Epigenetic programming of mu-opioid receptor gene in mouse brain is regulated by MeCP2 and Brg1 chromatin remodelling factor.
The pharmacological action of morphine as a pain medication is mediated primarily through the mu-opioid receptor (MOR). With few exceptions, MOR is expressed in brain regions where opioid actions take place. The basis for this unique spatial expression of MOR remains undetermined. Recently, we reported that DNA methylation of the MOR promoter plays an important role in regulating MOR in P19 cells. In this study, we show that the differential expression of MOR in microdissected mouse brain regions coincides with DNA methylation and histone modifications. MOR expression could be induced by a demethylating agent or a histone deacetylase inhibitor in MOR-negative cells, suggesting that the MOR gene can be silenced under epigenetic control. Increases in the in vivo interaction of methyl-CpG-binding protein 2 (MeCP2) were observed in the cerebellum, in which the MOR promoter was hypermethylated and MOR expression was the lowest among all brain regions tested. MeCP2 is associated closely with Rett syndrome, a neurodevelopmental disorder. We also established novel evidence for a functional role for MeCP2's association with the chromatin-remodelling factor Brg1 and DNA methyltransferase Dnmt1, suggesting a possible role for MeCP2 in chromatin remodelling during MOR gene regulation. We conclude that MOR gene expression is epigenetically programmed in various brain regions and that MeCP2 assists the epigenetic program during DNA methylation and chromatin remodelling of the MOR promoter.
Hwang
Cheol Kyu
CK
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA.
Song
Kyu Young
KY
Kim
Chun Sung
CS
Choi
Hack Sun
HS
Guo
Xiao-Hong
XH
Law
Ping-Yee
PY
Wei
Li-Na
LN
Loh
Horace H
HH
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002843:Chromatin / Q000378:metabolism*; D018899:CpG Islands; D004265:DNA Helicases / Q000378:metabolism*; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017450:Receptors, Opioid, mu / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*
D002843:Chromatin; D017931:DNA Primers; D006657:Histones; D051783:Methyl-CpG-Binding Protein 2; D009687:Nuclear Proteins; D017450:Receptors, Opioid, mu; D014157:Transcription Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases