Muscle wasted: a novel component of theDrosophilahistone locus body required for muscle integrity

Abstract

SummarySkeletal muscles arise by cellular differentiation and regulated gene expression. Terminal differentiation programmes such as muscle growth, extension and attachment to the epidermis, lead to maturation of the muscles. These events require changes in chromatin organization as genes are differentially regulated. Here, we identify and characterise muscle wasted (mute), a novel component of the Drosophila histone locus body (HLB). We demonstrate that a mutation in mute leads to severe loss of muscle mass and an increase in levels of normal histone transcripts. Importantly, Drosophila Myocyte enhancer factor 2 (Mef2), a central myogenic differentiation factor, and how, an RNA binding protein required for muscle and tendon cell differentiation, are downregulated. Mef2 targets are, in turn, misregulated. Notably, the degenerating muscles in mute mutants show aberrant localisation of heterochromatin protein 1 (HP1). We further show a genetic interaction between mute and the Stem-loop binding protein (Slbp) and a loss of muscle striations in Lsm11 mutants. These data demonstrate a novel role of HLB components and histone processing factors in the maintenance of muscle integrity. We speculate that mute regulates terminal muscle differentiation possibly through heterochromatic reorganisation.

A Conserved Interaction That Is Essential for the Biogenesis of Histone Locus Bodies

“…The homology, although very limited, also extends to the C-terminal regions (Fig. 7A) (28). In contrast, no obvious sequence similarity can be observed between the C-terminal regions of NPAT and Mxc (data not shown).…”

“…Studies on YARP suggested that it functions as a transcriptional regulator involved in controlling critical developmental decisions but provided no information on the role of its C-terminal domain (49,58). YARP is a homologue of Drosophila Mute, a protein of unknown function shown to localize to HLBs in Drosophila cells and embryos (28).…”

“…YARP is a homologue of Drosophila Mute that localizes to HLBs in Drosophila cells (28,29) and likely acts there as a repressor of histone gene transcription (28). We show that YARP localizes to HLBs in HeLa cells and that the NPAT-interacting domain shared by FLASH and YARP serves as an HLB localization signal.…”

“…This possibility was strongly supported by the fact that YARP shares a significant homology with Mute, a Drosophila protein that localizes to HLBs in Drosophila cultured cells and embryos (28,29). We first tested whether YARP and NPAT can form a complex when both proteins are expressed at physiologically relevant concentrations in human cells.…”

“…Mute, the Drosophila Homologue of YARP, Interacts with the C Terminus of Mxc-YARP throughout large parts of its length shares homology with Drosophila Mute, a component of the HLBs in Drosophila cells (28,29), arguing that these two proteins are functionally related. The homology, although very limited, also extends to the C-terminal regions (Fig.…”