Abstract 472: Smyd1 Variants Regulate Distinct Areas of Chromatin in the Cardiomyocyte
| Autor: | Timothy J. Parnell, Mickey R. Miller, Christopher J. Conley, Marta W. Szulik, Sarah Franklin |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Circulation Research. 125 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/res.125.suppl_1.472 |
| Popis: | Heart failure is one of the most devastating conditions that contributes to 25% of all deaths in the USA every year. The development of heart failure, which is often preceded by cardiac hypertrophy resulting from an increased workload, is accompanied by global changes in gene expression that resemble a more fetal-like transcriptome. Although many epigenetic factors have been identified, which influence these underlying changes in transcription during disease, we still know very little about how this process is regulated on a molecular level. Smyd1 is a unique histone methyltransferase that modifies lysine residues to regulate gene expression in the cardiomyocyte. Originally, Smyd1 was identified as a necessary regulator of cardiac development, but recently we have shown that Smyd1 is differentially expressed during cardiac hypertrophy and failure and that loss of Smyd1 (in conditional, cardiomyocyte-specific knockout mice) leads to hypertrophic growth, metabolic dysfunction and ultimately heart failure. In mice, the smyd1 gene produces two variants, Smyd1a and Smyd1b, which differ only by a 13 amino acid deletion. In addition, we have shown that overexpression of Smyd1a (but not Smyd1b) can prevent phenylephrine-induced hypertrophy, however, both variants are capable of suppressing ANF expression. Despite this interesting data, the specific genomic regions bound by these variants and the unique genes they regulate are unknown. Therefore, to identify the genes regulated by Smyd1 variants we performed ChIP-Seq in cardiomyocytes under normal and hypertrophic conditions. Interestingly, our analyses show that Smyd1a binds DNA more frequently than Smyd1b under basal conditions (2,392 vs 1,004 binding events, respectively) but that Smyd1b exhibits greater binding in hypertrophic conditions (2,414 vs 5,045 binding events). Moreover, bioinformatics analysis of these sites confirmed both conserved and unique binding preferences and showed that while both variants are most abundant in distal intergenic regions (32-57%), Smyd1a is uniquely enriched (24%) at gene promoters ( |
| Databáze: | OpenAIRE |
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