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Suberoylanilide hydroxamic acid (SAHA) has been reported preclinically to diffuse across the placenta and to be found in fetal plasma, suggesting that it can influence the fetus if taken by a pregnant cancer patient. In utero exposure of SAHA to mouse embryos during mid-gestation was found to perturb corticogenesis. However, the influence of in utero administration of SAHA to mouse embryos during mid-gestation on astrocyte, glial cell, and inhibitory neurons (interneurons) is yet to be reported. Pregnant dams were divided into control and SAHA groups and given methyl cellulose (as control) and SAHA orally once a day for 3 days during mid-gestation, starting from embryonic day (E)12 until E14. Astrocyte, interneuron, and behavior analyses were performed on the pups from postnatal day 7 until adulthood (3 months old). Brains were harvested and immunohistochemistry, Western Blot, and RT-PCR were performed on their cortex area. Transient exposure of SAHA to mouse embryos resulted in a decrease and increase in cortical astrocyte and interneuron, respectively. Meanwhile, adult SAHA mice displayed significantly increased anxiety, decreased memory, altered long-term cognitive functions, and reduced social interactions. Our study suggests that exposure to SAHA during prominent neurogenic periods might imbalance the normal excitatory:inhibitory neuron ratio required for the precise regulation of physiological functions in the brain.

Transcription factors (TFs) and epigenetic modifications function cooperatively to regulate various biological processes such as cell proliferation, differentiation, maturation, and metabolism. TF binding to regulatory regions of target genes controls their transcriptional activity through alteration of the epigenetic status around the binding regions, leading to transcription network formation regulating cell fates. Although nuclear factor I/A (Nfia) is a well-known TF that induces demethylation of astrocytic genes to confer astrocytic differentiation potential on neural stem/precursor cells (NS/PCs), the epigenetic role of NFIA in oligodendrocytic lineage progression remains unclear. Here, we show that oligodendrocyte differentiation/maturation is delayed in the brains of Nfia-knockout (KO) mice, and that NFIA-regulated DNA demethylation in NS/PCs plays an important role in determining the timing of their differentiation. We further demonstrate that the promoter activity of the oligodendrocyte transcription factor 1 (Olig1) gene, involved in oligodendrocyte differentiation/maturation, is suppressed by DNA methylation, which is in turn regulated by Nfia expression. Our results suggest that NFIA controls the timing of oligodendrocytic differentiation/maturation via demethylation of cell-type-specific gene promoters.

Prenatal exposure to valproic acid (VPA), an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running.

CHARGE syndrome is caused by heterozygous mutations in the chromatin remodeler, CHD7, and is characterized by a set of malformations that, on clinical grounds, were historically postulated to arise from defects in neural crest formation during embryogenesis. To better delineate neural crest defects in CHARGE syndrome, we generated induced pluripotent stem cells (iPSCs) from two patients with typical syndrome manifestations, and characterized neural crest cells differentiated in vitro from these iPSCs (iPSC-NCCs). We found that expression of genes associated with cell migration was altered in CHARGE iPSC-NCCs compared to control iPSC-NCCs. Consistently, CHARGE iPSC-NCCs showed defective delamination, migration and motility in vitro, and their transplantation in ovo revealed overall defective migratory activity in the chick embryo. These results support the historical inference that CHARGE syndrome patients exhibit defects in neural crest migration, and provide the first successful application of patient-derived iPSCs in modeling craniofacial disorders.