Article ; Online: The chromatin-binding protein Smyd1 restricts adult mammalian heart growth.
American journal of physiology. Heart and circulatory physiology
2016 Volume 311, Issue 5, Page(s) H1234–H1247
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Animals ; Blotting, Western ; Cardiomegaly/diagnostic imaging ; Cardiomegaly/genetics ; Cardiomegaly/metabolism ; Cell Enlargement ; Chromatin Assembly and Disassembly/genetics ; DNA-Binding Proteins/genetics ; Echocardiography ; Gene Expression Regulation ; Gene Knock-In Techniques ; HeLa Cells ; Heart Failure/diagnostic imaging ; Heart Failure/genetics ; Heart Failure/metabolism ; Humans ; Mice ; Mice, Knockout ; Muscle Proteins/genetics ; Myocardium/metabolism ; Myocardium/pathology ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Proteomics ; RNA, Messenger/metabolism ; Rats ; Real-Time Polymerase Chain Reaction ; Transcription Factors/genetics ; Up-Regulation ; Ventricular Remodeling/genetics |
| Chemical Substances | DNA-Binding Proteins ; Muscle Proteins ; RNA, Messenger ; Smyd1 protein, mouse ; Smyd1 protein, rat ; Transcription Factors |
| Language | English |
| Publishing date | 2016-09-23 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural |
| ZDB-ID | 603838-4 |
| ISSN | 1522-1539 ; 0363-6135 |
| ISSN (online) | 1522-1539 |
| ISSN | 0363-6135 |
| DOI | 10.1152/ajpheart.00235.2016 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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