e12927 (2010).
Brocks, D. et al. DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats. Nat. Genet. 49, 1052–1060 (2017).
Lindblad-Toh, K. et al. A high-resolution map of human evolutionary constraint using 29 mammals. Nature 478, 476–482 (2011).
Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).
Arner, E. et al. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science 347, 1010–1014 (2015).
Heintzman, N. D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009).
Mifsud, B. et al. Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Nat. Genet. 47, 598–606 (2015).
Schoenfelder, S. et al. The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements. Genome Res. 25, 582–597 (2015).
Dixon, J. R. et al. Chromatin architecture reorganization during stem cell differentiation. Nature 518, 331–336 (2015).
Heintzman, N. D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).
Weinert, B. T. et al. Time-resolved analysis reveals rapid dynamics and broad scope of the CBP/p300 acetylome. Cell 174, 231–244 (2018). This paper reports on the acetylation targets of p300 and CBP in mouse embryonic fibroblasts. Over 200 nuclear chromatin and transcriptional regulators are targeted by p300/CBP-mediated acetylation activity.
Bedford, D. C., Kasper, L. H., Fukuyama, T. & Brindle, P. K. Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases. Epigenetics 5, 9–15 (2010).
Mujtaba, S. et al. Structural mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation. Mol. Cell 13, 251–263 (2004).
Tang, Z. et al. SET1 and p300 act synergistically, through coupled histone modifications, in transcriptional activation by p53. Cell 154, 297–310 (2013).
Jin, Q. et al. Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. EMBO J. 30, 249–262 (2011).
Bose, D. A. et al. RNA binding to CBP stimulates histone acetylation and transcription. Cell 168, 135–149 (2017). This study reports on the interaction of CBP with eRNAs; eRNAs bind directly to the activation loop of CBP and stimulate CBP acetylation activity at H3K18 and H3K27.
Kueh, A. J., Dixon, M. P., Voss, A. K. & Thomas, T. HBO1 is required for H3K14 acetylation and normal transcriptional activity during embryonic development. Mol. Cell. Biol. 31, 845–860 (2011).
Saksouk, N. et al. HBO1 HAT complexes target chromatin throughout gene coding regions via multiple PHD finger interactions with histone H3 tail. Mol. Cell 33, 257–265 (2009).
Kaimori, J. Y. et al. Histone H4 lysine 20 acetylation is associated with gene repression in human cells. Sci. Rep. 6, 24318 (2016).
Zeng, L., Zhang, Q., Gerona-Navarro, G., Moshkina, N. & Zhou, M. M. Structural basis of site-specific histone recognition by the bromodomains of human coactivators PCAF and CBP/p300. Structure 16, 643–652 (2008).
Plotnikov, A. N. et al. Structural insights into acetylated-histone H4 recognition by the bromodomain-PHD finger module of human transcriptional coactivator CBP. Structure 22, 353–360 (2014).
Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).
Schwartz, S., Meshorer, E. & Ast, G. Chromatin organization marks exon-intron structure. Nat. Struct. Mol. Biol. 16, 990–995 (2009).
Moore, S. A., Ferhatoglu, Y., Jia, Y., Al-Jiab, R. A. & Scott, M. J. Structural and biochemical studies on the chromo-barrel domain of male specific lethal 3 (MSL3) reveal a binding preference for mono- or dimethyllysine 20 on histone H4. J. Biol. Chem. 285, 40879–40890 (2010).
Kim, D. et al. Corecognition of DNA and a methylated histone tail by the MSL3 chromodomain. Nat. Struct. Mol. Biol. 17, 1027–1029 (2010).
Taverna, S. D., Li, H., Ruthenburg, A. J., Allis, C. D. & Patel, D. J. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat. Struct. Mol. Biol. 14, 1025–1040 (2007).
Haynes, S. R. et al. The bromodomain: a conserved sequence found in human, Drosophila and yeast proteins. Nucleic Acids Res. 20, 2603 (1992).
Li, Y. et al. AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation. Cell 159, 558–571 (2014).
Singh, P. B. et al. A sequence motif found in a Drosophila heterochromatin protein is conserved in animals and plants. Nucleic Acids Res. 19, 789–794 (1991).
Kuo, A. J. et al. The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome. Nature 484, 115–119 (2012).
Kim, J. et al. Tudor, MBT and chromo domains gauge the degree of lysine methylation. EMBO Rep. 7, 397–403 (2006).
Li, H. et al. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442, 91–95 (2006).
Wysocka, J. et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 86–90 (2006).
Shi, X. et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442, 96–99 (2006).
Paggetti, J. et al. Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+cells. Oncogene 29, 5019–5031 (2010).
Dou, Y. et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 121, 873–885 (2005).
Cho, H. J. et al. GAS41 recognizes diacetylated histone H3 through a bivalent binding mode. ACS Chem. Biol. 13, 2739–2746 (2018).
Hsu, C. C. et al. Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer. Genes Dev. 32, 58–69 (2018).
Qiu, Y. et al. Combinatorial readout of unmodified H3R2 and acetylated H3K14 by the tandem PHD finger of MOZ reveals a regulatory mechanism for HOXA9 transcription. Genes Dev. 26, 1376–1391 (2012).
Newman, D. M. et al. Acetylation of the Cd8 locus by KAT6A determines memory T cell diversity. Cell Rep. 16, 3311–3321 (2016).
Miller, C. T., Maves, L. & Kimmel, C. B. Moz regulates Hox expression and pharyngeal segmental identity in zebrafish. Development 131, 2443–2461 (2004).
Sheikh, B. N., Downer, N. L., Kueh, A. J., Thomas, T. & Voss, A. K. Excessive versus physiologically relevant levels of retinoic acid in embryonic stem cell differentiation. Stem Cells 32, 1451–1458 (2014).
Pietrocola, F., Galluzzi, L., Bravo-San Pedro, J. M., Madeo, F. & Kroemer, G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805–821 (2015).
Choudhary, C., Weinert, B. T., Nishida, Y., Verdin, E. & Mann, M. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat. Rev. Mol. Cell Biol. 15, 536–550 (2014).
Marino, G. et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol. Cell 53, 710–725 (2014).
Tanner, K. G., Langer, M. R., Kim, Y. & Denu, J. M. Kinetic mechanism of the histone acetyltransferase GCN5 from yeast. J. Biol. Chem. 275, 22048–22055 (2000).
Montgomery, D. C. et al. Global profiling of acetyltransferase feedback regulation. J. Am. Chem. Soc. 138, 6388–6391 (2016).
Liu, Y. et al. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456, 269–273 (2008).
Lerin, C. et al. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha. Cell Metab. 3, 429–438 (2006).
Kemper, J. K. et al. FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab. 10, 392–404 (2009).
Jiang, W. et al. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol. Cell 43, 33–44 (2011).
Herr, D. J. et al. HDAC1 localizes to the mitochondria of cardiac myocytes and contributes to early cardiac reperfusion injury. J. Mol. Cell Cardiol. 114, 309–319 (2018).
Bakin, R. E. & Jung, M. O. Cytoplasmic sequestration of HDAC7 from mitochondrial and nuclear compartments upon initiation of apoptosis. J. Biol. Chem. 279, 51218–51225 (2004).
Onyango, P., Celic, I., McCaffery, J. M., Boeke, J. D. & Feinberg, A. P. SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc. Natl Acad. Sci. USA 99, 13653–13658 (2002).
Michishita, E., Park, J. Y., Burneskis, J. M., Barrett, J. C. & Horikawa, I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol. Biol. Cell 16, 4623–4635 (2005).
Chatterjee, A. et al. MOF acetyl transferase regulates transcription and respiration in mitochondria. Cell 167, 722–738 (2016). This article is the first report of a well-established KAT, MOF, localizing to the mitochondria. In HeLa cells cultured in the presence of galactose but not glucose, which induces the requirement for mitochondrial respiration, MOF is required to drive transcription of the mitochondrial genome.
Scher, M. B., Vaquero, A. & Reinberg, D. SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev. 21, 920–928 (2007).
Cheng, A. et al. Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise and metabolic and excitatory challenges. Cell Metab. 23, 128–142 (2016).
Kim, H. S. et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17, 41–52 (2010).
Gillet, L. C., Leitner, A. & Aebersold, R. Mass spectrometry applied to bottom-up proteomics: entering the high-throughput era for hypothesis testing. Annu. Rev. Anal. Chem. 9, 449–472 (2016).
Tharkeshwar, A. K., Gevaert, K. & Annaert, W. Organellar omics — a reviving strategy to untangle the biomolecular complexity of the cell. Proteomics 18, e1700113 (2018).
Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018).
Eisenberg, T. et al. Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan. Cell Metab. 19, 431–444 (2014).
Fullgrabe, J. et al. The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Nature 500, 468–471 (2013).
Huang, R. et al. Deacetylation of nuclear LC3 drives autophagy initiation under starvation. Mol. Cell 57, 456–466 (2015).
Lee, I. H. & Finkel, T. Regulation of autophagy by the p300 acetyltransferase. J. Biol. Chem. 284, 6322–6328 (2009).
Lin, S. Y. et al. GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science 336, 477–481 (2012).
Yao, T. P. et al. Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell 93, 361–372 (1998).
Tanaka, Y. et al. Extensive brain hemorrhage and embryonic lethality in a mouse null mutant of CREB-binding protein. Mech. Dev. 95, 133–145 (2000).
Thomas, T. et al. Monocytic leukemia zinc finger protein is essential for the development of long-term reconstituting hematopoietic stem cells. Genes Dev. 20, 1175–1186 (2006).
Katsumoto, T. et al. MOZ is essential for maintenance of hematopoietic stem cells. Genes Dev. 20, 1321–1330 (2006).
Thomas, T., Dixon, M. P., Kueh, A. J. & Voss, A. K. Mof (MYST1 or KAT8) is essential for progression of embryonic development past the blastocyst stage and required for normal chromatin architecture. Mol. Cell. Biol. 28, 5093–5105 (2008).
Hu, Y. et al. Homozygous disruption of the Tip60 gene causes early embryonic lethality. Dev. Dyn. 238, 2912–2921 (2009).
Xu, W. et al. Loss of Gcn5l2 leads to increased apoptosis and mesodermal defects during mouse development. Nat. Genet. 26, 229–232 (2000).
Bu, P., Evrard, Y. A., Lozano, G. & Dent, S. Y. Loss of Gcn5 acetyltransferase activity leads to neural tube closure defects and exencephaly in mouse embryos. Mol. Cell. Biol. 27, 3405–3416 (2007).
Niederreither, K. & Dolle, P. Retinoic acid in development: towards an integrated view. Nat. Rev. Genet. 9, 541–553 (2008).
Lin, W., Zhang, Z., Chen, C. H., Behringer, R. R. & Dent, S. Y. Proper Gcn5 histone acetyltransferase expression is required for normal anteroposterior patterning of the mouse skeleton. Dev. Growth Differ. 50, 321–330 (2008).
Petrij, F. et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376, 348–351 (1995).
Roelfsema, J. H. et al. Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. Am. J. Hum. Genet. 76, 572–580 (2005).
Tham, E. et al. Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features. Am. J. Hum. Genet. 96, 507–513 (2015).
Arboleda, V. A. et al. De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay. Am. J. Hum. Genet. 96, 498–506 (2015).
Yu, H. C., Geiger, E. A., Medne, L., Zackai, E. H. & Shaikh, T. H. An individual with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and additional features expands the phenotype associated with mutations in KAT6B. Am. J. Med. Genet. 164A, 950–957 (2014).
Clayton-Smith, J. et al. Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome. Am. J. Hum. Genet. 89, 675–681 (2011).
Simpson, M. A. et al. De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome. Am. J. Hum. Genet. 90, 290–294 (2012).
Kraft, M. et al. Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice. J. Clin. Invest. 121, 3479–3491 (2011).
Campeau, P. M. et al. Mutations in KAT6B, encoding a histone acetyltransferase, cause Genitopatellar syndrome. Am. J. Hum. Genet. 90, 282–289 (2012).
Vega, H. et al. Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. Nat. Genet. 37, 468–470 (2005).
Radvanszky, J. et al. Complex phenotypes blur conventional borders between Say-Barber-Biesecker-Young-Simpson syndrome and Genitopatellar syndrome. Clin. Genet. 91, 339–343 (2017).
Negri, G. et al. Clinical and molecular characterization of Rubinstein-Taybi syndrome patients carrying distinct novel mutations of the EP300 gene. Clin. Genet. 87, 148–154 (2015).
Gannon, T. et al. Further delineation of the KAT6B molecular and phenotypic spectrum. Eur. J. Hum. Genet. 23, 1165–1170 (2015).
Milani, D. et al. Rubinstein-Taybi syndrome: clinical features, genetic basis, diagnosis, and management. Ital. J. Pediatr. 41, 4 (2015).
Roelfsema, J. H. & Peters, D. J. Rubinstein-Taybi syndrome: clinical and molecular overview. Expert Rev. Mol. Med. 9, 1–16 (2007).
Vega, H. et al. Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome. J. Med. Genet. 47, 30–37 (2010).
Tzschach, A. et al. Chromosome aberrations involving 10q22: report of three overlapping interstitial deletions and a balanced translocation disrupting C10orf11. Eur. J. Hum. Genet. 18, 291–295 (2010).
Pelletier, N., Champagne, N., Stifani, S. & Yang, X. J. MOZ and MORF histone acetyltransferases interact with the Runt-domain transcription factor Runx2. Oncogene 21, 2729–2740 (2002).
Koolen, D. A. et al. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat. Genet. 44, 639–641 (2012).
Zollino, M. et al. Mutations in KANSL1 cause the 17q21.31 microdeletion syndrome phenotype. Nat. Genet. 44, 636–638 (2012).
Gilissen, C. et al. Genome sequencing identifies major causes of severe intellectual disability. Nature 511, 344–347 (2014).
Basilicata, M. F. et al. De novo mutations of MSL3 cause a X-linked syndrome marked by impaired histone H4 lysine 16 acetylation. Nat. Genet. 50, 1442–1451 (2018).
Yan, K. et al. Mutations in the chromatin regulator gene BRPF1 cause syndromic intellectual disability and deficient histone acetylation. Am. J. Hum. Genet. 100, 91–104 (2017).
Koolen, D. A. et al. Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J. Med. Genet. 45, 710–720 (2008).
Myers, K. A. et al. The epileptology of Koolen-de Vries syndrome: electro-clinico-radiologic findings in 31 patients. Epilepsia 58, 1085–1094 (2017).
Lopez-Atalaya, J. P. et al. Histone acetylation deficits in lymphoblastoid cell lines from patients with Rubinstein-Taybi syndrome. J. Med. Genet. 49, 66–74 (2012).
Villain, H., Florian, C. & Roullet, P. HDAC inhibition promotes both initial consolidation and reconsolidation of spatial memory in mice. Sci. Rep. 6, 27015 (2016).
Benito, E. et al. HDAC inhibitor-dependent transcriptome and memory reinstatement in cognitive decline models. J. Clin. Invest. 125, 3572–3584 (2015). The authors show that administration of the KDAC inhibitor SAHA (vorinostat) improves spatial memory and hippocampal neuronal function and reduces expression of inflammatory genes in mice.
Alarcon, J. M. et al. Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 42, 947–959 (2004).
Huntly, B. J. et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6, 587–596 (2004).
Largeot, A. et al. Expression of the MOZ-TIF2 oncoprotein in mice represses senescence. Exp. Hematol. 44, 231–237 (2016).
Zack, T. I. et al. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45, 1134–1140 (2013).
Sheikh, B. N. et al. MOZ (MYST3, KAT6A) inhibits senescence via the INK4A-ARF pathway. Oncogene 34, 5807–5820 (2015).
Sheikh, B. N. et al. MOZ (KAT6A) is essential for the maintenance of classically defined adult hematopoietic stem cells. Blood 128, 2307–2318 (2016).
Perez-Campo, F. M. et al. MOZ-mediated repression of p16INK4a is critical for the self-renewal of neural and hematopoietic stem cells. Stem Cells 32, 1591–1601 (2014).
Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat. Genet. 37, 391–400 (2005).
Pfister, S. et al. The histone acetyltransferase hMOF is frequently downregulated in primary breast carcinoma and medulloblastoma and constitutes a biomarker for clinical outcome in medulloblastoma. Int. J. Cancer 122, 1207–1213 (2008).
Cai, M. et al. Expression of hMOF in different ovarian tissues and its effects on ovarian cancer prognosis. Oncol. Rep. 33, 685–692 (2015).
Cao, L. et al. Correlation of low expression of hMOF with clinicopathological features of colorectal carcinoma, gastric cancer and renal cell carcinoma. Int. J. Oncol. 44, 1207–1214 (2014).
Zhu, L. et al. Expression of hMOF, but not HDAC4, is responsible for the global histone H4K16 acetylation in gastric carcinoma. Int. J. Oncol. 46, 2535–2545 (2015).
Zhang, J. et al. The histone acetyltransferase hMOF suppresses hepatocellular carcinoma growth. Biochem. Biophys. Res. Commun. 452, 575–580 (2014).
Shrimp, J. H. et al. Characterizing the covalent targets of a small molecule inhibitor of the lysine acetyltransferase P300. ACS Med. Chem. Lett. 7, 151–155 (2016).
Dahlin, J. L. et al. Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors. Nat. Commun. 8, 1527 (2017).
Lasko, L. M. et al. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature 550, 128–132 (2017). This study describes a highly specific and potent p300/CBP inhibitor, which shows strong efficacy against AR-positive prostate cancer in animal models.
Baell, J. B. et al. Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature 560, 253–257 (2018). This report describes highly potent MOZ–KAT6B inhibitors that bind and antagonize the acetyl-CoA binding site. The inhibitors are effective against RAS-V12-driven hepatocellular carcinoma and MYC-driven B cell lymphoma.
Halsall, J. A. & Turner, B. M. Histone deacetylase inhibitors for cancer therapy: an evolutionarily ancient resistance response may explain their limited success. Bioessays 38, 1102–1110 (2016).
Eckschlager, T., Plch, J., Stiborova, M. & Hrabeta, J. Histone deacetylase inhibitors as anticancer drugs. Int. J. Mol. Sci. 18, 1414 (2017).
Shida, T., Cueva, J. G., Xu, Z., Goodman, M. B. & Nachury, M. V. The major alpha-tubulin K40 acetyltransferase alphaTAT1 promotes rapid ciliogenesis and efficient mechanosensation. Proc. Natl Acad. Sci. USA 107, 21517–21522 (2010).
Akella, J. S. et al. MEC-17 is an alpha-tubulin acetyltransferase. Nature 467, 218–222 (2010).
Xu, Z. et al. Microtubules acquire resistance from mechanical breakage through intralumenal acetylation. Science 356, 328–332 (2017).
Hou, F. & Zou, H. Two human orthologues of Eco1/Ctf7 acetyltransferases are both required for proper sister-chromatid cohesion. Mol. Biol. Cell 16, 3908–3918 (2005).
Zhang, J. et al. Acetylation of Smc3 by Eco1 is required for S phase sister chromatid cohesion in both human and yeast. Mol. Cell 31, 143–151 (2008).
Unal, E. et al. A molecular determinant for the establishment of sister chromatid cohesion. Science 321, 566–569 (2008).
Ivanov, D. et al. Eco1 is a novel acetyltransferase that can acetylate proteins involved in cohesion. Curr. Biol. 12, 323–328 (2002).
Spencer, T. E. et al. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature 389, 194–198 (1997).
Chen, H. et al. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90, 569–580 (1997).
Sheppard, H. M., Harries, J. C., Hussain, S., Bevan, C. & Heery, D. M. Analysis of the steroid receptor coactivator 1 (SRC1)-CREB binding protein interaction interface and its importance for the function of SRC1. Mol. Cell. Biol. 21, 39–50 (2001).
Demarest, S. J. et al. Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators. Nature 415, 549–553 (2002).
Yao, T. P., Ku, G., Zhou, N., Scully, R. & Livingston, D. M. The nuclear hormone receptor coactivator SRC-1 is a specific target of p300. Proc. Natl Acad. Sci. USA 93, 10626–10631 (1996).
Brown, K., Chen, Y., Underhill, T. M., Mymryk, J. S. & Torchia, J. The coactivator p/CIP/SRC-3 facilitates retinoic acid receptor signaling via recruitment of GCN5. J. Biol. Chem. 278, 39402–39412 (2003).
Mizzen, C. A. et al. The TAFII250 subunit of TFIID has histone acetyltransferase activity. Cell 87, 1261–1270 (1996).
Hsieh, Y. J., Kundu, T. K., Wang, Z., Kovelman, R. & Roeder, R. G. The TFIIIC90 subunit of TFIIIC interacts with multiple components of the RNA polymerase III machinery and contains a histone-specific acetyltransferase activity. Mol. Cell. Biol. 19, 7697–7704 (1999).
Kundu, T. K., Wang, Z. & Roeder, R. G. Human TFIIIC relieves chromatin-mediated repression of RNA polymerase III transcription and contains an intrinsic histone acetyltransferase activity. Mol. Cell. Biol. 19, 1605–1615 (1999).
Winkler, G. S., Kristjuhan, A., Erdjument-Bromage, H., Tempst, P. & Svejstrup, J. Q. Elongator is a histone H3 and H4 acetyltransferase important for normal histone acetylation levels in vivo. Proc. Natl Acad. Sci. USA 99, 3517–3522 (2002).
Wittschieben, B. O. et al. A novel histone acetyltransferase is an integral subunit of elongating RNA polymerase II holoenzyme. Mol. Cell 4, 123–128 (1999).
Creppe, C. et al. Elongator controls the migration and differentiation of cortical neurons through acetylation of alpha-tubulin. Cell 136, 551–564 (2009).
Miskiewicz, K. et al. ELP3 controls active zone morphology by acetylating the ELKS family member Bruchpilot. Neuron 72, 776–788 (2011).
Glatt, S. & Muller, C. W. Structural insights into Elongator function. Curr. Opin. Struct. Biol. 23, 235–242 (2013).
Svejstrup, J. Q. Elongator complex: how many roles does it play? Curr. Opin. Cell Biol. 19, 331–336 (2007).
Karlsborn, T. et al. Elongator, a conserved complex required for wobble uridine modifications in eukaryotes. RNA Biol. 11, 1519–1528 (2014).
Glatt, S. et al. Structural basis for tRNA modification by Elp3 from Dehalococcoides mccartyi. Nat. Struct. Mol. Biol. 23, 794–802 (2016).
Selvadurai, K., Wang, P., Seimetz, J. & Huang, R. H. Archaeal Elp3 catalyzes tRNA wobble uridine modification at C5 via a radical mechanism. Nat. Chem. Biol. 10, 810–812 (2014).
Karlsborn, T., Tukenmez, H., Chen, C. & Bystrom, A. S. Familial dysautonomia (FD) patients have reduced levels of the modified wobble nucleoside mcm5s2U in tRNA. Biochem. Biophys. Res. Commun. 454, 441–445 (2014).
Huang, B., Johansson, M. J. & Bystrom, A. S. An early step in wobble uridine tRNA modification requires the Elongator complex. RNA 11, 424–436 (2005).
Scott, I., Webster, B. R., Li, J. H. & Sack, M. N. Identification of a molecular component of the mitochondrial acetyltransferase programme: a novel role for GCN5L1. Biochem. J. 443, 655–661 (2012).
Scott, I. et al. GCN5-like protein 1 (GCN5L1) controls mitochondrial content through coordinated regulation of mitochondrial biogenesis and mitophagy. J. Biol. Chem. 289, 2864–2872 (2014).
Jeong, J. W. et al. Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell 111, 709–720 (2002).
Yoon, H. et al. NAA10 controls osteoblast differentiation and bone formation as a feedback regulator of Runx2. Nat. Commun. 5, 5176 (2014).
Qian, X. et al. Phosphoglycerate kinase 1 phosphorylates beclin1 to induce autophagy. Mol. Cell 65, 917–931 (2017).
Seo, J. H. et al. ARD1-mediated Hsp70 acetylation balances stress-induced protein refolding and degradation. Nat. Commun. 7, 12882 (2016).
Lee, E. J. et al. SAMHD1 acetylation enhances its deoxynucleotide triphosphohydrolase activity and promotes cancer cell proliferation. Oncotarget 8, 68517–68529 (2017).
Shin, S. H. et al. Arrest defective 1 regulates the oxidative stress response in human cells and mice by acetylating methionine sulfoxide reductase A. Cell Death Dis. 5, e1490 (2014).
Magin, R. S., March, Z. M. & Marmorstein, R. The N-terminal acetyltransferase Naa10/ARD1 does not acetylate lysine residues. J. Biol. Chem. 291, 5270–5277 (2016).
Murray-Rust, T. A., Oldham, N. J., Hewitson, K. S. & Schofield, C. J. Purified recombinant hARD1 does not catalyse acetylation of Lys532 of HIF-1alpha fragments in vitro. FEBS Lett. 580, 1911–1918 (2006).
Evjenth, R. et al. Human Naa50p (Nat5/San) displays both protein N alpha- and N epsilon-acetyltransferase activity. J. Biol. Chem. 284, 31122–31129 (2009).
Hou, F., Chu, C. W., Kong, X., Yokomori, K. & Zou, H. The acetyltransferase activity of San stabilizes the mitotic cohesin at the centromeres in a shugoshin-independent manner. J. Cell Biol. 177, 587–597 (2007).
Yang, X. et al. HAT4, a Golgi apparatus-anchored B-type histone acetyltransferase, acetylates free histone H4 and facilitates chromatin assembly. Mol. Cell 44, 39–50 (2011).
Devaiah, B. N. et al. BRD4 is a histone acetyltransferase that evicts nucleosomes from chromatin. Nat. Struct. Mol. Biol. 23, 540–548 (2016).
Fan, J. et al. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol. Cell 53, 534–548 (2014).
Shan, C. et al. Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth. Mol. Cell 55, 552–565 (2014).
Notredame, C., Higgins, D. G. & Heringa, J. T-Coffee: a novel method for fast and accurate multiple sequence alignment. J. Mol. Biol. 302, 205–217 (2000).
Letunic, I. & Bork, P. Interactive tree of life (iTOL) v3: an online tool for the display and annotation of phylogenetic and other trees. Nucleic Acids Res. 44, W242–W245 (2016).
Chen, Y. et al. Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol. Cell. Proteomics 6, 812–819 (2007).
Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028 (2011).
Xie, Z. et al. Lysine succinylation and lysine malonylation in histones. Mol. Cell Proteomics 11, 100–107 (2012).
Kulkarni, R. A. et al. Discovering targets of non-enzymatic acylation by thioester reactivity profiling. Cell Chem. Biol. 24, 231–242 (2017).
Weinert, B. T. et al. Lysine succinylation is a frequently occurring modification in prokaryotes and eukaryotes and extensively overlaps with acetylation. Cell Rep. 4, 842–851 (2013).
Wagner, G. R. & Payne, R. M. Widespread and enzyme-independent Nepsilon-acetylation and Nepsilon-succinylation of proteins in the chemical conditions of the mitochondrial matrix. J. Biol. Chem. 288, 29036–29045 (2013).
Wagner, G. R. et al. A class of reactive acyl-CoA species reveals the non-enzymatic origins of protein acylation. Cell Metab. 25, 823–837 (2017).
Liu, X. et al. MOF as an evolutionarily conserved histone crotonyltransferase and transcriptional activation by histone acetyltransferase-deficient and crotonyltransferase-competent CBP/p300. Cell Discov. 3, 17016 (2017).
Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol. Cell 58, 203–215 (2015).
Kaczmarska, Z. et al. Structure of p300 in complex with acyl-CoA variants. Nat. Chem. Biol. 13, 21–29 (2017).
Han, Z. et al. Revealing the protein propionylation activity of the histone acetyltransferase MOF (males absent on the first). J. Biol. Chem. 293, 3410–3420 (2018).
Wang, Y. et al. KAT2A coupled with the alpha-KGDH complex acts as a histone H3 succinyltransferase. Nature 552, 273–277 (2017).
Leemhuis, H., Packman, L. C., Nightingale, K. P. & Hollfelder, F. The human histone acetyltransferase P/CAF is a promiscuous histone propionyltransferase. Chembiochem 9, 499–503 (2008).
Simithy, J. et al. Characterization of histone acylations links chromatin modifications with metabolism. Nat. Commun. 8, 1141 (2017).
Xiong, X. et al. Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2. Nat. Chem. Biol. 12, 1111–1118 (2016).
Flynn, E. M. et al. A subset of human bromodomains recognizes butyryllysine and crotonyllysine histone peptide modifications. Structure 23, 1801–1814 (2015).
Conrad, T. et al. The MOF chromobarrel domain controls genome-wide H4K16 acetylation and spreading of the MSL complex. Dev. Cell 22, 610–624 (2012).
Akhtar, A., Zink, D. & Becker, P. B. Chromodomains are protein-RNA interaction modules. Nature 407, 405–409 (2000).
Ali, M. et al. Tandem PHD fingers of MORF/MOZ acetyltransferases display selectivity for acetylated histone H3 and are required for the association with chromatin. J. Mol. Biol. 424, 328–338 (2012).
Champagne, K. S. et al. The crystal structure of the ING5 PHD finger in complex with an H3K4me3 histone peptide. Proteins 72, 1371–1376 (2008).
Poplawski, A. et al. Molecular insights into the recognition of N-terminal histone modifications by the BRPF1 bromodomain. J. Mol. Biol. 426, 1661–1676 (2014).
Lloyd, J. T. & Glass, K. C. Biological function and histone recognition of family IV bromodomain-containing proteins. J. Cell. Physiol. 233, 1877–1886 (2018).
Lubula, M. Y. et al. Structural insights into recognition of acetylated histone ligands by the BRPF1 bromodomain. FEBS Lett. 588, 3844–3854 (2014).
Vezzoli, A. et al. Molecular basis of histone H3K36me3 recognition by the PWWP domain of Brpf1. Nat. Struct. Mol. Biol. 17, 617–619 (2010).
Qin, S. et al. Recognition of unmodified histone H3 by the first PHD finger of bromodomain-PHD finger protein 2 provides insights into the regulation of histone acetyltransferases monocytic leukemic zinc-finger protein (MOZ) and MOZ-related factor (MORF). J. Biol. Chem. 286, 36944–36955 (2011).
Burke, T. W., Cook, J. G., Asano, M. & Nevins, J. R. Replication factors MCM2 and ORC1 interact with the histone acetyltransferase HBO1. J. Biol. Chem. 276, 15397–15408 (2001).
Kim, C. H. et al. The chromodomain-containing histone acetyltransferase TIP60 acts as a code reader, recognizing the epigenetic codes for initiating transcription. Biosci. Biotechnol. Biochem. 79, 532–538 (2015).
Sun, Y. et al. Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60. Nat. Cell Biol. 11, 1376–1382 (2009).
Zhang, P. et al. Structure of human MRG15 chromo domain and its binding to Lys36-methylated histone H3. Nucleic Acids Res. 34, 6621–6628 (2006).
Kim, S. et al. Mechanism of histone H3K4me3 recognition by the plant homeodomain of inhibitor of growth 3. J. Biol. Chem. 291, 18326–18341 (2016).
Akhtar, A. & Becker, P. B. The histone H4 acetyltransferase MOF uses a C2HC zinc finger for substrate recognition. EMBO Rep. 2, 113–118 (2001).
Nielsen, P. R. et al. Structure of the chromo barrel domain from the MOF acetyltransferase. J. Biol. Chem. 280, 32326–32331 (2005).
Zhang, X. et al. G9a-mediated methylation of ERalpha links the PHF20/MOF histone acetyltransferase complex to hormonal gene expression. Nat. Commun. 7, 10810 (2016).
Klein, B. J. et al. PHF20 readers link methylation of histone H3K4 and p53 with H4K16 acetylation. Cell Rep. 17, 1158–1170 (2016).
Adams-Cioaba, M. A. et al. Crystal structures of the Tudor domains of human PHF20 reveal novel structural variations on the Royal Family of proteins. FEBS Lett. 586, 859–865 (2012).
Li, S. & Shogren-Knaak, M. A. The Gcn5 bromodomain of the SAGA complex facilitates cooperative and cross-tail acetylation of nucleosomes. J. Biol. Chem. 284, 9411–9417 (2009).
Cieniewicz, A. M. et al. The bromodomain of Gcn5 regulates site specificity of lysine acetylation on histone H3. Mol. Cell Proteomics 13, 2896–2910 (2014).
Bian, C. et al. Sgf29 binds histone H3K4me2/3 and is required for SAGA complex recruitment and histone H3 acetylation. EMBO J. 30, 2829–2842 (2011).
Lai, I. L., Wang, S. Y., Yao, Y. L. & Yang, W. M. Transcriptional and subcellular regulation of the TRIP-Br family. Gene 388, 102–109 (2007).
Mi, W. et al. YEATS2 links histone acetylation to tumorigenesis of non-small cell lung cancer. Nat. Commun. 8, 1088 (2017).
Wang, Y. et al. Identification of the YEATS domain of GAS41 as a pH-dependent reader of histone succinylation. Proc. Natl Acad. Sci. USA 115, 2365–2370 (2018).
Cai, Y. et al. Identification of new subunits of the multiprotein mammalian TRRAP/TIP60-containing histone acetyltransferase complex. J. Biol. Chem. 278, 42733–42736 (2003).
Suganuma, T. et al. ATAC is a double histone acetyltransferase complex that stimulates nucleosome sliding. Nat. Struct. Mol. Biol. 15, 364–372 (2008).
Guelman, S. et al. The double-histone-acetyltransferase complex ATAC is essential for mammalian development. Mol. Cell. Biol. 29, 1176–1188 (2009).
Millan, F. et al. Whole exome sequencing reveals de novo pathogenic variants in KAT6A as a cause of a neurodevelopmental disorder. Am. J. Med. Genet. 170A, 1791–1798 (2016).
Kim, Y. R. et al. Identifying the KAT6B mutation via diagnostic exome sequencing to diagnose Say-Barber-Biesecker-Young-Simpson syndrome in three generations of a family. Ann. Rehabil. Med. 41, 505–510 (2017).
Fergelot, P. et al. Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations. Am. J. Med. Genet. 170A, 3069–3082 (2016).
Spena, S., Gervasini, C. & Milani, D. Ultra-rare syndromes: the example of Rubinstein-Taybi Syndrome. J. Pediatr. Genet. 4, 177–186 (2015).
Mullighan, C. G. et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471, 235–239 (2011).
Panagopoulos, I. et al. Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13). Hum. Mol. Genet. 10, 395–404 (2001).
Chaffanet, M. et al. MOZ is fused to p300 in an acute monocytic leukemia with t(8;22). Genes Chromosomes Cancer 28, 138–144 (2000).
Sobulo, O. M. et al. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3). Proc. Natl Acad. Sci. USA 94, 8732–8737 (1997).
Rowley, J. D. et al. All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. Blood 90, 535–541 (1997).
Ida, K. et al. Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13). Blood 90, 4699–4704 (1997).
Borrow, J. et al. The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat. Genet. 14, 33–41 (1996).
Carapeti, M., Aguiar, R. C., Goldman, J. M. & Cross, N. C. A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia. Blood 91, 3127–3133 (1998).
Esteyries, S. et al. NCOA3, a new fusion partner for MOZ/MYST3 in M5 acute myeloid leukemia. Leukemia 22, 663–665 (2008).
Kitabayashi, I. et al. Fusion of MOZ and p300 histone acetyltransferases in acute monocytic leukemia with a t(8;22)(p11;q13) chromosome translocation. Leukemia 15, 89–94 (2001).
Gayther, S. A. et al. Mutations truncating the EP300 acetylase in human cancers. Nat. Genet. 24, 300–303 (2000).
Ward, R., Johnson, M., Shridhar, V., van Deursen, J. & Couch, F. J. CBP truncating mutations in ovarian cancer. J. Med. Genet. 42, 514–518 (2005).
Gorrini, C. et al. Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 448, 1063–1067 (2007).
Muraoka, M. et al. p300 gene alterations in colorectal and gastric carcinomas. Oncogene 12, 1565–1569 (1996).
Dulak, A. M. et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat. Genet. 45, 478–486 (2013).
Panagopoulos, I., Gorunova, L., Bjerkehagen, B. & Heim, S. Novel KAT6B-KANSL1 fusion gene identified by RNA sequencing in retroperitoneal leiomyoma with t(10;17)(q22;q21). PLOS ONE 10, e0117010 (2015).
Moore, S. D. et al. Uterine leiomyomata with t(10;17) disrupt the histone acetyltransferase MORF. Cancer Res. 64, 5570–5577 (2004).
Peifer, M. et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat. Genet. 44, 1104–1110 (2012).
Simo-Riudalbas, L. et al. KAT6B is a tumor suppressor histone H3 lysine 23 acetyltransferase undergoing genomic loss in small cell lung cancer. Cancer Res. 75, 3936–3945 (2015).
Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B cell lymphoma. Nature 471, 189–195 (2011).
Northcott, P. A. et al. Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat. Genet. 41, 465–472 (2009).
The authors thank K. Lam, M. Shvedunova and S. Guhathakurta for their critical reading of the manuscript. The authors apologize to their colleagues whose work could not be cited here owing to space and topic constraints. B.N.S. acknowledges an Alexander von Humboldt fellowship. This work was supported by CRC 992, CRC 746 and CRC 1140 awarded to A.A.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
A combination of DNA, RNA and protein that packages DNA into a compact and well-organized higher structure.
Genomic element, varying from a few base pairs to many kilobases in size, that serves as the major binding site of transcription factors and acts in cis to promote the transcription of associated gene loci.
Genomic sequence commonly located just 5′ of the transcriptional start sites where the transcription apparatus assembles before activation of transcription.
Most basic units of chromatin. Each nucleosome possesses ~146 bp of DNA wrapped around a histone octamer (two each of H2A, H2B, H3 and H4).
Protein domain of ~110 amino acids in length that recognizes acetylated ε-lysine residues.
- Cryptic transcription
Transcription originating from unannotated transcription start sites that can occur in both intragenic and intergenic regions.
- Chromosome conformation capture
Molecular biology technique that allows physical contacts between specific DNA fragments to be mapped. This technique can also be coupled to deep sequencing to map chromatin interactions throughout the genome.
- Chromatin immunoprecipitation
(ChIP). Technique that allows detection of DNA fragments associated with a specific protein of interest.
- Enhancer RNAs
(eRNAs). RNAs produced from the transcription of genomic enhancer elements.
An ~50 amino acid protein domain that generally recognizes methylated lysines.
- PHD fingers
Protein domain, generally 50–80 amino acids in length, that binds to post-translationally modified lysine residues.
Developmental phase during early embryogenesis in which the three major embryonic layers (endoderm, ectoderm and mesoderm) as well as the anterior–posterior embryo axis are specified.
Terminally differentiated cells found in the kidney glomerulus that form part of the filtration barrier between blood and urine.
- Tricarboxylic acid
(TCA). The TCA cycle, also known as the citric acid cycle or Krebs cycle, is a set of mitochondrial chemical reactions that convert energy stored in acetyl-CoA to form energy intermediates such as NADH. These intermediates are used to generate ATP.
Brain area essential for laying down long-term memories. It is located below the cerebral cortex in the temporal lobe.
Extracellular signalling molecules, normally present during embryonic development, with the ability to induce cell fate.
The most caudal part of the developing forebrain that gives rise to the hypothalamus and thalamus.
- Corpus callosum
Set of ~250 million neuron projections (axons) that span and allow communication between the left and right sides of the brain.
About this article
Cite this article
Sheikh, B.N., Akhtar, A. The many lives of KATs — detectors, integrators and modulators of the cellular environment. Nat Rev Genet 20, 7–23 (2019). https://doi.org/10.1038/s41576-018-0072-4
Frontiers in Cell and Developmental Biology (2021)
Nature Cell Biology (2021)
Trends in Genetics (2021)
Young-Onset Carcinogenesis – The Potential Impact of Perinatal and Early Life Metabolic Influences on the Epigenome
Frontiers in Oncology (2021)