Transcriptional networks regulating the costamere, sarcomere, and other cytoskeletal structures in striated muscle

Abstract

Structural abnormalities in striated muscle have been observed in numerous transcription factor gain- and loss-of-function phenotypes in animal and cell culture model systems, indicating that transcription is important in regulating the cytoarchitecture. While most characterized cytoarchitectural defects are largely indistinguishable by histological and ultrastructural criteria, analysis of dysregulated gene expression in each mutant phenotype has yielded valuable information regarding specific structural gene programs that may be uniquely controlled by each of these transcription factors. Linking the formation and maintenance of each subcellular structure or subset of proteins within a cytoskeletal compartment to an overlapping but distinct transcription factor cohort may enable striated muscle to control cytoarchitectural function in an efficient and specific manner. Here we summarize available evidence that connects transcription factors, those with established roles in striated muscle such as MEF2 and SRF as well as other non-muscle transcription factors, to the regulation of a defined cytoskeletal structure. The notion that genes encoding proteins localized to the same subcellular compartment are coordinately transcriptionally regulated may prompt rationally designed approaches that target specific transcription factor pathways to correct structural defects in muscle disease.

MEF2 Transcription Factors Regulate Distinct Gene Programs in Mammalian Skeletal Muscle Differentiation

“…MEF2A was predicted to regulate genes involved in actin cytoskeletal rearrangement, consistent with its regulation of structural genes encoding proteins localized to the costamere in cardiac muscle (15,46). It is intriguing that regulation of the actin cytoskeleton was not identified among the top canonical pathways in the MEF2B, -C, or -D dysregulated gene sets, considering these MEF2 proteins have been shown to regulate muscle structural genes in vitro and in vivo (46). Although expression profiling clearly identified this category of genes in all of the MEF2 knockdowns, other pathways were found to be more significantly dysregulated in the MEF2B, -C, or -D gene sets.…”

MicroRNAs in the Myocyte Enhancer Factor 2 (MEF2)-regulated Gtl2-Dio3 Noncoding RNA Locus Promote Cardiomyocyte Proliferation by Targeting the Transcriptional Coactivator Cited2

“…On the basis of the established role of MEF2 in regulating the muscle cytoarchitecture, we were interested in determining whether the expression of sarcomere genes is dependent on these Gtl2-Dio3 miRNAs (18). As expected, acute knockdown of MEF2A in NRVMs resulted in significant down-regulation of sarcomere genes (Fig.…”

MEF2D Deficiency in Neonatal Cardiomyocytes Triggers Cell Cycle Re-entry and Programmed Cell Death in Vitro

“…Previous studies from our laboratory demonstrated that MEF2A (myocyte enhancer factor 2A), but not the related family members MEF2C and MEF2D, regulates the integrity of costameres, specialized focal adhesions in muscle (11,12). Because costamere structure was not significantly affected by MEF2C or MEF2D deficiency, we were interested in determining the processes dependent on these MEF2 protein isoforms in cardiomyocytes.…”