WNT/beta-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4.
WNT/beta-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4.
复制标题
DOI：
10.1159/000475666
复制
发表时间：
2017-07-01
期刊：
影响因子：
--
通讯作者：
Haggarty, Stephen J
中科院分区：
文献类型：
--
作者：
Hennig, Krista M;Fass, Daniel M;Haggarty, Stephen J
转录因子TCF 4基因座内的遗传变异可导致智力残疾和发育障碍Pitt-Hopkins综合征（PTHS），而非编码区内的单核苷酸多态性与精神分裂症相关。这些遗传学发现将TCF 4定位为转录和认知之间的联系;然而，TCF 4的神经生物学仍然知之甚少。在这里，我们定量了人诱导多能干细胞衍生的神经祖细胞和分化的神经元以及PTHS患者成纤维细胞中多种不同的TCF 4转录水平。我们确定了两类调节TCF 4表达的药物治疗：WNT途径激活和I类组蛋白脱乙酰酶抑制。在PTHS成纤维细胞中，这两种扰动都上调TCF 4转录物的子集。最后，使用染色质免疫沉淀测序结合全基因组转录组分析，我们确定了可能介导TCF 4缺失对神经可塑性影响的TCF 4靶基因。我们的研究确定了新的药理学测定，工具和目标，为开发治疗认知障碍。
Genetic variation within the transcription factor TCF4 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 TCF4 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 TCF4 expression: WNT pathway activation and inhibition of class I histone deacetylases. In PTHS fibroblasts, both of these perturbations upregulate a subset of TCF4 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.