A Drosophila Smyd4 Homologue Is a Muscle-Specific Transcriptional Modulator Involved in Development

Abstract

BackgroundSET and MYND domain (Smyd) proteins are involved in the transcriptional regulation of cellular proliferation and development in vertebrates. However, the in vivo functions and mechanisms by which these proteins act are poorly understood.Methodology/Principal FindingsWe have used biochemical and genetic approaches to study the role of a Smyd protein in Drosophila. We identified eleven Drosophila genes that encode Smyd proteins. CG14122 encodes a Smyd4 homologue that we have named dSmyd4. dSmyd4 repressed transcription and recruited class I histone deacetylases (HDACs). A region of dSmyd4 including the MYND domain interacted directly with ∼150 amino acids at the N-termini of dHDAC1 and dHDAC3. dSmyd4 interacts selectively with Ebi, a component of the dHDAC3/SMRTER co-repressor complex. During embryogenesis dSmyd4 was expressed throughout the mesoderm, with highest levels in the somatic musculature. Muscle-specific RNAi against dSmyd4 resulted in depletion of the protein and lead to severe lethality. Eclosion is the final moulting stage of Drosophila development when adult flies escape from the pupal case. 80% of dSmyd4 knockdown flies were not able to eclose, resulting in late pupal lethality. However, many aspects of eclosion were still able to occur normally, indicating that dSmyd4 is likely to be involved in the development or function of adult muscle.Conclusions/SignificanceRepression of transcription by dSmyd4 and the involvement of this protein in development suggests that aspects of Smyd protein function are conserved between vertebrates and invertebrates.

Smyd2 controls cytoplasmic lysine methylation of Hsp90 and myofilament organization

“…In this context, the formation of complexes around lysine methylation at the titin filament could be viewed as functionally analogous to the formation of complexes around lysine methylation at the chromatin fiber. In vertebrates, several Smyd family KMTases are expressed most highly in muscle cells (Gottlieb et al 2002;Fujii et al 2003;Tan et al 2006;Kawamura et al 2008;Sun et al 2008;Thompson and Travers 2008). Thus, it is attractive to speculate that the Smyd family of KMTases will prove to support sarcomeric contractile function through methylation of various muscle proteins.…”

The methyltransferase SMYD3 mediates the recruitment of transcriptional cofactors at the myostatin and c-Met genes and regulates skeletal muscle atrophy

“…Members of the SMYD family of histone methyltransferases are potential regulators of skeletal muscle mass, as they control gene expression in cardiac and skeletal muscle owing to their restricted or more abundant expression in myogenic tissues (Gottlieb et al 2002;Brown et al 2006;Thompson and Travers 2008). To date, five members of the SMYD family have been identified: SMYD1-5 (Brown et al 2006).…”

SMYD2 is induced during cell differentiation and participates in early development

“…In the other hand, SMYD4 is significantly reduced in tumor cells and its re-expression dramatically decreases cancer cell growth (Hu et al, 2009). Also, Drosophila SMYD4 homologue has been involved in muscle development (Thompson and Travers, 2008). Little is known so far about SMYD5.…”