title: Epigenetic control of type 2 and 3 deiodinases in myogenesis: role of Lysine-specific Demethylase enzyme and FoxO3.
abstract: The proliferation and differentiation of muscle precursor cells require myogenic regulatory factors and chromatin modifiers whose concerted action dynamically regulates access to DNA and allows reprogramming of cells towards terminal differentiation. Type 2 deiodinase (D2), the thyroid hormone (TH)-activating enzyme, is sharply upregulated during myoblast differentiation, whereas type 3 deiodinase (D3), the TH-inactivating enzyme, is downregulated. The molecular determinants controlling synchronized D2 and D3 expression in muscle differentiation are completely unknown. Here, we report that the histone H3 demethylating enzyme (LSD-1) is essential for transcriptional induction of D2 and repression of D3. LSD-1 relieves the repressive marks (H3-K9me2-3) on the Dio2 promoter and the activation marks (H3-K4me2-3) on the Dio3 promoter. LSD-1 silencing impairs the D2 surge in skeletal muscle differentiation while inducing D3 expression thereby leading to a global decrease in intracellular TH production. Furthermore, endogenous LSD-1 interacts with FoxO3a, and abrogation of FoxO3-DNA binding compromises the ability of LSD-1 to induce D2. Our data reveal a novel epigenetic control of reciprocal deiodinases expression and provide a molecular mechanism by which LSD-1, through the opposite regulation of D2 and D3 expression, acts as a molecular switch that dynamically finely tunes the cellular needs of active TH during myogenesis.
authors: IRCCS Fondazione SDN, 80143 Naples, Italy, Department of Molecular and Clinical Endocrinology and Oncology, University of Naples Federico II, 80131 Naples, Italy.
authors: Raffaele
authors: R
authors: Ambrosio
authors: Valentina
authors: V
authors: Damiano
authors: Annarita
authors: A
authors: Sibilio
authors: Maria Angela
authors: MA
authors: De Stefano
authors: Vittorio Enrico
authors: VE
authors: Avvedimento
authors: Domenico
authors: D
authors: Salvatore
authors: Monica
authors: M
authors: Dentice
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism; D006801:Humans; D007453:Iodide Peroxidase / Q000096:biosynthesis / Q000235:genetics*; D008745:Methylation; D051379:Mice; D024510:Muscle Development / Q000235:genetics*; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D015398:Signal Transduction; D013963:Thyroid Hormones / Q000494:pharmacology; D014158:Transcription, Genetic; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D056572:Histone Deacetylase Inhibitors; D056466:Histone Demethylases; D006657:Histones; D007453:Iodide Peroxidase; D010089:Oxidoreductases, N-Demethylating; D013963:Thyroid Hormones; D000097564:Iodothyronine Deiodinase Type II; C474033:FoxO3 protein, mouse; C117274:iodothyronine deiodinase type III; C504076:KDM1a protein, mouse
references: Dev Cell. 2004 May;6(5):673-84
references: 15130492
references: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19199-204
references: 19052240
references: Gastroenterology. 2012 Oct;143(4):1037-47
references: 22771508
references: Cell. 2004 Dec 29;119(7):941-53
references: 15620353
references: Endocr Rev. 2008 Dec;29(7):898-938
references: 18815314
references: Mol Cell. 2003 Jul;12(1):51-62
references: 12887892
references: Mol Cell. 2002 Nov;10(5):1119-28
references: 12453419
references: Nature. 2005 Sep 15;437(7057):436-9
references: 16079795
references: Curr Opin Struct Biol. 2010 Dec;20(6):739-48
references: 20970991
references: EMBO J. 2001 Apr 2;20(7):1739-53
references: 11285237
references: Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14466-71
references: 17720805
references: J Clin Invest. 2010 Nov;120(11):4021-30
references: 20978344
references: Mol Cell. 2000 Aug;6(2):233-44
references: 10983972
references: Thyroid. 2008 Feb;18(2):205-16
references: 18279021
references: Biochim Biophys Acta. 2013 Jul;1830(7):3937-45
references: 22634734
references: Mayo Clin Proc. 1976 Mar;51(3):176-9
references: 1256070
references: Expert Opin Ther Targets. 2011 Apr;15(4):493-504
references: 21261564
references: Nature. 2001 Mar 1;410(6824):116-20
references: 11242053
references: Curr Opin Genet Dev. 2005 Oct;15(5):528-35
references: 16055324
references: EMBO J. 1999 Sep 15;18(18):5099-107
references: 10487761
references: Semin Cell Dev Biol. 2005 Aug-Oct;16(4-5):596-611
references: 16129633
references: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7757-62
references: 12032356
references: Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):15751-6
references: 21896721
references: Science. 2008 Jan 11;319(5860):202-6
references: 18187655
references: Oncogene. 2010 Jun 24;29(25):3691-702
references: 20418916
references: Biochem Biophys Res Commun. 2010 Oct 22;401(3):327-32
references: 20833138
references: Nat Genet. 2009 May;41(5):521-3
references: 19330029
references: Development. 2009 Mar;136(6):879-89
references: 19234061
references: Diabetes. 2007 Mar;56(3):767-76
references: 17327447
references: Nat Cell Biol. 2007 Mar;9(3):347-53
references: 17277772
references: Semin Cell Dev Biol. 2005 Aug-Oct;16(4-5):585-95
references: 16099183
references: J Biol Chem. 2007 Jul 13;282(28):20070-4
references: 17537733
references: Mol Cell. 2007 Mar 23;25(6):801-12
references: 17363312
references: Nature. 2000 Nov 2;408(6808):106-11
references: 11081517
references: Dev Cell. 2008 Oct;15(4):534-46
references: 18854138
references: Front Biosci. 2001 Sep 01;6:D1024-47
references: 11532612
references: Annu Rev Biochem. 2010;79:155-79
references: 20373914
references: Nature. 2002 Sep 26;419(6905):407-11
references: 12353038
references: Mol Cell Biol. 2005 Nov;25(22):10171-82
references: 16260629