Vera-Montecinos América, Ramos Belén
Psiquiatria Molecular, Parc Sanitari Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Dr. Antoni Pujadas 42, 08830 Sant Boi de Llobregat, Spain.
Departamento de Ciencias Biológicas y Químicas, Facultad De Ciencias, Universidad San Sebastián, Sede Tres Pascualas Lientur 1457, Concepción 4080871, Chile.
Int J Mol Sci. 2025 Apr 12;26(8):3653. doi: 10.3390/ijms26083653.
Despite the emerging evidence of the role of transcriptional regulators in schizophrenia as key molecular effectors responsible for the dysregulation of multiple biological processes, limited information is available for brain areas that control higher cognitive functions, such as the cerebellum. To identify transcription factors that could control a wide panel of altered proteins in the cerebellar cortex in schizophrenia, we analyzed a dataset obtained using one-shot liquid chromatography-tandem mass spectrometry on the postmortem human cerebellar cortex in chronic schizophrenia (PXD024937 identifier in the ProteomeXchange repository). Our analysis revealed a panel of 11 enriched transcription factors (SP1, KLF7, SP4, EGR1, HNF4A, CTCF, GABPA, NRF1, NFYA, YY1, and MEF2A) that could be controlling 250 altered proteins. The top three significantly enriched transcription factors were SP1, YY1, and EGR1, and the transcription factors with the largest number of targets were SP1, KLF7, and SP4 which belong to the Krüppel superfamily. An enrichment in vesicle-mediated transport was found for SP1, KLF7, EGR1, HNF4A, CTCF, and MEF2A targets, while pathways related to signaling, inflammation/immune responses, apoptosis, and energy were found for SP1 and KLF7 targets. EGR1 targets were enriched in RNA processing, and GABPA and YY1 targets were mainly involved in organelle organization and assembly. This study provides a reduced panel of transcriptional regulators that could impact multiple pathways through the control of a number of targets in the cerebellum in chronic schizophrenia. These findings suggest that this panel of transcription factors could represent key targets for pharmacological interventions in schizophrenia.
尽管越来越多的证据表明转录调节因子在精神分裂症中作为导致多种生物过程失调的关键分子效应物发挥作用，但对于控制高级认知功能的脑区（如小脑），相关信息仍然有限。为了确定能够控制精神分裂症患者小脑皮质中大量改变的蛋白质的转录因子，我们分析了一个数据集，该数据集是通过对慢性精神分裂症患者死后人类小脑皮质进行单次液相色谱 - 串联质谱分析获得的（蛋白质组交换库中的标识符为PXD024937）。我们的分析揭示了一组11种富集的转录因子（SP1、KLF7、SP4、EGR1、HNF4A、CTCF、GABPA、NRF1、NFYA、YY1和MEF2A），它们可能控制250种改变的蛋白质。富集程度最高的前三个转录因子是SP1、YY1和EGR1，而靶标数量最多的转录因子是属于Krüppel超家族的SP1、KLF7和SP4。发现SP1、KLF7、EGR1、HNF4A、CTCF和MEF2A的靶标在囊泡介导的运输方面有富集，而与信号传导、炎症/免疫反应、细胞凋亡和能量相关的途径在SP1和KLF7的靶标中被发现。EGR1的靶标在RNA加工方面有富集，而GABPA和YY1的靶标主要参与细胞器的组织和组装。这项研究提供了一组减少的转录调节因子，它们可能通过控制慢性精神分裂症患者小脑中的多个靶标来影响多种途径。这些发现表明，这组转录因子可能代表精神分裂症药物干预的关键靶标。
