Barker Harlan R, Parkkila Seppo, Tolvanen Martti E E
Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland.
Fimlab Ltd., Tampere University Hospital, Tampere 33520, Finland.
Comput Struct Biotechnol J. 2025 May 30;27:2298-2312. doi: 10.1016/j.csbj.2025.05.052. eCollection 2025.
Transcription factor (TF) proteins play a critical role in the regulation of eukaryote gene expression via sequence-specific binding to genomic locations known as TF binding sites. We studied sites of genomic variation between modern human and Neanderthal promoters. We detected significant differences in the binding affinities of 110 TFs to the promoters of 75 target genes. The TFs were enriched for terms related to vision, motor neurons, homeobox, and brain, whereas the target genes and their direct interactors were enriched in terms related to autism, brain, connective tissue, trachea, prostate, skull morphology, and vision. Secondary analysis of single-cell data revealed that a subset of the identified TFs (CUX1, CUX2, ESRRG, FOXP1, FOXP2, MEF2C, POU6F2, PRRX1 and RORA) co-occur as marker genes in L4 glutamatergic neurons. The majority of these genes have known roles in autism and/or schizophrenia and are associated with human accelerated regions (elevated divergence in humans vs. other primates). Analysis of a single-nucleus dataset of cortical tissue showed that 15 of these TFs and 16 of their target genes are differentially expressed in autism vs. control, most commonly upregulated in developing neurons. Down regulation of these genes occurred in SV2C- and somatostatin-expressing interneurons, oligodendrocytes, and oligodendrocyte precursor cells. These results support the value of gene regulation studies for the evolution of human cognitive abilities and the neuropsychiatric disorders that accompany it.
转录因子（TF）蛋白通过与被称为TF结合位点的基因组位置进行序列特异性结合，在真核生物基因表达调控中发挥关键作用。我们研究了现代人类和尼安德特人启动子之间的基因组变异位点。我们检测到110种TF与75个靶基因启动子的结合亲和力存在显著差异。这些TF在与视觉、运动神经元、同源框和大脑相关的术语中富集，而靶基因及其直接相互作用分子在与自闭症、大脑、结缔组织、气管、前列腺、颅骨形态和视觉相关的术语中富集。单细胞数据的二次分析表明，一部分已鉴定的TF（CUX1、CUX2、ESRRG、FOXP1、FOXP2、MEF2C、POU6F2、PRRX1和RORA）作为标记基因在L4谷氨酸能神经元中共出现。这些基因中的大多数在自闭症和/或精神分裂症中具有已知作用，并且与人类加速区域相关（人类与其他灵长类动物相比差异升高）。对皮质组织的单核数据集分析表明，这些TF中的15种及其16个靶基因在自闭症与对照中差异表达，最常见的是在发育中的神经元中上调。这些基因在表达SV2C和生长抑素的中间神经元、少突胶质细胞和少突胶质前体细胞中下调。这些结果支持了基因调控研究对于人类认知能力进化及其伴随的神经精神疾病的价值。
