Rubinstein-Taybi syndrome (RSTS) is a rare multisystem developmental disorder with moderate to severe intellectual disability caused by heterozygous mutations of either CREBBP or EP300 genes encoding CBP/p300 chromatin regulators. We explored the gene programs and processes underlying the morphological and functional alterations shown by iPSC-derived neurons modeling RSTS to bridge the molecular changes resulting from defective CBP/p300 to cognitive impairment. By global transcriptome analysis, we compared the differentially expressed genes (DEGs) marking the transition from iPSC-derived neural progenitors to cortical neurons (iNeurons) of five RSTS patients carrying private CREBBP/EP300 mutations and manifesting differently graded neurocognitive signs with those of four healthy controls. Our data shows a defective and altered neuroprogenitor to neuron transcriptional program in the cells from RSTS patients. First, transcriptional regulation is weaker in RSTS as less genes than in controls are modulated, including genes of key processes of mature functional neurons, such as those for voltage-gated channels and neurotransmitters and their receptors. Second, regulation is subverted as genes acting at pre-terminal stages of neural differentiation in cell polarity and adhesive functions (members of the cadherin family) and axon extension/guidance (members of the semaphorins and SLIT receptors families) are improperly upregulated. Impairment or delay of RSTS neuronal differentiation program is also evidenced by decreased modulation of the overall number of neural differentiation markers, significantly impacting the initial and final stages of the differentiation cascade. Last, extensive downregulation of genes for RNA/DNA metabolic processes confirms that RSTS is a global transcription disorder, consistent with a syndrome driven by chromatin dysregulation. Interestingly, the morphological and functional alterations we have previously appointed as biomarkers of RSTS iNeurons provide functional support to the herein designed transcriptome profile pointing to key dysregulated neuronal genes as main contributors to patients’ cognitive deficit. The impact of RSTS transcriptome may go beyond RSTS as comparison of dysregulated genes across modeled neurodevelopmental disorders could unveil convergent genes of cognitive impairment.

Rubinstein-Taybi综合征（RSTS）是一种罕见的多系统发育障碍，由CREBBP或编码CBP / p300染色质调节剂的EP300基因的杂合突变引起，具有中度至重度智力障碍。我们探索了由iPSC衍生的神经元对RSTS进行建模所显示的形态和功能改变的基因程序和过程，以桥接由缺陷性CBP / p300导致的认知障碍的分子变化。通过全局转录组分析，我们比较了五种携带私人CREBBP / EP300的RSTS患者从iPSC衍生的神经祖细胞到皮层神经元（iNeurons）的差异表达基因（DEG）。突变，并表现出与四个健康对照者不同的神经认知迹象。我们的数据显示，来自RSTS患者的细胞中神经祖细胞的神经元转录程序存在缺陷和改变。首先，RSTS中的转录调控较弱，因为调控的基因少于对照组，包括成熟功能神经元关键过程的基因，例如电压门控通道，神经递质及其受体的基因。其次，调节被颠覆了，因为在细胞极性和粘附功能（钙黏着蛋白家族的成员）和轴突延伸/指导（信号量和SLIT受体家族的成员）的神经分化的前期阶段起作用的基因被上调了。RSTS神经元分化程序的受损或延迟也可以通过神经分化标记总数的减少调节来证明，这显着影响了分化级联反应的初始和最终阶段。最后，针对RNA / DNA代谢过程的基因的大量下调证实RSTS是一种全局转录疾病，与染色质失调驱动的综合征相一致。有趣的是，我们先前指定为RSTS iNeurons的生物标志物的形态和功能改变为本文设计的转录组图谱提供了功能支持，这些谱图谱指出关键的失调的神经元基因是导致患者认知功能障碍的主要因素。