Abstract
Modifications of histone tails are involved in the regulation of a wide range of biological processes including cell cycle, cell survival, cell division, and cell differentiation. Among the modifications, histone methylation plays a critical role in cardiac and skeletal muscle differentiation. In our earlier studies, we found that SMYD3 has methyltransferase activity to histone H3 lysine 4, and that its up-regulation is involved in the tumorigenesis of human colon, liver, and breast. To clarify the role of Smyd3 in development, we have studied its expression patterns in zebrafish embryos and the effect of its suppression on development using Smyd3-specific antisense morpholino-oligonucleotides. We here show that transcripts of smyd3 were expressed in zebrafish embryos at all developmental stages examined and that knockdown of smyd3 in embryos resulted in pericardial edema and defects in the trunk structure. In addition, these phenotypes were associated with abnormal expression of three heart-chamber markers including cmlc2, amhc and vmhc, and abnormal expression of myogenic regulatory factors including myod and myog. These data suggest that Smyd3 plays an important role in the development of heart and skeletal muscle.
Highlights
The regulation of gene expression is achieved, in part, through epigenetic mechanisms that govern the association of transcription factors to DNA, and the nature of DNA packaging into chromatin [1]
We termed the shorter ENSDART00000080847 transcript as smyd3_tv1 and the longer ENSDART00000105236 transcript as smyd3_tv2. Comparison of these sequences with the zebrafish genome revealed that smyd3 contains 12 exons, and that the two forms are generated by alternative splicing
Expression of myogenic markers in Smyd3 morphants To clarify the mechanism(s) underlying curved trunk, we investigated the expression of six markers; three terminal differentiation makers for skeletal muscle including skeletal muscle myosin light polypeptide 2, slow myosin heavy chain 1, and muscle creatine kinase, and three myogenic regulatory factors including myogenic differentiation, myogenic factor 5 and myogenin. mylz2, smyhc1, and mck are differentiation markers for first muscle, slow muscle, and both slow and first muscle, respectively [11]. myod and myf5 are expressed in the two lines of adaxial cells flanking the notocord of somites, while myog is expressed in the two lines of cells and paraxial mesoderm at 12 hpf
Summary
The regulation of gene expression is achieved, in part, through epigenetic mechanisms that govern the association of transcription factors to DNA, and the nature of DNA packaging into chromatin [1]. The structure of chromatin containing nucleosome proteins and DNA is controlled dynamically through the modifications in histone tails, which include methylation, acetylation, phosphorylation and ubiquitination [2]. Methylation of H3K4, H3K36, and H3K79 is associated with transcriptional activation, while that of H3K9, H3K27, and H4K20 is associated with transcriptional repression. These methylations are catalyzed by histone methyltransferases containing a SET domain, and reversed by demetylases containing a jumonji domain. There are five members of SMYD proteins; SMYD1, SMYD2, SMYD3, SMYD4, and SMYD5 Investigation on their catalytic activities disclosed that SMYD1, SMYD2 and SMYD3 have methyltransferase activities to histone H3 lysine4 [3,4,5], and that SMYD2 exerts methylation on histone H3 lysine and p53 [6,7]
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