title: Spontaneous sleep-wake cycle and sleep deprivation differently induce Bdnf1, Bdnf4 and Bdnf9a DNA methylation and transcripts levels in the basal forebrain and frontal cortex in rats.
abstract: Brain-derived neurotrophic factor (Bdnf) regulates neuronal plasticity, slow wave activity and sleep homeostasis. Environmental stimuli control Bdnf expression through epigenetic mechanisms, but there are no data on epigenetic regulation of Bdnf by sleep or sleep deprivation. Here we investigated whether 5-methylcytosine (5mC) DNA modification at Bdnf promoters p1, p4 and p9 influences Bdnf1, Bdnf4 and Bdnf9a expression during the normal inactive phase or after sleep deprivation (SD) (3, 6 and 12 h, end-times being ZT3, ZT6 and ZT12) in rats in two brain areas involved in sleep regulation, the basal forebrain and cortex. We found a daytime variation in cortical Bdnf expression: Bdnf1 expression was highest at ZT6 and Bdnf4 lowest at ZT12. Such variation was not observed in the basal forebrain. Also Bdnf p1 and p9 methylation levels differed only in the cortex, while Bdnf p4 methylation did not vary in either area. Factorial analysis revealed that sleep deprivation significantly induced Bdnf1 and Bdnf4 with the similar pattern for Bdnf9a in both basal forebrain and cortex; 12 h of sleep deprivation decreased 5mC levels at the cortical Bdnf p4 and p9. Regression analysis between the 5mC promoter levels and the corresponding Bdnf transcript expression revealed significant negative correlations for the basal forebrain Bdnf1 and cortical Bdnf9a transcripts in only non-deprived rats, while these correlations were lost after sleep deprivation. Our results suggest that Bdnf transcription during the light phase of undisturbed sleep-wake cycle but not after SD is regulated at least partially by brain site-specific DNA methylation.
authors.affiliation: Institute of Biomedicine, University of Helsinki, Helsinki, Finland; Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine, Kharkov, Ukraine.
authors.forename: Olena
authors.initials: O
authors.lastname: Ventskovska
authors.forename: Tarja
authors.initials: T
authors.lastname: Porkka-Heiskanen
authors.forename: Nina N
authors.initials: NN
authors.lastname: Karpova
mesh_terms: D000818:Animals; D066187:Basal Forebrain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005625:Frontal Lobe / Q000378:metabolism*; D008297:Male; D009473:Neuronal Plasticity; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D012890:Sleep / Q000235:genetics*; D012892:Sleep Deprivation / Q000235:genetics* / Q000503:physiopathology; D013997:Time Factors; D014851:Wakefulness / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger
keywords: Bdnf exon; circadian; diurnal; methylated DNA immunoprecipitation; sleep homeostasis