Proteomic analysis of FOXP proteins reveals interactions between cortical transcription factors associated with neurodevelopmental disorders
Proteomic analysis of FOXP proteins reveals interactions between cortical transcription factors associated with neurodevelopmental disorders
复制标题
DOI：
10.1093/hmg/ddy035
复制
发表时间：
2018-04-01
影响因子：
3.5
通讯作者：
Fisher, Simon E.
中科院分区：
文献类型：
--
作者：
Estruch, Sara B.;Graham, Sarah A.;Fisher, Simon E.
FOXP转录因子在神经发育中发挥重要作用，但对其转录活性如何调节知之甚少。FOXP蛋白通过相互形成同源和异源二聚体来协同调节基因表达。与其他转录因子的物理关联也可能调节FOXP蛋白的功能。然而，迄今为止发现的与foxp相互作用的转录因子很少。因此，我们试图通过蛋白复合物的亲和纯化和质谱分析，发现与脑表达的foxxp蛋白FOXP1、FOXP2和FOXP4相互作用的其他转录因子。我们确定了7个新的foxp相互作用转录因子（NR2F1, NR2F2, SATB1, SATB2, SOX5， YY1和ZMYM2），其中5个在皮质发育中具有明确的作用。因此，我们发现这些转录因子在大脑皮层深层和小脑浦肯野细胞中与FoxP2共表达，提示它们可能在体内与FoxPs协同调节神经基因的表达。此外，我们证明了FOXP1和FOXP2的致病突变，已知会导致神经发育障碍，严重破坏了与foxp相互作用的转录因子的相互作用。此外，我们在FOXP2序列中确定了介导这些相互作用的特定区域。因此，通过扩展FOXP相互作用组，我们发现了参与皮质发育的更广泛的神经转录因子网络的一部分，为大脑发育和神经发育障碍的转录结构提供了新的分子见解。
FOXP transcription factors play important roles in neurodevelopment, but little is known about how their transcriptional activity is regulated. FOXP proteins cooperatively regulate gene expression by forming homo-and hetero-dimers with each other. Physical associations with other transcription factors might also modulate the functions of FOXP proteins. However, few FOXP-interacting transcription factors have been identified so far. Therefore, we sought to discover additional transcription factors that interact with the brain-expressed FOXP proteins, FOXP1, FOXP2 and FOXP4, through affinity-purifications of protein complexes followed by mass spectrometry. We identified seven novel FOXP-interacting transcription factors (NR2F1, NR2F2, SATB1, SATB2, SOX5, YY1 and ZMYM2), five of which have well-estabslished roles in cortical development. Accordingly, we found that these transcription factors are co-expressed with FoxP2 in the deep layers of the cerebral cortex and also in the Purkinje cells of the cerebellum, suggesting that they may cooperate with the FoxPs to regulate neural gene expression in vivo. Moreover, we demonstrated that etiological mutations of FOXP1 and FOXP2, known to cause neurodevelopmental disorders, severely disrupted the interactions with FOXP-interacting transcription factors. Additionally, we pinpointed specific regions within FOXP2 sequence involved in mediating these interactions. Thus, by expanding the FOXP interactome we have uncovered part of a broader neural transcription factor network involved in cortical development, providing novel molecular insights into the transcriptional architecture underlying brain development and neurodevelopmental disorders.