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Related Concept Videos

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Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
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Related Experiment Video

Updated: Jun 3, 2025

Long-term Time Lapse Imaging of Mouse Cochlear Explants
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PKM2 controls cochlear development through lactate-dependent transcriptional regulation.

Mingxuan Wu1,2, Gaogan Jia1,2, Yaoqian Liu1,2

  • 1ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China.

Proceedings of the National Academy of Sciences of the United States of America
|January 8, 2025
PubMed
Summary

Glycolytic metabolism, driven by pyruvate kinase M2 (PKM2), is crucial for inner ear development and hair cell regeneration. PKM2 activity and subsequent lactate production epigenetically regulate gene expression essential for sensory epithelium formation.

Keywords:
PKM2developmentglycolytic metabolismhair cellregeneration

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Area of Science:

  • Developmental Biology
  • Metabolic Regulation
  • Epigenetics

Background:

  • Metabolic processes are vital for cell proliferation and differentiation during inner ear development.
  • Glucose metabolism's role in mammalian inner ear development and hair cell regeneration is not well understood.
  • Understanding these metabolic pathways is key to identifying targets for hair cell regeneration.

Purpose of the Study:

  • To investigate the role of glucose metabolism in mammalian inner ear development and hair cell regeneration.
  • To elucidate the specific mechanisms by which metabolic pathways influence cochlear development.
  • To explore the potential of targeting metabolic pathways for hair cell regeneration.

Main Methods:

  • Analysis of glycolytic activity in mouse and human cochlear prosensory epithelium.
  • Utilizing mouse cochlear organoids to study the effects of pyruvate kinase M2 (PKM2) deletion.
  • Employing PKM2 knockout mice to assess sensory epithelium morphogenesis.
  • Investigating histone H3 lactylation (H3K9la) and its effect on gene transcription.
  • Examining the impact of PKM2 overexpression in supporting cells (SCs) on hair cell generation in cochlear explants.

Main Results:

  • Glycolytic metabolism is highly active during cochlear prosensory epithelium expansion in mice and humans.
  • PKM2 is the predominant glycolytic enzyme in cochlear nonsensory epithelial cells.
  • PKM2 deletion shifts metabolism from glycolysis to oxidative phosphorylation, impairing organoid formation and sensory epithelium development.
  • Lactate produced via PKM2 promotes histone H3 lactylation, upregulating SOX gene transcription and aiding cochlear development.
  • Overexpression of PKM2 in SCs enhances hair cell generation in mouse and human cochlear explants.

Conclusions:

  • Glycolysis, mediated by PKM2 and leading to lactate production, is a key driver of sensory epithelium formation in the inner ear.
  • This glycolysis-lactate-histone lactylation pathway epigenetically regulates genes critical for cochlear development.
  • Targeting PKM2 and the glycolysis-lactate pathway offers a novel strategy for mammalian hair cell regeneration.