C-MYC transcriptionally amplifies SOX2 target genes to regulate self-renewal in multipotent otic progenitor cells

Area of Science:

• Regenerative Medicine
• Developmental Biology
• Otic Biology

Background:

• Sensorineural hearing loss results from irreversible loss of inner ear hair cells and neurons.
• Current treatments for hearing loss are limited due to the inability of these cells to regenerate.
• SOX2 and c-Myc are key genes involved in inner ear development.

Purpose of the Study:

• To create a self-renewing progenitor cell line from the inner ear.
• To investigate the roles of SOX2 and c-Myc in otic progenitor cell fate and self-renewal.
• To establish a model for studying hair cell and neuron regeneration.

Main Methods:

• Transient expression of C-MYC in SOX2-expressing otic progenitor cells to create immortalized multipotent otic progenitor (iMOP) cells.
• RNA-sequencing (RNA-seq) and Chromatin Immunoprecipitation sequencing (ChIP-seq) to analyze gene expression and regulatory elements.
• Growth factor withdrawal to induce differentiation.

Main Results:

• iMOP cells were successfully generated, exhibiting self-renewal capacity.
• C-MYC and SOX2 were found to co-occupy over 85% of the same promoters, regulating target genes including cell-cycle regulators.
• iMOP cells retained the potential to differentiate into functional hair cells and neurons upon growth factor withdrawal.

Conclusions:

• SOX2 and C-MYC cooperate to control cell-cycle progression and self-renewal in otic progenitor cells.
• Downregulation of C-MYC acts as a molecular switch, initiating differentiation.
• This study presents a promising cellular model for understanding and potentially treating sensorineural hearing loss.