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Updated: Jun 21, 2025
Direct Reprogramming of Human Fibroblasts into Myoblasts to Investigate Therapies for Neuromuscular Disorders
Published on: April 3, 2021
DiPRO1 distinctly reprograms muscle and mesenchymal cancer cells
Jeremy Rich1, Melanie Bennaroch1, Laura Notel1
1UMR8126 CNRS, Gustave Roussy Cancer campus, Université Paris-Saclay, Villejuif, France.
Abstract:
We have recently identified the uncharacterized ZNF555 protein as a component of a productive complex involved in the morbid function of the 4qA locus in facioscapulohumeral dystrophy. Subsequently named DiPRO1 (Death, Differentiation, and PROliferation related PROtein 1), our study provides substantial evidence of its role in the differentiation and proliferation of human myoblasts. DiPRO1 operates through the regulatory binding regions of SIX1, a master regulator of myogenesis. Its relevance extends to mesenchymal tumors, such as rhabdomyosarcoma (RMS) and Ewing sarcoma, where DiPRO1 acts as a repressor via the epigenetic regulators TIF1B and UHRF1, maintaining methylation of cis-regulatory elements and gene promoters. Loss of DiPRO1 mimics the host defense response to virus, awakening retrotransposable repeats and the ZNF/KZFP gene family. This enables the eradication of cancer cells, reprogramming the cellular decision balance towards inflammation and/or apoptosis by controlling TNF-α via NF-kappaB signaling. Finally, our results highlight the vulnerability of mesenchymal cancer tumors to si/shDiPRO1-based nanomedicines, positioning DiPRO1 as a potential therapeutic target.
Insights
We identified DiPRO1 (Death, Differentiation, and PROliferation related PROtein 1) as crucial for myoblast differentiation and proliferation. Its loss triggers anti-cancer responses, suggesting DiPRO1 as a therapeutic target for mesenchymal tumors.
Area of Science:
- Molecular biology
- Cancer research
- Epigenetics
Background:
- Facioscapulohumeral dystrophy involves the 4qA locus and uncharacterized proteins.
- Myogenesis is regulated by master regulators like SIX1.
- Mesenchymal tumors (RMS, Ewing sarcoma) have complex regulatory mechanisms.
Purpose of the Study:
- Identify the function of the uncharacterized ZNF555 protein.
- Elucidate DiPRO1's role in myoblast differentiation and proliferation.
- Investigate DiPRO1's involvement in mesenchymal tumor development and potential therapeutic strategies.
Main Methods:
- Protein identification and complex analysis.
- Myoblast differentiation and proliferation assays.
- Epigenetic analysis (methylation) and gene expression studies.
- In vitro cancer cell models and nanomedicine delivery systems.
Main Results:
- ZNF555, named DiPRO1, is essential for human myoblast differentiation and proliferation, interacting with SIX1.
- DiPRO1 represses mesenchymal tumors (RMS, Ewing sarcoma) by maintaining DNA methylation via TIF1B and UHRF1.
- DiPRO1 loss activates innate immune responses, including retrotransposable elements and ZNF/KZFP families.
- DiPRO1 regulates TNF-α via NF-kappaB signaling, promoting inflammation and apoptosis in cancer cells.
- Mesenchymal cancers exhibit vulnerability to DiPRO1-targeting nanomedicines.
Conclusions:
- DiPRO1 is a key regulator of myogenesis and a tumor suppressor in mesenchymal cancers.
- DiPRO1's epigenetic regulatory functions are critical for maintaining cellular homeostasis.
- Targeting DiPRO1 with nanomedicines offers a promising therapeutic avenue for mesenchymal tumors.
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