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首页> 外文期刊>Molecular cell >NOTCH1 Nuclear Interactome Reveals Key Regulators of Its Transcriptional Activity and Oncogenic Function
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NOTCH1 Nuclear Interactome Reveals Key Regulators of Its Transcriptional Activity and Oncogenic Function

机译：NOTCH1核相互作用组揭示了其转录活性和致癌功能的关键调控因子。

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摘要

Activating mutations in NOTCH1, an essential regulator of T cell development, are frequently found in human T cell acute lymphoblastic leukemia (T-ALL). Despite important advances in our understanding of Notch signal transduction, the regulation of Notch functions in the nucleus remains unclear. Using immunoaffinity purification, we identified NOTCH1 nuclear partners in T-ALL cells and showed that, beyond the well-characterized core activation complex (ICN1-CSL-MAML1), NOTCH1 assembles a multifunctional complex containing the transcription coactivator AF4p12, the PBAF nucleosome remodeling complex, and the histone demethylases LSD1 and PHF8 acting through their demethylase activity to promote epigenetic modifications at Notch-target genes. Remarkably, LSD1 functions as a corepressor when associated with CSL-repressor complex and as a NOTCH1 coactivator upon Notch activation. Our work provides new insights into the molecular mechanisms that govern Notch transcriptional activity and represents glimpse into NOTCH1 interaction landscape, which will help in deciphering mechanisms of NOTCH1 functions and regulation.
机译：在人类T细胞急性淋巴细胞白血病（T-ALL）中经常发现NOTCH1的活化突变，它是T细胞发育的重要调节剂。尽管我们在了解Notch信号转导方面取得了重要进展，但尚不清楚核中Notch功能的调控。使用免疫亲和纯化，我们在T-ALL细胞中鉴定了NOTCH1核伴侣，并表明，除了特征明确的核心激活复合物（ICN1-CSL-MAML1）外，NOTCH1组装了一个多功能复合物，其中包含转录共激活子AF4p12，PBAF核小体重塑复合物，而组蛋白脱甲基酶LSD1和PHF8通过其脱甲基酶活性来促进Notch靶基因的表观遗传修饰。值得注意的是，当LSD1与CSL-阻遏物复合物关联时，它起核心抑制剂的作用，并且在Notch激活时起NOTCH1的共激活剂的作用。我们的工作为控制Notch转录活性的分子机制提供了新的见识，并代表了对NOTCH1相互作用态势的一瞥，这将有助于破译NOTCH1的功能和调控机制。

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