DNA methylation regulates CHRNA7 transcription and can be modulated by valproate
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DNA methylation regulates CHRNA7 transcription and can be modulated by valproate. / Dyrvig, Mads; Mikkelsen, Jens D.; Lichota, Jacek.
In: Neuroscience Letters, Vol. 704, 06.2019, p. 145-152.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - DNA methylation regulates CHRNA7 transcription and can be modulated by valproate
AU - Dyrvig, Mads
AU - Mikkelsen, Jens D.
AU - Lichota, Jacek
PY - 2019/6
Y1 - 2019/6
N2 - The CHRNA7 gene encoding the α7 nicotinic acetylcholine receptor (nAChR) has repeatedly been linked with schizophrenia and the P50 sensory gating deficit. The α7 nAChR is considered a promising drug target for treatment of cognitive dysfunction in schizophrenia and improves memory and executive functions in patients and healthy individuals. However, clinical trials with pro-cognitive drugs are challenged by large inter-individual response variations and these have been linked to genotypic variations reducing CHRNA7 expression and α7 nAChR function. Genetic variants as well as environmental conditions may cause epigenetic dysregulation and it has previously been found that DNA methylation of a region surrounding the transcription start site of CHRNA7 is important for tissue specific regulation and gene silencing. In the present study we identify two additional regions involved in epigenetic regulation of the CHRNA7 promoter. In human temporal cortex we find large variations in expression of CHRNA7 and establish evidence for a significant correlation with DNA methylation levels of one region. We then establish evidence that genotypic variations can influence methylation levels of the CHRNA7 promoter. Epigenetic dysregulation can be reversed by pharmacological intervention and in HeLa cells. Valproate, a commonly used mood stabiliser, caused demethylation and increased CHRNA7 expression in HeLA cells. Similar demethylation effect and increased CHRNA7 expression was obtained in SH-SY5Y cells stimulated concomitantly with valproate and nicotine. In summary, both genetic and epigenetic information could be useful to predict treatment outcomes in patients and epigenetic modulation may serve as a mechanism for potentiating the effects of α7 nAChR agonists.
AB - The CHRNA7 gene encoding the α7 nicotinic acetylcholine receptor (nAChR) has repeatedly been linked with schizophrenia and the P50 sensory gating deficit. The α7 nAChR is considered a promising drug target for treatment of cognitive dysfunction in schizophrenia and improves memory and executive functions in patients and healthy individuals. However, clinical trials with pro-cognitive drugs are challenged by large inter-individual response variations and these have been linked to genotypic variations reducing CHRNA7 expression and α7 nAChR function. Genetic variants as well as environmental conditions may cause epigenetic dysregulation and it has previously been found that DNA methylation of a region surrounding the transcription start site of CHRNA7 is important for tissue specific regulation and gene silencing. In the present study we identify two additional regions involved in epigenetic regulation of the CHRNA7 promoter. In human temporal cortex we find large variations in expression of CHRNA7 and establish evidence for a significant correlation with DNA methylation levels of one region. We then establish evidence that genotypic variations can influence methylation levels of the CHRNA7 promoter. Epigenetic dysregulation can be reversed by pharmacological intervention and in HeLa cells. Valproate, a commonly used mood stabiliser, caused demethylation and increased CHRNA7 expression in HeLA cells. Similar demethylation effect and increased CHRNA7 expression was obtained in SH-SY5Y cells stimulated concomitantly with valproate and nicotine. In summary, both genetic and epigenetic information could be useful to predict treatment outcomes in patients and epigenetic modulation may serve as a mechanism for potentiating the effects of α7 nAChR agonists.
KW - CHRNA7
KW - DNA methylation
KW - Gene expression
KW - Promoter SNP
KW - Schizophrenia
KW - Valproate
U2 - 10.1016/j.neulet.2019.04.015
DO - 10.1016/j.neulet.2019.04.015
M3 - Journal article
C2 - 30974230
AN - SCOPUS:85064151647
VL - 704
SP - 145
EP - 152
JO - Neuroscience letters. Supplement
JF - Neuroscience letters. Supplement
SN - 0167-6253
ER -
ID: 241991745