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CHD7 regulates otic lineage specification and hair cell differentiation in human inner ear organoids

Author

Listed:
  • Jing Nie

    (Indiana University School of Medicine)

  • Yoshitomo Ueda

    (Indiana University School of Medicine)

  • Alexander J. Solivais

    (Indiana University School of Medicine)

  • Eri Hashino

    (Indiana University School of Medicine
    Indiana University School of Medicine)

Abstract

Mutations in CHD7 cause CHARGE syndrome, affecting multiple organs including the inner ear in humans. We investigate how CHD7 mutations affect inner ear development using human pluripotent stem cell-derived organoids as a model system. We find that loss of CHD7 or its chromatin remodeling activity leads to complete absence of hair cells and supporting cells, which can be explained by dysregulation of key otic development-associated genes in mutant otic progenitors. Further analysis of the mutant otic progenitors suggests that CHD7 can regulate otic genes through a chromatin remodeling-independent mechanism. Results from transcriptome profiling of hair cells reveal disruption of deafness gene expression as a potential underlying mechanism of CHARGE-associated sensorineural hearing loss. Notably, co-differentiating CHD7 knockout and wild-type cells in chimeric organoids partially rescues mutant phenotypes by restoring otherwise severely dysregulated otic genes. Taken together, our results suggest that CHD7 plays a critical role in regulating human otic lineage specification and hair cell differentiation.

Suggested Citation

  • Jing Nie & Yoshitomo Ueda & Alexander J. Solivais & Eri Hashino, 2022. "CHD7 regulates otic lineage specification and hair cell differentiation in human inner ear organoids," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34759-8
    DOI: 10.1038/s41467-022-34759-8
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    References listed on IDEAS

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    1. Xiao-Ping Liu & Karl R. Koehler & Andrew M. Mikosz & Eri Hashino & Jeffrey R. Holt, 2016. "Functional development of mechanosensitive hair cells in stem cell-derived organoids parallels native vestibular hair cells," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    2. Karl R. Koehler & Andrew M. Mikosz & Andrei I. Molosh & Dharmeshkumar Patel & Eri Hashino, 2013. "Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture," Nature, Nature, vol. 500(7461), pages 217-221, August.
    3. Joseph C. Burns & Michael C. Kelly & Michael Hoa & Robert J. Morell & Matthew W. Kelley, 2015. "Single-cell RNA-Seq resolves cellular complexity in sensory organs from the neonatal inner ear," Nature Communications, Nature, vol. 6(1), pages 1-16, December.
    4. Jeanine L. Van Nostrand & Colleen A. Brady & Heiyoun Jung & Daniel R. Fuentes & Margaret M. Kozak & Thomas M. Johnson & Chieh-Yu Lin & Chien-Jung Lin & Donald L. Swiderski & Hannes Vogel & Jonathan A., 2014. "Inappropriate p53 activation during development induces features of CHARGE syndrome," Nature, Nature, vol. 514(7521), pages 228-232, October.
    5. Ying Ma & Shiquan Sun & Xuequn Shang & Evan T. Keller & Mengjie Chen & Xiang Zhou, 2020. "Integrative differential expression and gene set enrichment analysis using summary statistics for scRNA-seq studies," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    6. Amy E. Kiernan & Anna L. Pelling & Keith K. H. Leung & Anna S. P. Tang & Donald M. Bell & Charles Tease & Robin Lovell-Badge & Karen P. Steel & Kathryn S. E. Cheah, 2005. "Sox2 is required for sensory organ development in the mammalian inner ear," Nature, Nature, vol. 434(7036), pages 1031-1035, April.
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