The histone Methylase SMYD3 regulates skeletal muscle differentiation by modulating Myostatin expression

Epigenetic regulation of gene expression plays a pivotal role in the establishment of developmental programs and the maintenance of the differentiated state. The development and the propagation of gene expression patterns involve protein complexes that modify chromatin through covalent modifications of histones. To date there are five well characterized and prominently methylated lysine positions in histone H3 and H4 tails. According to their associated functions, histone H3 Lys4 (H3K4) and Lys36 and 79 (H3K36; H3K79) methylation are classified as transcriptional “ON” marks, while histone H3 lysine 9 (H3-K9), Lys 27 (H3K27), and histone H4 Lys20 (H4K20) methylation represent “OFF” marks, which are mainly involved in the organization of repressive chromatin structures. Each of these individual lysine positions can occur in three distinct methylation states: mono-, di-, and tri-methylation. The state of histone methylation depends on the interplay between demethylases and histonemethylases. It has been shown that a family of proteins containing a Jumonji domain demethylates histone lysines residues (Takeuchi et al., 2006). All known histonemethylases, with one exception (DOT1L), catalyze methyl transfer via the SET domain. Several SET-containing methyltransferases, as for example Ezh2, MLL-family members and Set1, have been well described and are well characterized, but very little is known about the SMYD family of methlylases. Understanding transcriptional regulatory mechanisms is one of the major challenges for the research in the post genomic, establishing how transcription factors and chromatin modifications are coordinated to control gene expression.