Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air.
The mouse insulin-like growth factor II receptor (Igf2r) gene and its antisense transcript Air are reciprocally imprinted in most tissues, but in the brain, Igf2r is biallelically expressed despite the imprinted Air expression. To investigate the molecular mechanisms of such brain-specific relaxation of Igf2r imprinting, we analyzed its expression and epigenetic modifications in neurons, glial cells and fibroblasts by the use of primary cortical cell cultures. In glial cells and fibroblasts, Igf2r was maternally expressed and Air was paternally expressed, whereas in the primary cultured neurons, Igf2r was biallelically expressed and Air was not expressed. In the differentially methylated region 2 (DMR2), which includes the Air promoter, allele-specific DNA methylation, differential H3 and H4 acetylation and H3K4 and K9 di-methylation were maintained in each cultured cell type. In DMR1, which includes the Igf2r promoter, maternal-allele-specific DNA hypomethylation, histones H3 and H4 acetylation and H3K4 di-methylation were apparent in glial cells and fibroblasts. However, in neurons, biallelic DNA hypomethylation and biallelic histones H3 and H4 acetylation and H3K4 di-methylation were detected. These data indicate that lack of reciprocal imprinting of Igf2r and Air in the brain results from neuron-specific relaxation of Igf2r imprinting associated with neuron-specific histone modifications in DMR1 and lack of Air expression. Our observation of biallelic Igf2r expression with no Air expression in neurons sheds light on the function of Air as a critical effector in Igf2r silencing and suggests that neuron-specific epigenetic modifications related to the lineage determination of neural stem cells play a critical role in controlling imprinting by antisense transcripts.
Yamasaki
Yoko
Y
Department of Human Genetics, Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
Kayashima
Tomohiko
T
Soejima
Hidenobu
H
Kinoshita
Akira
A
Yoshiura
Ko-Ichiro
K
Matsumoto
Naomichi
N
Ohta
Tohru
T
Urano
Takeshi
T
Masuzaki
Hideaki
H
Ishimaru
Tadayuki
T
Mukai
Tsunehiro
T
Niikawa
Norio
N
Kishino
Tatsuya
T
D000818:Animals; D001921:Brain / Q000196:embryology; D019175:DNA Methylation; D047108:Embryonic Development; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000502:physiology*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017527:Receptor, IGF Type 2 / Q000235:genetics*
D006657:Histones; D017527:Receptor, IGF Type 2