Dissecting myogenin-mediated retinoid X receptor signaling in myogenic differentiation
Saadia Khilji1, Munerah Hamed1, Jihong Chen2
1Department of Cellular and Molecular Medicine and Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Abstract:
Deciphering the molecular mechanisms underpinning myoblast differentiation is a critical step in developing the best strategy to promote muscle regeneration in patients suffering from muscle-related diseases. We have previously established that a rexinoid x receptor (RXR)-selective agonist, bexarotene, enhances the differentiation and fusion of myoblasts through a direct regulation of MyoD expression, coupled with an augmentation of myogenin protein. Here, we found that RXR signaling associates with the distribution of myogenin at poised enhancers and a distinct E-box motif. We also found an association of myogenin with rexinoid-responsive gene expression and identified an epigenetic signature related to histone acetyltransferase p300. Moreover, RXR signaling augments residue-specific histone acetylation at enhancers co-occupied by p300 and myogenin. Thus, genomic distribution of transcriptional regulators is an important designate for identifying novel targets as well as developing therapeutics that modulate epigenetic landscape in a selective manner to promote muscle regeneration.
Insights
RXR signaling, enhanced by bexarotene, promotes muscle regeneration by regulating myogenin at enhancers. This finding offers new therapeutic targets for muscle diseases by modulating the epigenetic landscape.
Area of Science:
- Molecular Biology
- Epigenetics
- Muscle Regeneration
Background:
- Understanding myoblast differentiation is key for treating muscle diseases.
- Previous work showed bexarotene enhances myoblast differentiation via MyoD and myogenin.
- This study investigates the molecular mechanisms of RXR signaling in myogenesis.
Purpose of the Study:
- To elucidate the role of RXR signaling in myoblast differentiation and muscle regeneration.
- To identify specific molecular targets and epigenetic modifications involved in this process.
- To explore therapeutic strategies for muscle-related diseases.
Main Methods:
- Investigated the association of myogenin with RXR signaling at enhancers and E-box motifs.
- Analyzed rexinoid-responsive gene expression and epigenetic signatures.
- Examined histone acetylation at co-occupied enhancers using histone acetyltransferase p300.
Main Results:
- RXR signaling correlates with myogenin distribution at poised enhancers and specific E-box motifs.
- Myogenin was associated with rexinoid-responsive gene expression and p300 epigenetic signatures.
- RXR signaling enhances histone acetylation at enhancers occupied by p300 and myogenin.
Conclusions:
- RXR signaling plays a crucial role in myoblast differentiation and muscle regeneration.
- The genomic distribution of transcriptional regulators like myogenin is vital for identifying therapeutic targets.
- Targeting the epigenetic landscape offers a promising strategy for promoting muscle regeneration.
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