Buffering noise: KAT2A modular contributions to stabilization of transcription and cell identity in cancer and development

•KAT2A maintains cellular phenotypes by limiting transcriptional variability•KAT2A-containing complexes SAGA and ATAC control distinct phenotypes•KAT2A maintenance of leukemia stem cells is likely exerted through KAT2A a histone acetyltransferase recently identified as vulnerability in at least some forms Acute Myeloid Leukemia (AML). Its loss or inhibition prompts out self-renewal into differentiation with ultimate exhaustion the pool. We have linked Kat2a requirement AML to noise, reflecting an evolutionary-conserved role promoting burst-like promoter activity stabilizing gene expression. suggest that this role, contributes preservation cell identity. exerts its context two macromolecular complexes, Spt-Ada-Gcn5-Acetyltransferase (SAGA) Ada-Two-A-Containing (ATAC), but specific contribution each complex stabilization expression currently unknown. By reviewing targets requirements cancer development, we regulates lineage-specific programs, biosynthetic ribosomal protein translation-associated genes, on which may be differentially dependent. While our data KAT2A-mediated regulation noise ATAC, discuss potential caveats probe general vs. complex-specific contributions stability, implications for perturbation Correct specification fate identity critical tissue homeostasis can achieved tight control. catalyzes vivo deposition acetyl groups Histone 3 Lysine 9 (H3K9), lesser extent H3K14 [1Kuo MH Brownell JE Sobel RE Ranalli TA Cook RG Edmondson DG et al.Transcription-linked acetylation Gcn5p histones H3 H4 lysines.Nature. 1996; 383: 269-272https://doi.org/10.1038/383269a0Crossref PubMed Scopus (478) Google Scholar,2Li B Sun J Dong Z Xue P He X Liao L al.GCN5 modulates osteogenic periodontal ligament DKK1 inflammatory microenvironment.Scientific Reports. 2016; 6https://doi.org/10.1038/srep26542Google Scholar]. More recently, has also been shown mediate other acyl residues, namely succinylation H3K79 [3Wang Y Guo YR Liu K Yin R Xia al.KAT2A coupled α-KGDH acts succinyltransferase.Nature. 2017; 552: 273-277https://doi.org/10.1038/nature25003Crossref (90) All these modifications associate transcription activation, suggested stabilize, not necessarily initiate [4Jin Q Yu LR Wang Zhang Kasper LH Lee al.Distinct roles GCN5/PCAF-mediated H3K9ac CBP/p300-mediated H3K18/27ac nuclear receptor transactivation.EMBO Journal. 2011; 30: 249-262https://doi.org/10.1038/emboj.2010.318Crossref (0) Scholar], locus mammalian cells. In addition acylations, lysine non-histone proteins, activating (e.g. Egr2 [5Wang Yun C Gao Xu al.The Acetyltransferase GCN5 Is Required iNKT Cell Development EGR2 Acetylation.Cell 20: 600-612https://doi.org/10.1016/j.celrep.2017.06.065Abstract Full Text PDF E2A-PBX1 [6Holmlund T Lindberg MJ Grander D Wallberg AE acetylates stability oncoprotein acute lymphoblastic leukemia.Leukemia. 2013; 27: 578-585https://doi.org/10.1038/leu.2012.265Crossref (41) Scholar] repressive Cebpα [7Bararia Kwok HS Welner RS Numata A Sárosi MB Yang H al.Acetylation C/EBPα inhibits granulopoietic function.Nature Communications. 7https://doi.org/10.1038/ncomms10968Crossref (24) PGC-1α [8Lerin Rodgers JT Kalume DE Kim S hee Pandey Puigserver controls glucose metabolism repression PGC-1α.Cell Metabolism. 2006; 3: 429-438https://doi.org/10.1016/j.cmet.2006.04.013Abstract Scholar]) consequences activity. Some include factors Scholar, 8Lerin 9Sakai M Tujimura-Hayakawa Yagi Yano Mitsushima Unoki-Kubota GCN5-CITED2-PKA signalling module hepatic cAMP-induced substrate switch.Nature 7: 1-15https://doi.org/10.1038/ncomms13147Crossref (11) indicating additional pathway regulation. Other are effector such p53 [10Barlev NA Chehab NH Mansfield Harris KG Halazonetis TD activates recruitment coactivators/histone acetyltransferases.Molecular Cell. 2001; 8: 1243-1254https://doi.org/10.1016/S1097-2765(01)00414-2Abstract α-tubulin [11Ouyang Mu Lu Li Zhu al.Autophagic degradation KAT2A/GCN5 promotes directional migration vascular smooth muscle reducing TUBA/α-tubulin acetylation.Autophagy. 2019; https://doi.org/10.1080/15548627.2019.1707488Google cycle regulators including CDC6 [12Paolinelli Mendoza-Maldonado Cereseto Giacca Acetylation phosphorylation phase cycle.Nature Structural Molecular Biology. 2009; 16: 412-420https://doi.org/10.1038/nsmb.1583Crossref cyclin [13Orpinell Fournier Riss Nagy Krebs AR Frontini transferase mitotic progression targeting substrates.EMBO 2010; 29: 2381-2394https://doi.org/10.1038/emboj.2010.125Crossref PLK4 [14Fournier Orpinell Grauffel Scheer E Garnier JM Ye al.KAT2A/KAT2B-targeted acetylome reveals preventing centrosome amplification.Nature 7https://doi.org/10.1038/ncomms13227Crossref recent years, Tora colleagues used shot-gun proteomics catalogue proteins endogenously acetylated Further above, global was involved (MAP4K4, PRKG2, STK4), actin-mediated contraction (MYH2, TPM3) transport (RHOD, XPO1). Perspective, will focus KAT2A, more extensively characterized. plays crucial development. one 2 highly homologous orthologues Gcn5, first described [15Brownell Zhou Kobayashi Roth SY al.Tetrahymena A: homolog yeast linking activation.Cell. 84: 843-851https://doi.org/10.1016/S0092-8674(00)81063-6Abstract (1202) The orthologue, Kat2b/Pcaf, largely mutually exclusive pattern Kat2a. dominates hematopoiesis, neural tissue, well development [16Yamauchi Yamauchi Kuwata Tamura Yamashita Bae N overlapping acetylase PCAF closely related PCAF-B/GCN5 mouse embryogenesis.Proceedings National Academy Sciences United States America. 2000; 97: 11303-11306https://doi.org/10.1073/pnas.97.21.11303Crossref whereas Kat2b prevails skeletal muscle. essential along evolutionary scale. It metamorphosis oogenesis D. melanogaster [17Carré Szymczak Pidoux Antoniewski Acetylase dGcn5 Key Player Drosophila Metamorphosis.Molecular Cellular 2005; 25: 8228-8238https://doi.org/10.1128/mcb.25.18.8228-8238.2005Crossref developing embryo, ubiquitously expressed between E7.5 E9.0, exception heart allantois, decreases after E16.5 [18Xu W Evrard YA Wakamiya Behringer RR Loss Gcn512 leads increased apoptosis mesodermal defects during development.Nature Genetics. 26: 229-232https://doi.org/10.1038/79973Crossref could reduced terminal differentiation. Conversely, minimally early stages upregulated adult tissues, particularly Scholar,18Xu Kat2a, Kat2b, embryonic null mice die E10.5, extensive apoptosis; embryos display notochord, somites, tube formation [19Hirsch CL Akdemir ZC Jayakumaran G Trcka Weiss al.Myc rewire alternative splicing network somatic reprogramming.Genes Development. 2015; 803-816https://doi.org/10.1101/gad.255109.114Crossref Despite normal unhindered viability double Kat2a/Kat2b mutants severe phenotype than single animals, earlier E7.5, suggesting functional redundancy. Redundancy paralogs proposed zebrafish, where combined results fin developmental [20Ghosh TK Aparicio-Sánchez JJ Buxton Ketley Mohamed Rutland CS TBX5 KAT2B limb development.Journal Cardiology. 2018; 114: 185-198https://doi.org/10.1016/j.yjmcc.2017.11.013Abstract strictly required pluripotent (ESCs) [21Lin Srajer Phan HM Furuta Dent SYR Developmental Gcn5-/- vitro.Developmental Dynamics. 2007; 236: 1547-1557https://doi.org/10.1002/dvdy.21160Crossref it stabilizes pluripotency regulatory networks [22Moris Edri Seyres Kulkarni Domingues AF Balayo al.Histone Stabilizes Pluripotency Control Transcriptional Heterogeneity.STEM CELLS. 36: 1828-1838https://doi.org/10.1002/stem.2919Crossref (5) allows reprogramming induced (iPS) Additionally, survival correct lineage embryoid bodies specifically FGF signaling [23Wang Koutelou Hirsch McCarthy Schibler Lin Regulates Signaling Activates Selective MYC Target Genes Early Embryoid Body Differentiation.Stem 10: 287-299https://doi.org/10.1016/j.stemcr.2017.11.009Abstract (10) co-factor Myc family c- N-Myc, both play key embryogenesis [24Stanton BR Perkins AS Tessarollo Sassoon DA Parada LF N-myc function lethality failure epithelial component embryo develop.Genes 1992; 6: 2235-2247https://doi.org/10.1101/gad.6.12a.2235Crossref [25Lin CH CW Tanaka Fero ML Eisenman RN Gene epigenetic remodeling murine c-Myc.PLoS ONE. 4https://doi.org/10.1371/journal.pone.0007839Crossref (59) Myc, [26Patel JH Du Ard PG Phillips Carella Chen C-J c-MYC Oncoprotein Substrate Acetyltransferases hGCN5/PCAF TIP60.Molecular 2004; 24: 10826-10834https://doi.org/10.1128/mcb.24.24.10826-10834.2004Crossref activation target genes [27Liu Tesfai Martinez c-Myc transformation domain recruits human STAGA requires TRRAP activation.Journal Biological Chemistry. 2003; 278: 20405-20412https://doi.org/10.1074/jbc.M211795200Abstract proliferation progenitor cells, phenocopying N-Myc [28Martínez-Cerdeño V Lemen Chan Wey SR al.N-Myc regulate significantly programs cells.PLoS 2012; e39456https://doi.org/10.1371/journal.pone.0039456Crossref modulate Wnt/ ß-catenin [2Li Specifically, mediates H3K9/K14ac promoter, lymphoid blood lineages, but, interestingly, Scholar,29Domingues Giotopoulos Gupta Vinnenberg Arede al.Loss enhances depletes myeloid stem-like cells.ELife. 2020; 9https://doi.org/10.7554/eLife.51754Crossref detail, participates maturation [30Kikuchi Nakayama Kuribayashi F Imajoh-Ohmi Nishitoh Takami IRF-4 followed Blimp-1 immature cells.Journal Leukocyte 2014; 95: 399-404https://doi.org/10.1189/jlb.0413232Crossref subtypes [31Gao Kong Song Gcn5 Positively Activation.The Journal Immunology. 198: 3927-3938https://doi.org/10.4049/jimmunol.1600312Crossref innate natural killer (iNKT) involve acetylation. On hand, factor Egr2. Kat2a-mediated Cebpa, contrast, represses limits granulocytic [32Bararia High associates bad prognosis Breast Cancer [33Li HBXIP breast via GCN5-mediated microtubule acetylation.Biochemical Biophysical Research 458: 720-725https://doi.org/10.1016/j.bbrc.2015.02.036Crossref (15) 34Zhao Pang Function TGF β1 mesenchymal transition cancer.Oncology Letters. 3955-3963https://doi.org/10.3892/ol.2018.9134PubMed 35Chen Luo Yuan Huang Cai al.Pygo2 Associates MLL2 Methyltransferase Complexes To Augment Wnt Expression Stem-Like Expansion.Molecular 5621-5635https://doi.org/10.1128/mcb.00465-10Crossref (60) Non-Small Lung Carcinoma [36Chen Wei Si Leng al.Lysine potentiates growth non-small lung promotion E2F1, D1, E1 expression.Journal 288: 14510-14521https://doi.org/10.1074/jbc.M113.458737Abstract Scholar,37Mustachio LM Roszik Farria AT Guerra Repression attenuates cancer.American Research. 9: 1830-1845PubMed Colon [38Yin YW Jin HJ Zhao Fang elevated regulated E2F1 colon cancer.Gene Expression. 187-196https://doi.org/10.3727/105221615X14399878166230Crossref (39) acetylation-mediated co-activation E2F maintain (Figure 1A). Melanoma, WDHD1 enhanced H3K9 H3K56ac levels [39Li Jaramillo-Lambert AN Williams And-1 Gcn5.Oncogene. 31: 643-652https://doi.org/10.1038/onc.2011.261Crossref (17) Increased poor Renal 1B), mechanism elucidated. high confer advantage Pancreatic Adenocarcinoma 1C), and, extent, low grade Glioma (Cox coefficient = -0.167, FDR=0.125), act oncogene-like, tumor suppressor-like manner. Interestingly, lines [40Tong Yan Ma Shao succinyltransferase activity-mediated 14-3-3ζ upregulation β-catenin stabilization-dependent glycolysis pancreatic carcinoma cells.Cancer 469: 1-10https://doi.org/10.1016/j.canlet.2019.09.015Crossref (3) This raises possibility stage-specific roles, [41Basheer Meduri Mazan Sasca al.Contrasting disease evolution identify EZH2 therapeutic AML.Journal Experimental Medicine. 216: 966-981https://doi.org/10.1084/jem.20181276Crossref although mechanistic support hypothesis lacking. Significantly, no recurrent mutations cancer, co-opted level establishment and/or tumorigenic programs. lack indeed reflect conflicting over-expression different progression, sustained selective advantage. contrast disease-specific effects, would individual tumors. candidate CRISPR drop-out screen [42Tzelepis Koike-Yusa de Braekeleer Metzakopian Dovey OM al.A Dropout Screen Identifies Genetic Vulnerabilities Therapeutic Targets Leukemia.Cell 17: 1193-1205https://doi.org/10.1016/j.celrep.2016.09.079Abstract representing subset genetic abnormalities commonly found clinic. heterogeneous disease, encompassing spectrum biological histories prognoses dependent mutational event initiating driving [43Arber Orazi Hasserjian Thiele Borowitz le Beau MM 2016 revision World Health Organization classification neoplasms leukemia.Blood. 127: 2391-2405https://doi.org/10.1182/blood-2016-03-643544Crossref their [44Goardon Marchi Atzberger Quek Schuh Soneji al.Coexistence LMPP-like GMP-like Stem Cells Leukemia.Cancer 19: 138-152https://doi.org/10.1016/j.ccr.2010.12.012Abstract (391) Scholar,45Quek Otto GW Garnett Lhermitte Karamitros Stoilova al.Genetically leukemic CD34− arrested hemopoietic precursor-like stage.Journal 213: 1513-1535https://doi.org/10.1084/jem.20151775Crossref showed undifferentiated cultured patient-derived vitro. vivo, knockout incompatible long-term (LSCs) MLL-AF9 model [29Domingues Kat2a-depleted (KO) LSCs lost repopulating capacity, did fully progress myelo-monocytic performed single-cell analysis wild-type (WT) KO inspected relative composition trajectories from differentiated WT aligned almost linear trajectory. were distributed multiple discontinuous trajectories. interpreted observation uncoordinated routes decision-making, initiated coherently completed depleted potential. observed similar scenario incoherent diversification upon catalytic ESCs Indeed, Kat2a-inhibited incapable sustaining pluripotency, lagged ability proceed remained frozen slowly-exiting irreversible state limbo. variability transcription. At molecular level, instability identities generated corresponded cell-to-cell Transcription inherently variable, transcribed episodically, rather continuously, what known bursts [46Chubb JR Liverpool TB Bursts pulses: insights studies mechanisms.Current Opinion Genetics & 478-484https://doi.org/10.1016/j.gde.2010.06.009Crossref characterized frequency – rate switch OFF ON status size number mRNA molecules burst. higher burst [47Hornung Bar-Ziv Rosin Tokuriki Tawfik DS Oren al.Noise-mean relationship mutated promoters.Genome 22: 2409-2417https://doi.org/10.1101/gr.139378.112Crossref lower size-to-burst ratio [48Ochiai Hayashi Umeda Yoshimura Harada Shimizu al.