Impact of Dlk1-Dio3 noncoding RNA locus promoter deletions on myosin heavy chain expression in skeletal muscle differentiation
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Abstract
Skeletal muscle differentiation is an intricate process crucial for tissue development and maintenance. It involves a cascade of molecular events driven by the coordinated expression of gene networks and signaling pathways. Key regulatory factors, including transcription factors and growth factors, modulate transition of proliferating myoblasts into mature multi-nucleated muscle fibers through proliferation, alignment, fusion, and maturation. These processes are accompanied by dynamic changes in cellular morphology, cytoskeletal organization, and protein expression, ultimately culminating in the formation of functional muscle fibers capable of contraction. Understanding the molecular mechanisms of skeletal muscle differentiation is pivotal for unraveling muscle-related disorders and developing targeted therapeutic interventions. Noncoding RNAs (ncRNAs) have gained recognition for their pivotal roles in gene regulatory networks. Despite this, their involvement in skeletal muscle diseases remains poorly understood. A subset of maternally expressed ncRNAs within the imprinted Dlk1-Dio3 noncoding RNA (ncRNA) locus on mouse chromosome 12 has been implicated in crucial processes such as skeletal muscle development, regeneration, and differentiation. This study aimed to elucidate the molecular mechanisms underlying skeletal muscle differentiation by investigating the importance of Dlk1-Dio3 ncRNA dosage in this process. Specifically, deletions in the promoter at the 5’ end of the ncRNA region were previously generated in the C2C12 myoblast cell line. These deletions were anticipated to impact the expression of maternally expressed ncRNAs, including long noncoding RNAs (lncRNAs) and miRNAs, transcribed as a ~200 kilobase (kb) polycistronic transcript upstream of the Meg3 lncRNA at the 5’ end of the ncRNA cluster.
To elucidate the functional significance of the Dk1-Dio3 ncRNA locus in skeletal muscle differentiation myoblasts were generated for the two different deletions in the Meg3 proximal promoter, which differentially affected the expression of its ncRNAs. This analysis revealed the pivotal role of the Dlk1-Dio3 ncRNA locus in modulating the expression of myosin heavy chain (MHC) and influencing the progression of myoblast differentiation.
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2024