The chromatin-binding protein Smyd1 restricts adult mammalian heart growth.
All terminally differentiated organs face two challenges, maintaining their cellular identity and restricting organ size. The molecular mechanisms responsible for these decisions are of critical importance to organismal development, and perturbations in their normal balance can lead to disease. A hallmark of heart failure, a condition affecting millions of people worldwide, is hypertrophic growth of cardiomyocytes. The various forms of heart failure in human and animal models share conserved transcriptome remodeling events that lead to expression of genes normally silenced in the healthy adult heart. However, the chromatin remodeling events that maintain cell and organ size are incompletely understood; insights into these mechanisms could provide new targets for heart failure therapy. Using a quantitative proteomics approach to identify muscle-specific chromatin regulators in a mouse model of hypertrophy and heart failure, we identified upregulation of the histone methyltransferase Smyd1 during disease. Inducible loss-of-function studies in vivo demonstrate that Smyd1 is responsible for restricting growth in the adult heart, with its absence leading to cellular hypertrophy, organ remodeling, and fulminate heart failure. Molecular studies reveal Smyd1 to be a muscle-specific regulator of gene expression and indicate that Smyd1 modulates expression of gene isoforms whose expression is associated with cardiac pathology. Importantly, activation of Smyd1 can prevent pathological cell growth. These findings have basic implications for our understanding of cardiac pathologies and open new avenues to the treatment of cardiac hypertrophy and failure by modulating Smyd1.
Department of Internal Medicine, Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah; and franklin@cvrti.utah.edu.
Sarah
S
Franklin
Departments of Anesthesiology & Perioperative Medicine, Medicine (Cardiology) and Physiology, David Geffen School of Medicine, University of California, Los Angeles, California.
Todd
T
Kimball
Department of Molecular Genetics and the Institute for Cellular and Molecular Biology, University of Texas at Austin, Texas.
Tara L
TL
Rasmussen
Departments of Anesthesiology & Perioperative Medicine, Medicine (Cardiology) and Physiology, David Geffen School of Medicine, University of California, Los Angeles, California.
Manuel
M
Rosa-Garrido
Departments of Anesthesiology & Perioperative Medicine, Medicine (Cardiology) and Physiology, David Geffen School of Medicine, University of California, Los Angeles, California.
Haodong
H
Chen
Departments of Anesthesiology & Perioperative Medicine, Medicine (Cardiology) and Physiology, David Geffen School of Medicine, University of California, Los Angeles, California.
Tam
T
Tran
Department of Internal Medicine, Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah; and.
Mickey R
MR
Miller
Departments of Anesthesiology & Perioperative Medicine, Medicine (Cardiology) and Physiology, David Geffen School of Medicine, University of California, Los Angeles, California.
Ricardo
R
Gray
Departments of Anesthesiology & Perioperative Medicine, Medicine (Cardiology) and Physiology, David Geffen School of Medicine, University of California, Los Angeles, California.
Shanxi
S
Jiang
Departments of Anesthesiology & Perioperative Medicine, Medicine (Cardiology) and Physiology, David Geffen School of Medicine, University of California, Los Angeles, California.
Shuxun
S
Ren
Departments of Anesthesiology & Perioperative Medicine, Medicine (Cardiology) and Physiology, David Geffen School of Medicine, University of California, Los Angeles, California.
Yibin
Y
Wang
Department of Molecular Genetics and the Institute for Cellular and Molecular Biology, University of Texas at Austin, Texas.
Haley O
HO
Tucker
Departments of Anesthesiology & Perioperative Medicine, Medicine (Cardiology) and Physiology, David Geffen School of Medicine, University of California, Los Angeles, California.
Thomas M
TM
Vondriska
D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D049108:Cell Enlargement; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004452:Echocardiography; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006367:HeLa Cells; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D040901:Proteomics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation; D020257:Ventricular Remodeling / Q000235:genetics
D004268:DNA-Binding Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C096485:Smyd1 protein, mouse; C000620932:Smyd1 protein, rat; D014157:Transcription Factors
Smyd1; cardiac hypertrophy; epigenetics; heart failure; histone methyltransferase
Circ Res. 2009 Jul 2;105(1):12-5
19520971
Genes Dev. 2003 Aug 15;17(16):1937-56
12893779
Nucleic Acids Res. 2009 Nov;37(21):7059-71
19783823
Dev Genet. 1998;22(3):250-62
9621432
Exp Mol Med. 2010 Oct 31;42(10):703-11
20980790
Am J Physiol Heart Circ Physiol. 2013 Dec 1;305(11):H1624-38
24077883
PLoS One. 2011;6(6):e21640
21738746
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2713-8
16477022
Cell. 2012 Sep 28;151(1):221-32
22981225
Nat Commun. 2014 Sep 24;5:4907
25249388
Cardiovasc Res. 2005 Dec 1;68(3):376-86
16024006
Genome Res. 2003 Nov;13(11):2498-504
14597658
Mol Biol Cell. 2013 Nov;24(22):3511-21
24068325
J Clin Invest. 2003 Sep;112(6):863-71
12975471
Anadolu Kardiyol Derg. 2010 Aug;10(4):303-9
20693124
Nature. 2007 Mar 22;446(7134):444-8
17334357
PLoS One. 2010 Mar 17;5(3):e9748
20305823
FASEB J. 2003 Sep;17(12):1592-608
12958166
Circulation. 2014 Jan 21;129(3):e28-e292
24352519
Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5632-7
21415370
N Engl J Med. 2008 Mar 27;358(13):1370-80
18367740
J Card Fail. 2006 Apr;12(3):227-39
16624689
Neuron. 2005 Oct 20;48(2):303-14
16242410
Nature. 2010 Jul 1;466(7302):62-7
20596014
Bioinformatics. 2009 Apr 15;25(8):1091-3
19237447
Heart Fail Rev. 2007 Dec;12 (3-4):331-43
17516164
Biochim Biophys Acta. 2013 Apr;1833(4):812-22
23047121
Circ Res. 2001 Jul 6;89(1):20-5
11440973
Mol Cell Proteomics. 2008 Mar;7(3):560-72
18065756
Novartis Found Symp. 2006;274:3-12; discussion 13-9, 152-5, 272-6
17019803
Circulation. 2008 Aug 26;118(9):934-46
18697823
J Vis Exp. 2012 Dec 28;(70):null
23299252
Cell. 2002 Aug 23;110(4):479-88
12202037
Mol Cell Proteomics. 2012 Jun;11(6):M111.014258
22270000
Dev Biol. 2016 Feb 1;410(1):86-97
26688546
Cell. 2012 Sep 28;151(1):206-20
22981692
Mol Cell Proteomics. 2011 Jan;10(1):M110.000703
20807835
J Biol Chem. 2006 Oct 6;281(40):29479-90
16891311
Cell. 2008 Jun 13;133(6):978-93
18555775
Nature. 2005 Jan 20;433(7023):278-85
15662416
J Mol Cell Cardiol. 2012 Oct;53(4):552-8
22846883
Circ Res. 2002 May 31;90(10):1044-54
12039793
Dis Model Mech. 2016 Mar;9(3):347-59
26935107
J Clin Invest. 2013 Jan;123(1):37-45
23281408
Circ Res. 2008 Dec 5;103(12):1359-62
18988895
Cell. 2013 Aug 1;154(3):569-82
23911322
Nature. 2006 Nov 30;444(7119):629-32
17108971
Nature. 2000 Sep 14;407(6801):221-6
11001064
J Clin Invest. 2005 Mar;115(3):527-37
15765134
Nat Genet. 2002 May;31(1):25-32
11923873
Circ Res. 2005 Mar 18;96(5):592-9
15718504
Cardiovasc Res. 2005 Sep 1;67(4):583-93
16002056
J Clin Invest. 2011 Jun;121(6):2447-56
21555854