ROLE OF SMYD3 IN SKELETAL MUSCLE ATROPHY AND MOUSE EMBRYONIC STEM CELL

Epigenetic regulation of gene expression plays a pivotal role in the establishment of developmental programs and the maintenance of the differentiated state. Among the different actors involved in this scenery, the modifications of histones tail are implicated with the propagation of gene expression patterns. Our group is focused on SMYD3, a histone-methyltransferase which is reported to be is highly expressed in normal conditions only in the embryo, in adult skeletal muscle and in few other tissues. In light of SMYD3 restricted expression, we asked whether it might play a role during myogenesis and/or muscle maintenance but also when it plays its role during development. We firstly have clarified the role of the histone-methyltransferase SMYD3 as a modulator of two factors involved in muscle-growth regulation and muscle atrophy, myostatin and c-Met transcription. Our results uncover a novel role for SMYD3 in recruiting the bromodomain protein BRD4. SMYD3 engages BRD4 and the positive transcription elongation factor complex (p-TEFb), triggering the phosphorylation on Serine 2 of the RNA Polymerase II, which favors the transcription elongation. Our data show that treatment with the BRD4 inhibitor JQ1 protects myotubes size reduction induced by dexamethasone administration and hinders pro-atrophic factors upregulation. These results suggest that JQ1 may represent a novel pharmacological avenue to alleviate muscle loss associated with muscle atrophy. We then clarify the role played by SMYD3 in embryonic development. Recent study in zebrafish model suggests that SMYD3 plays an important role in the development of heart. Therefore we decided to investigate the role of SMYD3 by employing mouse embryonic stem cells (mESC) as a model of developmental differentiation toward cardiomyocytes. We observed that the expression levels of cardiac markers as well as cardiovascuolar progenitor markers were increased in SMYD3 depleted embryoid bodies. To further disclose the role of SMYD3 in embryoid bodies differentiation we also analyzed markers of the primitive streak and transcripts involved in EMT. We report the SMYD3 played a role during early stages of embryonic stem cells differentiation.