Miao Jiapei, Chong Shasha
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Curr Opin Genet Dev. 2025 Feb;90:102285. doi: 10.1016/j.gde.2024.102285. Epub 2024 Dec 3.
Eukaryotic transcription is a complex process regulated by transcription factors (TFs), coactivators, and RNA polymerase machineries, many of which contain sizable intrinsically disordered regions (IDRs). Many TFs activate transcription through multivalent IDR-IDR interactions. Optimal levels of such multivalent interactions associated with appropriate IDR concentrations, interaction strengths, or interaction valencies are required for effective transcriptional activation. The interaction selectivity of IDRs is crucial for the precise regulation of transcription, and this selectivity is dependent on the IDR sequences. Furthermore, IDRs modulate gene expression by bringing chromatin sites together to form transcriptionally active chromatin hubs. Mutations in IDRs may cause dysregulation of their multivalent interactions, contributing to diseases, including cancers and neurodegenerative disorders. Understanding the effects of IDR-related mutations on transcription control and genome organization opens new opportunities for developing targeted therapeutic strategies. In this review, we discuss recent reports documenting important functions of IDRs in transcriptional regulation and their implications for human health and disease.
真核生物转录是一个由转录因子（TFs）、共激活因子和RNA聚合酶机制调控的复杂过程，其中许多都包含相当大的内在无序区域（IDRs）。许多转录因子通过多价IDR-IDR相互作用激活转录。有效的转录激活需要与适当的IDR浓度、相互作用强度或相互作用价态相关的这种多价相互作用达到最佳水平。IDRs的相互作用选择性对于转录的精确调控至关重要，而这种选择性取决于IDR序列。此外，IDRs通过将染色质位点聚集在一起形成转录活性染色质枢纽来调节基因表达。IDRs中的突变可能导致其多价相互作用失调，从而引发包括癌症和神经退行性疾病在内的多种疾病。了解IDR相关突变对转录控制和基因组组织的影响为开发靶向治疗策略开辟了新机会。在本综述中，我们讨论了最近的报告，这些报告记录了IDRs在转录调控中的重要功能及其对人类健康和疾病的影响。
