title: Yeast phospholipase C is required for normal acetyl-CoA homeostasis and global histone acetylation.
abstract: Phospholipase C (Plc1p) is required for the initial step of inositol polyphosphate (InsP) synthesis, and yeast cells with deletion of the PLC1 gene are completely devoid of any InsPs and display aberrations in transcriptional regulation. Here we show that Plc1p is required for a normal level of histone acetylation; plc1Δ cells that do not synthesize any InsPs display decreased acetylation of bulk histones and global hypoacetylation of chromatin histones. In accordance with the role of Plc1p in supporting histone acetylation, plc1Δ mutation is synthetically lethal with mutations in several subunits of SAGA and NuA4 histone acetyltransferase (HAT) complexes. Conversely, the growth rate, sensitivity to multiple stresses, and the transcriptional defects of plc1Δ cells are partially suppressed by deletion of histone deacetylase HDA1. The histone hypoacetylation in plc1Δ cells is due to the defect in degradation of repressor Mth1p, and consequently lower expression of HXT genes and reduced conversion of glucose to acetyl-CoA, a substrate for HATs. The histone acetylation and transcriptional defects can be partially suppressed and the overall fitness improved in plc1Δ cells by increasing the cellular concentration of acetyl-CoA. Together, our data indicate that Plc1p and InsPs are required for normal acetyl-CoA homeostasis, which, in turn, regulates global histone acetylation.
authors.affiliation: From the Department of Biological Sciences, St. John's University, Queens, New York 11439.
authors.forename: Luciano
authors.initials: L
authors.lastname: Galdieri
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chang
authors.forename: Swati
authors.initials: S
authors.lastname: Mehrotra
authors.forename: Ales
authors.initials: A
authors.lastname: Vancura
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000107:Acetylation; D001692:Biological Transport; D002843:Chromatin / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006706:Homeostasis; D007295:Inositol Phosphates / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D013696:Temperature; D014158:Transcription, Genetic; D010738:Type C Phospholipases / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; D007295:Inositol Phosphates; D029701:Saccharomyces cerevisiae Proteins; D000105:Acetyl Coenzyme A; D051548:Histone Acetyltransferases; D010738:Type C Phospholipases; C522285:Plc1 protein, S cerevisiae; D006655:Histone Deacetylases; D005947:Glucose
keywords: Acetyl-coenzyme A; Chromatin; Chromatin Histone Modification; Histones; Inositol Phosphates; Metabolism; Phospholipase C; Transcription
references.citation: Science. 2001 Aug 10;293(5532):1074-80
references.pmid: 11498575
references.citation: EMBO J. 2002 Sep 16;21(18):4959-68
references.pmid: 12234935
references.citation: EMBO J. 2004 Oct 27;23(21):4243-52
references.pmid: 15457216
references.citation: Yeast. 1997 Jul;13(9):837-48
references.pmid: 9234672
references.citation: Cell. 2007 Feb 23;128(4):693-705
references.pmid: 17320507
references.citation: Microbiol Mol Biol Rev. 1999 Sep;63(3):554-69
references.pmid: 10477308
references.citation: Genetics. 1997 Oct;147(2):451-65
references.pmid: 9335585
references.citation: Adv Enzyme Regul. 2010;50(1):324-37
references.pmid: 20006638
references.citation: Mol Cell Biol. 2003 Dec;23(24):9136-49
references.pmid: 14645525
references.citation: J Biol Chem. 2012 Jan 2;287(1):701-711
references.pmid: 22094464
references.citation: Cell. 2005 Nov 18;123(4):581-92
references.pmid: 16286007
references.citation: Mol Biol Cell. 2003 Aug;14(8):3230-41
references.pmid: 12925759
references.citation: Mol Cell Biol. 2000 Mar;20(6):1899-910
references.pmid: 10688638
references.citation: J Bacteriol. 2001 Feb;183(4):1441-51
references.pmid: 11157958
references.citation: Nature. 2004 Jan 22;427(6972):370-4
references.pmid: 14737171
references.citation: Genes Dev. 2006 Mar 15;20(6):660-5
references.pmid: 16543219
references.citation: Cell. 2008 Aug 22;134(4):624-33
references.pmid: 18724935
references.citation: Mol Cell Biol. 2001 Sep;21(17):5710-22
references.pmid: 11486011
references.citation: Science. 2007 Apr 6;316(5821):106-9
references.pmid: 17412958
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):1911-4
references.pmid: 15665079
references.citation: Nat Cell Biol. 2006 Jul;8(7):668-76
references.pmid: 16783364
references.citation: Microbiol Mol Biol Rev. 2000 Jun;64(2):435-59
references.pmid: 10839822
references.citation: Mol Cell Biol. 2006 Oct;26(20):7587-600
references.pmid: 17015479
references.citation: Microbiol Mol Biol Rev. 2006 Mar;70(1):253-82
references.pmid: 16524925
references.citation: Mol Cell Biol. 1999 Jul;19(7):4561-71
references.pmid: 10373505
references.citation: Biochem Soc Trans. 2005 Feb;33(Pt 1):247-52
references.pmid: 15667318
references.citation: Eukaryot Cell. 2008 Jun;7(6):967-79
references.pmid: 18375619
references.citation: Genes Dev. 2006 Mar 15;20(6):700-10
references.pmid: 16543222
references.citation: Chromosoma. 2008 Feb;117(1):1-13
references.pmid: 17943301
references.citation: Science. 2007 Apr 6;316(5821):109-12
references.pmid: 17412959
references.citation: Annu Rev Biochem. 2001;70:81-120
references.pmid: 11395403
references.citation: J Biol Chem. 1996 Jun 28;271(26):15837-44
references.pmid: 8663039
references.citation: Eukaryot Cell. 2006 Jan;5(1):167-73
references.pmid: 16400179
references.citation: Mol Cell. 2006 Jul 21;23(2):207-17
references.pmid: 16857587
references.citation: FEMS Microbiol Rev. 2008 Jul;32(4):673-704
references.pmid: 18559076
references.citation: Mol Genet Genomics. 2009 May;281(5):511-23
references.pmid: 19205744
references.citation: Annu Rev Genet. 2008;42:27-81
references.pmid: 18303986
references.citation: Mol Cell Biol. 1996 Nov;16(11):6419-26
references.pmid: 8887670
references.citation: Mol Biosyst. 2007 Sep;3(9):590-7
references.pmid: 17700858
references.citation: Curr Genet. 2003 Oct;44(1):19-25
references.pmid: 14508605
references.citation: Science. 2007 May 18;316(5827):1050-4
references.pmid: 17510366
references.citation: Nat Cell Biol. 2006 Jul;8(7):711-6
references.pmid: 16783363
references.citation: Mol Cell Biol. 1999 May;19(5):3338-48
references.pmid: 10207058
references.citation: Science. 2009 May 22;324(5930):1021-2
references.pmid: 19460991
references.citation: Mol Cell Biol. 2006 Aug;26(16):6117-29
references.pmid: 16880522
references.citation: Cell. 2004 Jun 11;117(6):721-33
references.pmid: 15186774
references.citation: Nat Genet. 2004 Aug;36(8):900-5
references.pmid: 15247917
references.citation: Annu Rev Biochem. 2007;76:75-100
references.pmid: 17362198
references.citation: Mol Microbiol. 2000 Jan;35(1):161-72
references.pmid: 10632886
references.citation: Mol Gen Genet. 1993 May;239(1-2):196-204
references.pmid: 8389977
references.citation: Mol Cell. 2011 May 20;42(4):426-37
references.pmid: 21596309
references.citation: Methods Enzymol. 1991;194:3-21
references.pmid: 2005794
references.citation: J Biol Chem. 2006 Sep 8;281(36):26144-9
references.pmid: 16844691
references.citation: Nature. 2006 Mar 30;440(7084):637-43
references.pmid: 16554755
references.citation: Nucleic Acids Res. 2006 Mar 09;34(5):1427-38
references.pmid: 16528100
references.citation: Mol Biol Cell. 2007 Jul;18(7):2419-28
references.pmid: 17429070
references.citation: Genes Dev. 1998 Jan 15;12(2):198-207
references.pmid: 9436980
references.citation: Genes Dev. 2006 Sep 15;20(18):2507-12
references.pmid: 16980580
references.citation: Mol Cell Biol. 1995 Mar;15(3):1564-72
references.pmid: 7862149
references.citation: Nat Genet. 2002 Nov;32(3):370-7
references.pmid: 12410229
references.citation: Biochim Biophys Acta. 2006 May-Jun;1761(5-6):552-9
references.pmid: 16781889
references.citation: Mol Cell. 2004 Oct 22;16(2):199-209
references.pmid: 15494307
references.citation: Mol Cell Biol. 1993 Sep;13(9):5861-76
references.pmid: 8395015
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5836-41
references.pmid: 17389396
references.citation: Science. 2000 Mar 17;287(5460):2026-9
references.pmid: 10720331
references.citation: Curr Opin Genet Dev. 2003 Apr;13(2):136-42
references.pmid: 12672490
references.citation: Science. 1999 Jul 2;285(5424):96-100
references.pmid: 10390371
references.citation: J Exp Bot. 2005 Jan;56(410):273-86
references.pmid: 15618299
references.citation: Mol Genet Genomics. 2003 May;269(2):261-70
references.pmid: 12756538
references.citation: Biochemistry. 2002 Feb 26;41(8):2509-15
references.pmid: 11851397
references.citation: Nucleic Acids Res. 2009 Jul;37(12):3969-80
references.pmid: 19406923
references.citation: Cell. 2003 Mar 7;112(5):725-36
references.pmid: 12628191
references.citation: Microbiology (Reading). 2009 Dec;155(Pt 12):3827-3837
references.pmid: 19684065
references.citation: Science. 2009 May 22;324(5930):1076-80
references.pmid: 19461003
references.citation: Nat Rev Mol Cell Biol. 2012 Mar 07;13(4):270-6
references.pmid: 22395772
references.citation: Science. 2013 Jan 11;339(6116):148-50
references.pmid: 23307727
references.citation: Nat Chem Biol. 2008 Jan;4(1):16-7
references.pmid: 18084274
references.citation: Mol Cell. 2000 Dec;6(6):1297-307
references.pmid: 11163204
references.citation: Chembiochem. 2011 Jan 24;12(2):290-8
references.pmid: 21243716
references.citation: Nature. 2000 Nov 23;408(6811):495-8
references.pmid: 11100734
references.citation: Science. 2003 Jan 3;299(5603):112-4
references.pmid: 12434013
references.citation: Nat Rev Mol Cell Biol. 2006 Sep;7(9):657-66
references.pmid: 16912715
references.citation: Biochem Cell Biol. 2009 Feb;87(1):107-16
references.pmid: 19234527
references.citation: Mol Cell Biol. 2003 Jan;23(2):629-35
references.pmid: 12509460
references.citation: Mutat Res. 2007 May 1;618(1-2):41-51
references.pmid: 17306842
references.citation: Mol Cell Biol. 2000 Apr;20(7):2350-7
references.pmid: 10713159
references.citation: Mol Cell. 2007 Jan 12;25(1):31-42
references.pmid: 17218269
references.citation: Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1804-8
references.pmid: 8383328
references.citation: Nature. 2003 Jan 23;421(6921):448-53
references.pmid: 12540921
references.citation: Genes Dev. 2008 Aug 1;22(15):2062-74
references.pmid: 18676811
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7551-6
references.pmid: 12796514
references.citation: Mol Cell Biol. 2011 Apr;31(8):1610-23
references.pmid: 21321079
references.citation: Mol Cell Biol. 2000 May;20(10):3597-607
references.pmid: 10779349
references.citation: Mol Cell. 2001 Jan;7(1):117-26
references.pmid: 11172717
references.citation: Nature. 2007 Apr 5;446(7136):640-5
references.pmid: 17410169
references.citation: Cell. 2005 Nov 18;123(4):593-605
references.pmid: 16286008
references.citation: Oncogene. 2007 Aug 13;26(37):5521-7
references.pmid: 17694091
references.citation: Mol Cell Biol. 2003 Mar;23(6):1910-21
references.pmid: 12612066
references.citation: Trends Biochem Sci. 1999 Nov;24(11):437-40
references.pmid: 10542411
references.citation: Science. 2003 Jan 3;299(5603):114-6
references.pmid: 12434012
references.citation: J Biol Chem. 2005 Feb 11;280(6):4264-9
references.pmid: 15561716
references.citation: Cell. 2005 Aug 26;122(4):517-27
references.pmid: 16122420
references.citation: Nat Genet. 2002 Nov;32(3):378-83
references.pmid: 12379856
references.citation: Methods Mol Biol. 2012;809:255-65
references.pmid: 22113281
references.citation: Annu Rev Biochem. 2003;72:481-516
references.pmid: 12676793
references.citation: Biochim Biophys Acta. 2007 Mar;1771(3):255-70
references.pmid: 16950653
references.citation: J Biol Chem. 2012 Jul 6;287(28):23865-76
references.pmid: 22580297
references.citation: Cell. 2010 Dec 10;143(6):897-910
references.pmid: 21145457