Epigenetic regulation of Atoh1 guides hair cell development in the mammalian cochlea.
In the developing cochlea, sensory hair cell differentiation depends on the regulated expression of the bHLH transcription factor Atoh1. In mammals, if hair cells die they do not regenerate, leading to permanent deafness. By contrast, in non-mammalian vertebrates robust regeneration occurs through upregulation of Atoh1 in the surviving supporting cells that surround hair cells, leading to functional recovery. Investigation of crucial transcriptional events in the developing organ of Corti, including those involving Atoh1, has been hampered by limited accessibility to purified populations of the small number of cells present in the inner ear. We used µChIP and qPCR assays of FACS-purified cells to track changes in the epigenetic status of the Atoh1 locus during sensory epithelia development in the mouse. Dynamic changes in the histone modifications H3K4me3/H3K27me3, H3K9ac and H3K9me3 reveal a progression from poised, to active, to repressive marks, correlating with the onset of Atoh1 expression and its subsequent silencing during the perinatal (P1 to P6) period. Inhibition of acetylation blocked the increase in Atoh1 mRNA in nascent hair cells, as well as ongoing hair cell differentiation during embryonic organ of Corti development ex vivo. These results reveal an epigenetic mechanism of Atoh1 regulation underlying hair cell differentiation and subsequent maturation. Interestingly, the H3K4me3/H3K27me3 bivalent chromatin structure observed in progenitors persists at the Atoh1 locus in perinatal supporting cells, suggesting an explanation for the latent capacity of these cells to transdifferentiate into hair cells, and highlighting their potential as therapeutic targets in hair cell regeneration.
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, 1425 San Pablo St., Los Angeles, CA 90033, USA.
Zlatka P
ZP
Stojanova
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, 1425 San Pablo St., Los Angeles, CA 90033, USA.
Tao
T
Kwan
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, 1425 San Pablo St., Los Angeles, CA 90033, USA Caruso Department of Otolaryngology, Keck School of Medicine of the University of Southern California, Suite 5100, 1450 San Pablo Street, Los Angeles, CA 90033, USA nsegil@med.usc.edu.
Neil
N
Segil
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D002469:Cell Separation; D002843:Chromatin / Q000737:chemistry; D003051:Cochlea / Q000196:embryology*; D053595:Embryonic Stem Cells / Q000166:cytology; D044127:Epigenesis, Genetic; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006198:Hair Cells, Auditory / Q000166:cytology*; D006657:Histones / Q000737:chemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009925:Organ of Corti / Q000473:pathology; D013997:Time Factors
D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D049452:Green Fluorescent Proteins; D006657:Histones; C500943:Atoh1 protein, mouse
Epigenetics of Atoh1 regulation; Epigenetics of inner ear development; Mouse; Sensory hair cell differentiation