Repressor element 1-silencing transcription factor deficiency yields profound hearing loss through Kv7.4 channel upsurge in auditory neurons and hair cells

  1. Haiwei Zhang
  2. Hongchen Li
  3. Mingshun Lu
  4. Shengnan Wang
  5. Xueya Ma
  6. Fei Wang
  7. Jiaxi Liu
  8. Xinyu Li
  9. Haichao Yang
  10. Fan Zhang
  11. Haitao Shen
  12. Noel J Buckley
  13. Nikita Gamper
  14. Ebenezer N Yamoah  Is a corresponding author
  15. Ping Lv  Is a corresponding author
  1. Hebei Medical University, China
  2. University of Oxford, United Kingdom
  3. University of Leeds, United Kingdom
  4. University of Nevada Reno, United States

Abstract

Repressor element 1-silencing transcription factor (REST) is a transcriptional repressor that recognizes neuron-restrictive silencer elements in the mammalian genomes in a tissue- and cell-specific manner. The identity of REST target genes and molecular details of how REST regulates them are emerging. We performed conditional null deletion of Rest (cKO), mainly restricted to murine hair cells (HCs) and auditory neurons (aka spiral ganglion neurons (SGNs)). Null-inactivation of full-length REST did not affect the development of normal HCs and SGNs but manifested as progressive hearing loss in adult mice. We found that the inactivation of REST resulted in an increased abundance of Kv7.4 channels at the transcript, protein, and functional levels. Specifically, we found that SGNs and HCs from Rest cKO mice displayed increased Kv7.4 expression and augmented Kv7 currents; SGN’s excitability was also significantly reduced. Administration of a compound with Kv7.4 channel activator activity, fasudil, recapitulated progressive hearing loss in mice. In contrast, inhibition of the Kv7 channels by XE991 rescued the auditory phenotype of Rest cKO mice. Previous studies identified some loss-of-function mutations within the Kv7.4-coding gene, Kcnq4, as a causative factor for progressive hearing loss in mice and humans. Thus, the findings reveal that a critical homeostatic Kv7.4 channel level is required for proper auditory functions.

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Author details

  1. Haiwei Zhang

    Department of Pharmacology, Hebei Medical University, Hebei, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8209-9395
  2. Hongchen Li

    Department of Pharmacology, Hebei Medical University, Hebei, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2639-8726
  3. Mingshun Lu

    Department of Pharmacology, Hebei Medical University, Hebei, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Shengnan Wang

    Department of Pharmacology, Hebei Medical University, Hebei, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Xueya Ma

    Department of Pharmacology, Hebei Medical University, Hebei, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Fei Wang

    Department of Pharmacology, Hebei Medical University, Hebei, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Jiaxi Liu

    Department of Pharmacology, Hebei Medical University, Hebei, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Xinyu Li

    Department of Pharmacology, Hebei Medical University, Hebei, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Haichao Yang

    Department of Pharmacology, Hebei Medical University, Hebei, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Fan Zhang

    Department of Pharmacology, Hebei Medical University, Hebei, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Haitao Shen

    Laboratory of Pathology, Hebei Medical University, Hebei, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Noel J Buckley

    Department of Psychiatry, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Nikita Gamper

    Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5806-0207
  14. Ebenezer N Yamoah

    Department of Physiology and Cell Biology, University of Nevada Reno, Reno, United States
    For correspondence
    enyamoah@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9797-085X
  15. Ping Lv

    Department of Pharmacology, Hebei Medical University, Hebei, China
    For correspondence
    lping77@hotmail.com
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institute on Deafness and Other Communication Disorders (DC015135,DC016099)

  • Ebenezer N Yamoah

National Institute on Aging (AG060504-01,P01 AG051443)

  • Ebenezer N Yamoah

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Tanya T Whitfield, University of Sheffield, United Kingdom

Ethics

Animal experimentation: All experimental animal protocols were performed following the Animal Care and Ethical Committee of Hebei Medical University (Shijiazhuang, China). 01644

Version history

  1. Received: January 4, 2022
  2. Preprint posted: March 4, 2022 (view preprint)
  3. Accepted: September 16, 2022
  4. Accepted Manuscript published: September 20, 2022 (version 1)
  5. Version of Record published: September 30, 2022 (version 2)

Copyright

© 2022, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Haiwei Zhang
  2. Hongchen Li
  3. Mingshun Lu
  4. Shengnan Wang
  5. Xueya Ma
  6. Fei Wang
  7. Jiaxi Liu
  8. Xinyu Li
  9. Haichao Yang
  10. Fan Zhang
  11. Haitao Shen
  12. Noel J Buckley
  13. Nikita Gamper
  14. Ebenezer N Yamoah
  15. Ping Lv
(2022)
Repressor element 1-silencing transcription factor deficiency yields profound hearing loss through Kv7.4 channel upsurge in auditory neurons and hair cells
eLife 11:e76754.
https://doi.org/10.7554/eLife.76754

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https://doi.org/10.7554/eLife.76754

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