title: An epigenetic trap stabilizes singular olfactory receptor expression.
abstract: The molecular mechanisms regulating olfactory receptor (OR) expression in the mammalian nose are not yet understood. Here, we identify the transient expression of histone demethylase LSD1 and the OR-dependent expression of adenylyl cyclase 3 (Adcy3) as requirements for initiation and stabilization of OR expression. As a transcriptional coactivator, LSD1 is necessary for desilencing and initiating OR transcription, but as a transcriptional corepressor, it is incompatible with maintenance of OR expression, and its downregulation is imperative for stable OR choice. Adcy3, a sensor of OR expression and a transmitter of an OR-elicited feedback, mediates the downregulation of LSD1 and promotes the differentiation of olfactory sensory neurons (OSNs). This novel, three-node signaling cascade locks the epigenetic state of the chosen OR, stabilizes its singular expression, and prevents the transcriptional activation of additional OR alleles for the life of the neuron.
authors.affiliation: Tetrad Program, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Lyons
authors.forename: William E
authors.initials: WE
authors.lastname: Allen
authors.forename: Tracie
authors.initials: T
authors.lastname: Goh
authors.forename: Lulu
authors.initials: L
authors.lastname: Tsai
authors.forename: Gilad
authors.initials: G
authors.lastname: Barnea
authors.forename: Stavros
authors.initials: S
authors.lastname: Lomvardas
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D056466:Histone Demethylases; D051379:Mice; D018345:Mice, Knockout; D009297:Nasal Mucosa / Q000378:metabolism; D018034:Olfactory Receptor Neurons / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D018035:Receptors, Odorant / Q000235:genetics*; D011984:Sensory Receptor Cells / Q000378:metabolism*
chemical_list: D018035:Receptors, Odorant; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D010089:Oxidoreductases, N-Demethylating; D000262:Adenylyl Cyclases; C421784:adenylate cyclase 3