Sexually Dimorphic Epigenetic Regulation of Brain-Derived Neurotrophic Factor in Fetal Brain in the Valproic Acid Model of Autism Spectrum Disorder.
Sexually Dimorphic Epigenetic Regulation of Brain-Derived Neurotrophic Factor in Fetal Brain in the Valproic Acid Model of Autism Spectrum Disorder.
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DOI：
10.1159/000481134
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发表时间：
2017
影响因子：
2.9
通讯作者：
Krueger BK
中科院分区：
文献类型：
--
作者：
Konopko MA;Densmore AL;Krueger BK
出生前接触抗癫痫、稳定情绪的药物丙戊酸(VPA)会增加自闭症谱系障碍(ASDS)的发生率；怀孕的啮齿动物在宫内服用VPA会导致类似ASD的行为，如重复、刻板印象的活动和社交能力下降。在这两种情况下，男性比女性受到的影响更大。我们之前曾报道，在妊娠12.5天给怀孕的小鼠注射VPA，可以迅速诱导胎儿大脑中BDNF蛋白和mRNA的瞬时增加，增加6倍。在这里，我们研究了VPA诱导BDNF表达的性别差异及其潜在的表观遗传学机制。通过对BDNF蛋白编码序列(外显子9)的探索，我们发现VPA对总脑组织BDNF mRNA的刺激没有性别差异；然而，VPA对BDNF中9个5‘非翻译外显子(5’UTES)中的两个外显子(外显子1和4)的单个转录本的刺激在女性胎脑中表现得更大。这些BDNF转录本与不同的细胞类型或神经元内的亚细胞隔间有关。由于VPA是组蛋白去乙酰化酶抑制剂，因此用染色质免疫沉淀法分析了胎脑中BDNF5‘端的共价组蛋白修饰。VPA增加了外显子1、2、4和6附近多个H3和H4赖氨酸残基的乙酰化；性别之间的差异很小。VPA对H3K4me3基因外显子1、4、6外显子上H3K4me3基因甲基化的影响也显著高于男性，即VPA对H3K4me3基因的性二态刺激与含有外显子1、4的BDNF转录本相关，但不影响外显子6的转录。因此，在所分析的六个表观遗传标记中，只有H3K4me3可以解释VPA诱导的BDNF转录子在胎脑中的性别二态表达。外显子1-和外显子4-BDNF转录本在女性中的优先表达可能通过保护女性免受遗传变异或环境因素(如VPA)对发育中的大脑的不利影响而导致ASD的性别差异。
Prenatal exposure to the anti-epileptic, 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 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 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 six epigenetic marks analyzed, only H3K4me3 can account for the sexually dimorphic expression of Bdnf transcripts induced by VPA in 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 adverse effects of genetic variants or environmental factors such as VPA on the developing brain.
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