# Bmi1 controls auditory sensory epithelial cell proliferation through genome-wide H3K27me3 modifications

## TL;DR

Bmi1 regulates cochlear cell proliferation by controlling chromatin structure, and its loss leads to hearing issues due to overexpression of Cdkn2c.

## Contribution

This study reveals Bmi1's role in auditory epithelial cell regulation via H3K27me3 and identifies Cdkn2c as a potential therapeutic target for hearing loss.

## Key findings

- Bmi1 depletion causes widespread gene upregulation and chromatin accessibility in neonatal cochlea.
- Cdkn2c overexpression due to Bmi1 loss impairs cell proliferation in auditory epithelial cells.
- Inhibiting Cdkn2c rescues proliferative capacity in Bmi1 knockout mice.

## Abstract

Bmi1, a key component of the Polycomb repressive complex 1, plays a critical role in regulating gene expression by modulating chromatin structure. Its depletion is known to cause hair cell loss in the neonatal mouse cochlea. This study aimed to investigate the epigenetic mechanisms and transcriptional consequences of Bmi1 depletion in the neonatal auditory sensory epithelium.

Analysis of neonatal Bmi1 knockout mice using H3K27me3 chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing revealed significant transcriptional alterations, particularly in genes governing cell proliferation, senescence, and death. Bmi1 depletion resulted in widespread gene upregulation and increased chromatin accessibility, which correlated with reduced H3K27me3 enrichment. Notably, expression of Cdkn2c, a key cell cycle regulator, was significantly upregulated. Inhibition of Cdkn2c rescued the proliferative capacity of inner ear epithelial cells in Bmi1 knockout mice.

These findings demonstrate that Bmi1 maintains transcriptional repression and chromatin state in the developing cochlea, primarily through H3K27me3 deposition. Depletion disrupts this control, leading to Cdkn2c overexpression and impaired cell proliferation. This identifies Cdkn2c and its regulatory pathway as potential therapeutic targets for hearing loss associated with hair cell depletion.

The online version contains supplementary material available at 10.1186/s13072-025-00642-1.