PMID- 29073621
OWN - NLM
STAT- MEDLINE
DCOM- 20180928
LR  - 20240327
IS  - 1421-9859 (Electronic)
IS  - 0378-5866 (Print)
IS  - 0378-5866 (Linking)
VI  - 39
IP  - 6
DP  - 2017
TI  - Sexually Dimorphic Epigenetic Regulation of Brain-Derived Neurotrophic Factor in 
      Fetal Brain in the Valproic Acid Model of Autism Spectrum Disorder.
PG  - 507-518
LID - 10.1159/000481134 [doi]
AB  - Prenatal exposure to the antiepileptic, mood-stabilizing drug, valproic acid 
      (VPA), increases the incidence of autism spectrum disorders (ASDs); in utero 
      administration of VPA to pregnant rodents induces ASD-like behaviors such as 
      repetitive, stereotyped activity, and decreased socialization. In both cases, 
      males are more affected than females. We previously reported that VPA, 
      administered to pregnant mice at gestational day 12.5, rapidly induces a 
      transient, 6-fold increase in BDNF (brain-derived neurotrophic factor) protein 
      and mRNA in the fetal brain. Here, we investigate sex differences in the 
      induction of Bdnf expression by VPA as well as the underlying epigenetic 
      mechanisms. We found no sex differences in the VPA stimulation of total brain 
      Bdnf mRNA as indicated by probing for the BDNF protein coding sequence (exon 9); 
      however, stimulation of individual transcripts containing two of the nine 
      5'-untranslated exons (5'UTEs) in Bdnf (exons 1 and 4) by VPA was greater in 
      female fetal brains. These Bdnf transcripts have been associated with different 
      cell types or subcellular compartments within neurons. Since VPA is a histone 
      deacetylase inhibitor, covalent histone modifications at Bdnf 5'UTEs in the fetal 
      brain were analyzed by chromatin immunoprecipitation. VPA increased the 
      acetylation of multiple H3 and H4 lysine residues in the vicinity of exons 1, 2, 
      4, and 6; minimal differences between the sexes were observed. H3 lysine 4 
      trimethylation (H3K4me3) at those exons was also stimulated by VPA. Moreover, the 
      VPA-induced increase in H3K4me3 at exons 1, 4, and 6 was significantly greater in 
      females than in males, i.e., sexually dimorphic stimulation of H3K4me3 by VPA 
      correlated with Bdnf transcripts containing exons 1 and 4, but not 6. Neither 
      H3K27me3 nor cytosine methylation at any of the 117 CpGs in the vicinity of the 
      transcription start sites of exons 1, 4, and 6 was affected by VPA. Thus, of the 
      6 epigenetic marks analyzed, only H3K4me3 can account for the sexually dimorphic 
      expression of Bdnf transcripts induced by VPA in the fetal brain. Preferential 
      expression of exon 1- and exon 4-Bdnf transcripts in females may contribute to 
      sex differences in ASDs by protecting females from the adverse effects of genetic 
      variants or environmental factors such as VPA on the developing brain.
CI  - (c) 2017 S. Karger AG, Basel.
FAU - Konopko, Melissa A
AU  - Konopko MA
AD  - Department of Physiology, University of Maryland School of Medicine, Baltimore, 
      MD, USA.
FAU - Densmore, Allison L
AU  - Densmore AL
FAU - Krueger, Bruce K
AU  - Krueger BK
LA  - eng
GR  - R01 HD067135/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20171027
PL  - Switzerland
TA  - Dev Neurosci
JT  - Developmental neuroscience
JID - 7809375
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 614OI1Z5WI (Valproic Acid)
SB  - IM
MH  - Animals
MH  - Autism Spectrum Disorder/chemically induced
MH  - Brain/*drug effects/growth & development
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Chromatin Immunoprecipitation/methods
MH  - Disease Models, Animal
MH  - Epigenesis, Genetic/drug effects
MH  - Female
MH  - Mice, Inbred C57BL
MH  - Neurons/metabolism
MH  - *Sex Characteristics
MH  - Valproic Acid/*pharmacology
PMC - PMC6020162
MID - NIHMS904951
OTO - NOTNLM
OT  - Autism
OT  - Autism spectrum disorder
OT  - Brain-derived neurotrophic factor
OT  - DNA CpG methylation
OT  - Female protective effect
OT  - Gene transcription
OT  - Histone modifications
OT  - RNA splicing
OT  - Valproic acid
COIS- CONFLICT OF INTEREST STATEMENT The authors report no conflicts of interest.
EDAT- 2017/10/27 06:00
MHDA- 2018/10/03 06:00
PMCR- 2018/10/27
CRDT- 2017/10/27 06:00
PHST- 2017/07/03 00:00 [received]
PHST- 2017/08/30 00:00 [accepted]
PHST- 2017/10/27 06:00 [pubmed]
PHST- 2018/10/03 06:00 [medline]
PHST- 2017/10/27 06:00 [entrez]
PHST- 2018/10/27 00:00 [pmc-release]
AID - 000481134 [pii]
AID - 10.1159/000481134 [doi]
PST - ppublish
SO  - Dev Neurosci. 2017;39(6):507-518. doi: 10.1159/000481134. Epub 2017 Oct 27.