title: The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis.
abstract: How the proto-oncogene c-Myc balances the processes of stem-cell self-renewal, proliferation and differentiation in adult tissues is largely unknown. We explored c-Myc's transcriptional roles at the epidermal differentiation complex, a locus essential for skin maturation. Binding of c-Myc can simultaneously recruit (Klf4, Ovol-1) and displace (Cebpa, Mxi1 and Sin3a) specific sets of differentiation-specific transcriptional regulators to epidermal differentiation complex genes. We found that Sin3a causes deacetylation of c-Myc protein to directly repress c-Myc activity. In the absence of Sin3a, genomic recruitment of c-Myc to the epidermal differentiation complex is enhanced, and re-activation of c-Myc-target genes drives aberrant epidermal proliferation and differentiation. Simultaneous deletion of c-Myc and Sin3a reverts the skin phenotype to normal. Our results identify how the balance of two transcriptional key regulators can maintain tissue homeostasis through a negative feedback loop.
authors.affiliation: Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Cambridge CB2 1QR, UK.
authors.forename: Elisabete M
authors.initials: EM
authors.lastname: Nascimento
authors.forename: Claire L
authors.initials: CL
authors.lastname: Cox
authors.forename: Stewart
authors.initials: S
authors.lastname: MacArthur
authors.forename: Shobbir
authors.initials: S
authors.lastname: Hussain
authors.forename: Matthew
authors.initials: M
authors.lastname: Trotter
authors.forename: Sandra
authors.initials: S
authors.lastname: Blanco
authors.forename: Menon
authors.initials: M
authors.lastname: Suraj
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nichols
authors.forename: Bernd
authors.initials: B
authors.lastname: Kübler
authors.forename: Salvador Aznar
authors.initials: SA
authors.lastname: Benitah
authors.forename: Brian
authors.initials: B
authors.lastname: Hendrich
authors.forename: Duncan T
authors.initials: DT
authors.lastname: Odom
authors.forename: Michaela
authors.initials: M
authors.lastname: Frye
mesh_terms: D000818:Animals; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D006706:Homeostasis / Q000235:genetics*; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D000090062:Kruppel-Like Factor 4; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D056264:Sin3 Histone Deacetylase and Corepressor Complex
references.citation: Physiol Rev. 2010 Oct;90(4):1337-81
references.pmid: 20959618
references.citation: Cell Stem Cell. 2009 Jun 5;4(6):499-502
references.pmid: 19497277
references.citation: Oncogene. 1996 Mar 7;12(5):1165-72
references.pmid: 8649810
references.citation: Genes Dev. 2008 Oct 15;22(20):2755-66
references.pmid: 18923074
references.citation: BMC Bioinformatics. 2007 Jun 26;8:221
references.pmid: 17594472
references.citation: Mol Cell Biol. 2006 Nov;26(22):8418-26
references.pmid: 16954380
references.citation: Genomics. 1996 Nov 1;37(3):295-302
references.pmid: 8938441
references.citation: Nat Rev Mol Cell Biol. 2008 Oct;9(10):810-5
references.pmid: 18698328
references.citation: Nucleic Acids Res. 1995 May 25;23(10):1686-90
references.pmid: 7784172
references.citation: Development. 2003 Nov;130(21):5241-55
references.pmid: 12954714
references.citation: Cell. 1997 May 2;89(3):341-7
references.pmid: 9150133
references.citation: J Cell Biol. 2007 Nov 19;179(4):717-31
references.pmid: 17998397
references.citation: Mol Cell Biol. 2005 Aug;25(16):6990-7004
references.pmid: 16055712
references.citation: Stem Cells. 2010 Aug;28(8):1424-34
references.pmid: 20572009
references.citation: Curr Biol. 2006 May 23;16(10):971-81
references.pmid: 16713953
references.citation: J Cell Biol. 2006 Apr 24;173(2):253-64
references.pmid: 16636146
references.citation: Cell. 2010 Apr 30;141(3):432-45
references.pmid: 20434984
references.citation: Nature. 2008 Oct 2;455(7213):679-83
references.pmid: 18716624
references.citation: Genomics. 1993 Oct;18(1):92-9
references.pmid: 8276421
references.citation: Curr Biol. 2001 Apr 17;11(8):558-68
references.pmid: 11369200
references.citation: Cell. 2010 Aug 6;142(3):480-93
references.pmid: 20691906
references.citation: Cell. 2008 Mar 21;132(6):1049-61
references.pmid: 18358816
references.citation: EMBO Rep. 2003 May;4(5):484-90
references.pmid: 12776737
references.citation: J Biol. 2009 Sep 28;8(8):77
references.pmid: 19804609
references.citation: J Cell Biol. 2009 Jul 13;186(1):27-40
references.pmid: 19596847
references.citation: Oncogene. 1995 Dec 21;11(12):2487-501
references.pmid: 8545105
references.citation: Cell. 1993 Jan 29;72(2):211-22
references.pmid: 8425218
references.citation: Nat Genet. 1999 Aug;22(4):356-60
references.pmid: 10431239
references.citation: J Cell Biol. 2008 Oct 6;183(1):37-48
references.pmid: 18824566
references.citation: BMC Biol. 2009 Sep 28;7:63
references.pmid: 19785743
references.citation: Genes Dev. 2005 Jul 1;19(13):1581-95
references.pmid: 15998811
references.citation: Science. 2000 Dec 22;290(5500):2306-9
references.pmid: 11125145
references.citation: Cancer Res. 2006 May 1;66(9):4591-601
references.pmid: 16651409
references.citation: Cell. 1993 Jan 29;72(2):223-32
references.pmid: 8425219
references.citation: Mol Cell Biol. 2010 Dec;30(24):5686-97
references.pmid: 20956564
references.citation: Genome Biol. 2004;5(10):R80
references.pmid: 15461798
references.citation: Biometrics. 2009 Mar;65(1):40-51
references.pmid: 18537947
references.citation: EMBO J. 1995 Nov 15;14(22):5646-59
references.pmid: 8521822
references.citation: Nucleic Acids Res. 2009 Jul;37(Web Server issue):W247-52
references.pmid: 19487240
references.citation: Mol Cell Biol. 2007 Mar;27(6):2059-73
references.pmid: 17242204
references.citation: Cell. 2007 Mar 9;128(5):889-900
references.pmid: 17320163
references.citation: Nat Genet. 1999 Jan;21(1):70-1
references.pmid: 9916792
references.citation: Curr Opin Genet Dev. 2009 Oct;19(5):461-8
references.pmid: 19811902
references.citation: Mol Cell Biol. 2004 Dec;24(24):10826-34
references.pmid: 15572685
references.citation: Nat Rev Cancer. 2008 Mar;8(3):234-42
references.pmid: 18292777
references.citation: Cell. 1991 May 3;65(3):395-407
references.pmid: 1840505
references.citation: Immunity. 2001 Jan;14(1):45-55
references.pmid: 11163229
references.citation: Mol Cell. 2008 Nov 7;32(3):359-70
references.pmid: 18995834
references.citation: Nat Rev Mol Cell Biol. 2009 Mar;10(3):207-17
references.pmid: 19209183
references.citation: Cell. 1997 May 2;89(3):349-56
references.pmid: 9150134
references.citation: Nat Cell Biol. 2010 Oct;12(10):973-81
references.pmid: 20852628
references.citation: Science. 1991 Mar 8;251(4998):1211-7
references.pmid: 2006410
references.citation: J Biol Chem. 2009 Oct 16;284(42):29125-35
references.pmid: 19700410
references.citation: Mol Cell Biol. 2000 Jan;20(2):556-62
references.pmid: 10611234
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4168-72
references.pmid: 18332431
references.citation: Development. 2003 Jun;130(12):2793-808
references.pmid: 12736221
references.citation: Nat Cell Biol. 2009 Oct;11(10):1181-90
references.pmid: 19749746
references.citation: Nat Cell Biol. 2006 Jul;8(7):764-70
references.pmid: 16767079
references.citation: BMC Bioinformatics. 2008 Dec 22;9:552
references.pmid: 19099609