title: Alteration of genic 5-hydroxymethylcytosine patterning in olfactory neurons correlates with changes in gene expression and cell identity.
abstract: The modified DNA base 5-hydroxymethylcytosine (5hmC) is enriched in neurons where it may contribute to gene regulation and cellular identity. To determine how 5hmC influences gene expression in an in vivo neuronal population, we assessed the patterning and function of the base along the developmental lineage of the main olfactory epithelium-from multipotent stem cells through neuronal progenitors to mature olfactory sensory neurons (mOSNs). We find that 5hmC increases over gene bodies during mOSN development with substantial patterning occuring between the progenitor and mOSN stages. Although gene-body 5hmC levels correlate with gene expression in all three developmental cell types, this association is particularly pronounced within mOSNs. Overexpression of Tet3 in mOSNs markedly alters gene-body 5hmC levels and gene expression in a manner consistent with a positive role for 5hmC in transcription. Moreover, Tet3 overexpression disrupts olfactory receptor expression and the targeting of axons to the olfactory bulb, key molecular and anatomical features of the olfactory system. Our results suggest a physiologically significant role for gene-body 5hmC in transcriptional facilitation and the maintenance of cellular identity independent of its function as an intermediate to demethylation.
authors: Neuroscience Graduate Program, University of California, San Francisco, CA 94158, USA.
authors: Bradley M
authors: BM
authors: Colquitt
authors: William E
authors: WE
authors: Allen
authors: Gilad
authors: G
authors: Barnea
authors: Stavros
authors: S
authors: Lomvardas
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009830:Olfactory Bulb / Q000166:cytology / Q000378:metabolism; D009831:Olfactory Mucosa / Q000166:cytology / Q000378:metabolism; D018034:Olfactory Receptor Neurons / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D049452:Green Fluorescent Proteins; D044503:5-Methylcytosine; D003596:Cytosine; D049308:Dioxygenases; C551915:Tet3 protein, mouse
keywords: epigenetics; neurodevelopment; olfaction
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