Abstract
DNA methylation is an important epigenetic mark that regulates gene expression. Dnmt1 plays an important role in maintaining DNA methylation patterns on daughter DNA strands. Studies have shed light into the functional role of Dnmt1 regulation in the hematopoietic and epidermal systems. Here we show that Dnmt1 is required for myogenesis. Loss of Dnmt1 results in reduced expression of myogenic genes and defects in myogenic differentiation. We have utilized a conditional knockout mouse approach to examine the functional consequences of Dnmt1 depletion specifically in the developing muscle. These mice were born runted, with smaller body weights, and reduced ability to form myotubes in vitro. We show that expression of Id-1, a negative regulator of myogenesis, is enhanced in Dnmt1-deficient cultures, leading to enhanced transdifferentiation of myoblasts toward the osteogenic lineage. Thus, these studies demonstrate that Dnmt1 influences cellular identity and determines lineage fidelity.
Highlights
In the present study, we have analysed the effect of DNA methyltransferases (Dnmts)[1] depletion during murine myogenesis
We show that loss of Dnmt[1] results in hypomethylation of the Id-1 promoter, a negative regulator of myogenesis, leading to increased propensity of myoblasts transdifferentiate into the osteogenic lineage
DNA methylation has been well studied in embryos and during development, but only recently has the role of Dnmts been examined in somatic cells
Summary
We have analysed the effect of Dnmt[1] depletion during murine myogenesis. Absence of Dnmt[1] in myoblasts lead to reduced myogenic gene expressions and defects in myoblast fusion that results in the formation of smaller myotubes. Mice with muscle-specific deletion of Dnmt[1] are runted and display smaller body weight. We show that loss of Dnmt[1] results in hypomethylation of the Id-1 promoter, a negative regulator of myogenesis, leading to increased propensity of myoblasts transdifferentiate into the osteogenic lineage. These studies will lead to a better understanding of the epigenetic mechanisms that regulate muscle development, having implications in interventions aimed at combating musculoskeletal disorders such as muscular dystrophy
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