Smyd1 Orchestrates Early Heart Development Through Positive and Negative Gene Regulation

Abstract

SET and MYND domain-containing protein 1 (Smyd1) is a striated muscle-specific histone methyltransferase. Our previous work demonstrated that deletion of Smyd1 in either cardiomyocytes or the outflow tract (OFT) resulted in embryonic lethality at E9.5, with cardiac structural defects such as truncation of the OFT and right ventricle and impaired expansion and proliferation of the second heart field (SHF). The cardiac phenotype was accompanied by the downregulation of ISL LIM Homeobox 1 (Isl1) and upregulation of atrial natriuretic factor (ANF). However, the mechanisms of Smyd1 regulating Isl1 and ANF during embryonic heart development remain to be elucidated. Here, we employed various biochemical and molecular biological approaches including chromatin immunoprecipitation polymerase chain reaction (ChIP-PCR), pGL3 fluorescence reporter system, and co-immunoprecipitation (CoIP) and found that Smyd1 interacted with absent small homeotic-2-like protein (ASH2L) and activated the promoter of Isl1 by trimethylating H3K4. We also found that Smyd1 associated with HDAC to repress ANF expression using trichostatin A (TSA), a deacetylase inhibitor. In conclusion, Smyd1 participates in early heart development by upregulating the expression of Isl1 and downregulating the expression of ANF.

The Methyltransferase Smyd1 Mediates LPS-Triggered Up-Regulation of IL-6 in Endothelial Cells

“…These data suggest that LPS triggers IL6-related immune responses, at least in part via up-regulation of Smyd1. A relationship between Smyd1 and the degree of methylation of H3K4 was previously demonstrated in heart and skeletal muscle cells [ 35 , 36 , 37 , 38 , 39 ]. Accordingly, SMYD1 elevates the levels of PGC-1α, a major regulator of mitochondrial biogenesis, in the adult heart of mice [ 39 ], and Isl1, a transcription factor important for embryogenesis, in the embryonic heart of mice [ 38 ] via H3K4me3 methylation in the corresponding promoter region.…”

Histone Methylation Related Therapeutic Challenge in Cardiovascular Diseases

“…In ECs, MRTF-A interacts with Ash2 and WDR5, the components of COMPASS, and is recruited to the ET-1 promoter, exerting critical functions in vasoconstriction and endothelial dysfunction in CVDs in response to Ang II stimulation ( 66 , 67 ). SMYD1-mediated histone methylation modulates the expression of Hand2 and Irx4 , which are essential cardiac transcription factors for RV formation [ Figure 2 ; ( 68 , 69 )]. Histone demethylase JHDM2A deficiency modulates the PPARγ pathway via H3K9 modification ( 70 ).…”

“…For example, G9a mediates H3K9 dimethylation and further suppresses the expression of cardiomyocyte-related genes ( 81 ). SMYD1 is a modulator of cardiac transcription factors for RV formation ( 68 ). H3K27me3, one of the most established histone modifiers, is modulated by EZH2, UTX, and JMJD3, and affects CVD progress [ Figure 3 ; ( 45 , 82 – 84 )].…”

Histone Methylation Related Therapeutic Challenge in Cardiovascular Diseases

“…In ECs, MRTF-A interacts with Ash2 and WDR5, the components of COMPASS, and is recruited to the ET-1 promoter, exerting critical functions in vasoconstriction and endothelial dysfunction in CVDs in response to Ang II stimulation [66,67]. SMYD1-mediated www.videleaf.com histone methylation modulates the expression of Hand2 and Irx4, which are essential cardiac transcription factors for RV formation [68,69] (Figure 2). Histone demethylase JHDM2A deficiency modulates the PPARγ pathway via H3K9 modification [70].…”