title: Epigenetic regulation of autophagy by the methyltransferase G9a.
abstract: Macroautophagy is an evolutionarily conserved cellular process involved in the clearance of proteins and organelles. Although the cytoplasmic machinery that orchestrates autophagy induction during starvation, hypoxia, or receptor stimulation has been widely studied, the key epigenetic events that initiate and maintain the autophagy process remain unknown. Here we show that the methyltransferase G9a coordinates the transcriptional activation of key regulators of autophagosome formation by remodeling the chromatin landscape. Pharmacological inhibition or RNA interference (RNAi)-mediated suppression of G9a induces LC3B expression and lipidation that is dependent on RNA synthesis, protein translation, and the methyltransferase activity of G9a. Under normal conditions, G9a associates with the LC3B, WIPI1, and DOR gene promoters, epigenetically repressing them. However, G9a and G9a-repressive histone marks are removed during starvation and receptor-stimulated activation of naive T cells, two physiological inducers of macroautophagy. Moreover, we show that the c-Jun N-terminal kinase (JNK) pathway is involved in the regulation of autophagy gene expression during naive-T-cell activation. Together, these findings reveal that G9a directly represses genes known to participate in the autophagic process and that inhibition of G9a-mediated epigenetic repression represents an important regulatory mechanism during autophagy.
authors.affiliation: Department of Immunology and Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Amaia
authors.initials: A
authors.lastname: Artal-Martinez de Narvajas
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Gomez
authors.forename: Jin-San
authors.initials: JS
authors.lastname: Zhang
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Mann
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Taoda
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Gorman
authors.forename: Marta
authors.initials: M
authors.lastname: Herreros-Villanueva
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Gress
authors.forename: Volker
authors.initials: V
authors.lastname: Ellenrieder
authors.forename: Luis
authors.initials: L
authors.lastname: Bujanda
authors.forename: Do-Hyung
authors.initials: DH
authors.lastname: Kim
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Alexander
authors.initials: A
authors.lastname: Koenig
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D006367:HeLa Cells; D006649:Histocompatibility Antigens / Q000235:genetics* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D002843:Chromatin; D006649:Histocompatibility Antigens; C502070:MAP1LC3B protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C522812:WIPI1 protein, human; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose
references.citation: Genes Dev. 2007 May 15;21(10):1169-78
references.pmid: 17470536
references.citation: Cancer Res. 2010 Oct 15;70(20):7830-40
references.pmid: 20940408
references.citation: Dev Cell. 2009 Nov;17(5):699-711
references.pmid: 19922874
references.citation: Nat Cell Biol. 2011 Feb;13(2):132-41
references.pmid: 21258367
references.citation: Nat Chem Biol. 2011 Jul 10;7(8):566-74
references.pmid: 21743462
references.citation: Cell Signal. 2010 Jun;22(6):894-9
references.pmid: 20060892
references.citation: J Cell Mol Med. 2011 Sep;15(9):2007-10
references.pmid: 21564513
references.citation: N Engl J Med. 2013 Feb 14;368(7):651-62
references.pmid: 23406030
references.citation: Science. 2011 Jun 17;332(6036):1429-33
references.pmid: 21617040
references.citation: Mol Cell Biol. 2005 Dec;25(23):10338-51
references.pmid: 16287849
references.citation: Nat Rev Mol Cell Biol. 2011 Dec 14;13(1):7-12
references.pmid: 22166994
references.citation: J Cell Biol. 2001 Feb 19;152(4):657-68
references.pmid: 11266458
references.citation: Nat Rev Mol Cell Biol. 2007 Nov;8(11):931-7
references.pmid: 17712358
references.citation: J Biol Chem. 2010 Mar 26;285(13):9636-9641
references.pmid: 20118233
references.citation: J Biol Chem. 2007 Dec 28;282(52):37298-302
references.pmid: 17986448
references.citation: FEBS Lett. 1993 Oct 25;333(1-2):169-74
references.pmid: 8224160
references.citation: Genes Dev. 2002 Jul 15;16(14):1779-91
references.pmid: 12130538
references.citation: Curr Opin Immunol. 2010 Jun;22(3):321-5
references.pmid: 20392618
references.citation: Epigenetics. 2011 Sep 1;6(9):1095-104
references.pmid: 21814037
references.citation: Methods Enzymol. 2009;452:181-97
references.pmid: 19200883
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4788-93
references.pmid: 21383122
references.citation: Cell Death Differ. 2007 Jun;14(6):1181-90
references.pmid: 17363962
references.citation: Cell Res. 2011 Dec;21(12):1723-39
references.pmid: 22064703
references.citation: Int J Cell Biol. 2012;2012:179207
references.pmid: 22829830
references.citation: EMBO J. 2012 Mar 7;31(5):1095-108
references.pmid: 22343943
references.citation: J Cell Biol. 2011 Jan 10;192(1):17-27
references.pmid: 21220506
references.citation: N Engl J Med. 2008 Mar 13;358(11):1148-59
references.pmid: 18337604
references.citation: EMBO Rep. 2010 Jan;11(1):37-44
references.pmid: 20010805
references.citation: PLoS One. 2008 Apr 30;3(4):e2037
references.pmid: 18446223
references.citation: Genes Dev. 2006 Nov 15;20(22):3089-103
references.pmid: 17085482
references.citation: PLoS One. 2012;7(3):e34034
references.pmid: 22470510
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19363-8
references.pmid: 19889976
references.citation: Eur J Cancer. 2010 Oct;46(15):2806-20
references.pmid: 20656472
references.citation: Science. 2011 Jan 28;331(6016):456-61
references.pmid: 21205641
references.citation: J Biol Chem. 2007 Aug 17;282(33):24131-45
references.pmid: 17580304
references.citation: Cell Res. 2010 Jul;20(7):748-62
references.pmid: 20548331
references.citation: Oncogene. 2008 Aug 14;27(35):4860-4
references.pmid: 18408756
references.citation: Hepatol Res. 2007 Nov;37(11):974-83
references.pmid: 17584191
references.citation: PLoS Biol. 2011 Jan 04;9(1):e1000569
references.pmid: 21245904
references.citation: Cancer Res. 2010 Mar 15;70(6):2318-27
references.pmid: 20197466
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11257-62
references.pmid: 15269344
references.citation: Cell Death Differ. 2013 Jan;20(1):1-2
references.pmid: 23222486
references.citation: Autophagy. 2011 Dec;7(12):1448-61
references.pmid: 22082875
references.citation: Autophagy. 2011 Mar;7(3):279-96
references.pmid: 21189453