C-MYC Transcriptionally Amplifies SOX2 Target Genes to Regulate Self-Renewal in Multipotent Otic Progenitor Cells

Kelvin Y Kwan,Jun Shen,David P Corey

doi:10.1016/j.stemcr.2014.11.001

Abstract

SummarySensorineural hearing loss is caused by the loss of sensory hair cells and neurons of the inner ear. Once lost, these cell types are not replaced. Two genes expressed in the developing inner ear are c-Myc and Sox2. We created immortalized multipotent otic progenitor (iMOP) cells, a fate-restricted cell type, by transient expression of C-MYC in SOX2-expressing otic progenitor cells. This activated the endogenous C-MYC and amplified existing SOX2-dependent transcripts to promote self-renewal. RNA-seq and ChIP-seq analyses revealed that C-MYC and SOX2 occupy over 85% of the same promoters. C-MYC and SOX2 target genes include cyclin-dependent kinases that regulate cell-cycle progression. iMOP cells continually divide but retain the ability to differentiate into functional hair cells and neurons. We propose that SOX2 and C-MYC regulate cell-cycle progression of these cells and that downregulation of C-MYC expression after growth factor withdrawal serves as a molecular switch for differentiation.

Highlights

The six sensory organs of the inner ear—the cochlea, utricle, saccule, and three semicircular canals—mediate our ability to hear and balance
By comparing the overlap of promoter binding regions, we found that 4,231 genes or $85% of SOX2 target gene promoters were occupied by C-MYC (Figure 2B)
Unlike reprogramming of induced pluripotent stem cells (iPSCs), induction with a single factor, C-MYC, amplifies the SOX2 target genes that are responsible for self-renewal in otic cell types, but does not perturb the expression of lineage-restricted genes or the potential to differentiate

Summary

Introduction

The six sensory organs of the inner ear—the cochlea, utricle, saccule, and three semicircular canals—mediate our ability to hear and balance. Within these organs, sensory hair cells mediate the conversion from mechanical to neural signals, releasing neurotransmitter onto neurons of the eighth nerve. A variety of insults, such as loud noises and ototoxic drugs, can cause hair cell death. They can cause acute loss of afferent nerve terminals and delayed degeneration of the auditory nerve (Kujawa and Liberman, 2009). Degeneration of hair cells and neurons significantly contributes to hearing loss, as these cells are not replaced. To regenerate auditory hair cells and neurons, we must understand how progenitor cells give rise to these cell types

Results

Discussion

Conclusion