Hennig Krista M, Fass Daniel M, Zhao Wen-Ning, Sheridan Steven D, Fu Ting, Erdin Serkan, Stortchevoi Alexei, Lucente Diane, Cody Jannine D, Sweetser David, Gusella James F, Talkowski Michael E, Haggarty Stephen J
Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Massachusetts, USA.
Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.
Mol Neuropsychiatry. 2017 Jul;3(1):53-71. doi: 10.1159/000475666. Epub 2017 Jul 14.
Genetic variation within the transcription factor locus can cause the intellectual disability and developmental disorder Pitt-Hopkins syndrome (PTHS), whereas single-nucleotide polymorphisms within noncoding regions are associated with schizophrenia. These genetic findings position TCF4 as a link between transcription and cognition; however, the neurobiology of TCF4 remains poorly understood. Here, we quantitated multiple distinct transcript levels in human induced pluripotent stem cell-derived neural progenitors and differentiated neurons, and PTHS patient fibroblasts. We identify two classes of pharmacological treatments that regulate expression: WNT pathway activation and inhibition of class I histone deacetylases. In PTHS fibroblasts, both of these perturbations upregulate a subset of transcripts. Finally, using chromatin immunoprecipitation sequencing in conjunction with genome-wide transcriptome analysis, we identified TCF4 target genes that may mediate the effect of TCF4 loss on neuroplasticity. Our studies identify new pharmacological assays, tools, and targets for the development of therapeutics for cognitive disorders.
转录因子基因座内的遗传变异可导致智力残疾和发育障碍皮特-霍普金斯综合征（PTHS），而非编码区内的单核苷酸多态性与精神分裂症有关。这些遗传学发现将TCF4定位为转录与认知之间的联系；然而，TCF4的神经生物学仍知之甚少。在这里，我们对人诱导多能干细胞衍生的神经祖细胞、分化神经元以及PTHS患者成纤维细胞中的多种不同转录本水平进行了定量分析。我们确定了两类调节其表达的药物治疗方法：WNT信号通路激活和I类组蛋白去乙酰化酶抑制。在PTHS成纤维细胞中，这两种干扰均会上调一部分转录本。最后，结合全基因组转录组分析使用染色质免疫沉淀测序，我们确定了可能介导TCF4缺失对神经可塑性影响的TCF4靶基因。我们的研究为认知障碍治疗药物的开发确定了新的药理分析方法、工具和靶点。
