title: Epigenetic alterations by NuRD and PRC2 in the neonatal mouse cochlea.
abstract: Mammalian cochlear supporting cells remain quiescent at postnatal ages and age-dependent changes in supporting cell proliferative capacity are evident. Ectopic Atoh1 expression in neonatal supporting cells converts only a small percentage of these cells into hair cell-like cells. Despite tremendous potential for therapeutics, cellular reprogramming in the mammalian inner ear remains a slow inefficient process that requires weeks, with most cells failing to reprogram. Cellular reprogramming studies in other tissues have shown that epigenetic inhibitors can significantly improve reprogramming efficiency. Very little is known about epigenetic regulation in the mammalian inner ear, and almost nothing is known about the histone modifications. Histone modifications are vital for proper transcriptional regulation, and aberrant histone modifications can cause defects in the regulation of genes required for normal tissue development and maintenance. Our data indicate that cofactors of repressive complexes such as NuRD and PRC2 are present in the neonatal organ of Corti. These NuRD cofactors are present throughout most of the organ of Corti from E18.5 until P4. By P6, these NuRD cofactors are mostly undetectable by immunofluorescence and completely lost by P7, but are detectable again at P8 and continue to be present through P21. The PRC2 enzymatic subunit, EZH2 is also highly present from E18.5 to P0 in the organ of Corti, but lost between P2 and P4. However, EZH2 staining is evident again throughout the organ of Corti by P6 and persists through P21. Our data provide evidence that HDACs, DNA methyltransferases, histone methyltransferases, and histone demethylases are expressed postnatally within the organ of Corti, and may be targets for drug inhibition to increase the capacity, speed, and efficiency of reprogramming a supporting cell into a hair cell.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, MS323, 262 Danny Thomas Place, Memphis, TN 38105, USA. Electronic address: wanda.layman@stjude.org.
authors.forename: Wanda S
authors.initials: WS
authors.lastname: Layman
authors.forename: Mario A
authors.initials: MA
authors.lastname: Sauceda
authors.forename: Jian
authors.initials: J
authors.lastname: Zuo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D054338:Cell Transdifferentiation / Q000235:genetics; D003051:Cochlea / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D056466:Histone Demethylases; D008297:Male; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009925:Organ of Corti / Q000254:growth & development / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism*; D011247:Pregnancy
chemical_list: D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D010089:Oxidoreductases, N-Demethylating; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; C509277:Mi-2beta protein, mouse; D004265:DNA Helicases
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