title: Genomic imprinting variations in the mouse type 3 deiodinase gene between tissues and brain regions.
abstract: The Dio3 gene, which encodes for the type 3 deiodinase (D3), controls thyroid hormone (TH) availability. The lack of D3 in mice results in tissue overexposure to TH and a broad neuroendocrine phenotype. Dio3 is an imprinted gene, preferentially expressed from the paternally inherited allele in the mouse fetus. However, heterozygous mice with paternal inheritance of the inactivating Dio3 mutation exhibit an attenuated phenotype when compared with that of Dio3 null mice. To investigate this milder phenotype, the allelic expression of Dio3 was evaluated in different mouse tissues. Preferential allelic expression of Dio3 from the paternal allele was observed in fetal tissues and neonatal brain regions, whereas the biallelic Dio3 expression occurred in the developing eye, testes, and cerebellum and in the postnatal brain neocortex, which expresses a larger Dio3 mRNA transcript. The newborn hypothalamus manifests the highest degree of Dio3 expression from the paternal allele, compared with other brain regions, and preferential allelic expression of Dio3 in the brain relaxed in late neonatal life. A methylation analysis of two regulatory regions of the Dio3 imprinted domain revealed modest but significant differences between tissues, but these did not consistently correlate with the observed patterns of Dio3 allelic expression. Deletion of the Dio3 gene and promoter did not result in significant changes in the tissue-specific patterns of Dio3 allelic expression. These results suggest the existence of unidentified epigenetic determinants of tissue-specific Dio3 imprinting. The resulting variation in the Dio3 allelic expression between tissues likely explains the phenotypic variation that results from paternal Dio3 haploinsufficiency.
authors.affiliation: Department of Molecular Medicine (M.E.M., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Centre for Endocrinology (M.C.), William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 1BB, United Kingdom; Department of Obstetrics and Gynecology and Human Genetics (A.S., A.K.N.), McGill University, Montréal, Québec, Canada H9X 3V9; Department of Microbiology and Immunology (S.F.), Dartmouth Medical School, Lebanon, New Hampshire 03756; and Department of Genetics (A.C.F.-S.), University of Cambridge, Cambridge CB2 1TN, United Kingdom.
authors.forename: M Elena
authors.initials: ME
authors.lastname: Martinez
authors.forename: Marika
authors.initials: M
authors.lastname: Charalambous
authors.forename: Aabida
authors.initials: A
authors.lastname: Saferali
authors.forename: Steven
authors.initials: S
authors.lastname: Fiering
authors.forename: Anna K
authors.initials: AK
authors.lastname: Naumova
authors.forename: Donald
authors.initials: D
authors.lastname: St Germain
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ferguson-Smith
authors.forename: Arturo
authors.initials: A
authors.lastname: Hernandez
mesh_terms: D000483:Alleles; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D018392:Genomic Imprinting / Q000235:genetics*; D007453:Iodide Peroxidase / Q000235:genetics*; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D013963:Thyroid Hormones / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D013963:Thyroid Hormones; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase