Abstract
The histone demethylase LSD1 plays a pivotal role in cellular differentiation, particularly in silencing lineage-specific genes. However, little is known about how LSD1 regulates neurosensory differentiation in the inner ear. Here we show that LSD1 interacts directly with the transcription factor Pax2 to form the NuRD co-repressor complex at the Pax2 target gene loci in a mouse otic neuronal progenitor cell line (VOT-N33). VOT-N33 cells expressing a Pax2-response element reporter were GFP-negative when untreated, but became GFP positive after forced differentiation or treatment with a potent LSD inhibitor. Pharmacological inhibition of LSD1 activity resulted in the enrichment of mono- and di-methylation of H3K4, upregulation of sensory neuronal genes and an increase in the number of sensory neurons in mouse inner ear organoids. Together, these results identify the LSD1/NuRD complex as a previously unrecognized modulator for Pax2-mediated neuronal differentiation in the inner ear.
Highlights
Mechanosensitive hair cells and afferent spiral ganglion neurons in the inner ear are derived from multipotent otic progenitors during embryonic development
Pax2 and Lysine-specific demethylase 1 (LSD1) are co-expressed in otic progenitors in vivo and in vitro
We found that Pax2 was expressed in the ventral part of the otic vesicle, whereas LSD1 was expressed throughout (Fig 1A)
Summary
Mechanosensitive hair cells and afferent spiral ganglion neurons in the inner ear are derived from multipotent otic progenitors during embryonic development. Elucidating the transcriptional network associated with differentiation of these cell types has been an area of intense investigation over the past decade [1, 2]. Epigenetic modifications have emerged as a key mechanism controlling the processes of cellular differentiation and cell fate specification. One such modification is the methylation of lysine on the tails of the core histones H3 and H4 [9].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
