视黄酸诱导抗泛素化的RIP140/LSD1复合物以微调神经元分化中的Pax6基因。
Retinoic Acid Induces Ubiquitination-Resistant RIP140/LSD1 Complex to Fine-Tune Pax6 Gene in Neuronal Differentiation.
作者信息
Wu Cheng-Ying, Persaud Shawna D, Wei Li-Na
机构信息
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
出版信息
Stem Cells. 2016 Jan;34(1):114-23. doi: 10.1002/stem.2190. Epub 2015 Oct 9.
Abstract
Receptor-interacting protein 140 (RIP140) is a wide-spectrum coregulator for hormonal regulation of gene expression, but its activity in development/stem cell differentiation is unknown. Here, we identify RIP140 as an immediate retinoic acid (RA)-induced dual-function chaperone for LSD1 (lysine-specific demethylase 1). RIP140 protects LSD1's catalytic domain and antagonizes its Jade-2-mediated ubiquitination and degradation. In RA-induced neuronal differentiation, the increased RIP140/LSD1 complex is recruited by RA-elevated Pit-1 to specifically reduce H3K4me2 modification on the Pax6 promoter, thereby repressing RA-induction of Pax6. This study reveals a new RA-induced gene repressive mechanism that modulates the abundance, enzyme quality, and recruitment of histone modifier LSD1 to neuronal regulator Pax6, which provides a homeostatic control for RA induction of neuronal differentiation.
摘要
受体相互作用蛋白140（RIP140）是一种用于基因表达激素调节的广谱共调节因子，但其在发育/干细胞分化中的活性尚不清楚。在此，我们鉴定出RIP140是一种视黄酸（RA）即时诱导的赖氨酸特异性去甲基化酶1（LSD1）双功能伴侣蛋白。RIP140保护LSD1的催化结构域，并拮抗其Jade-2介导的泛素化和降解。在RA诱导的神经元分化过程中，RA上调的Pit-1招募增加的RIP140/LSD1复合物，以特异性降低Pax6启动子上的H3K4me2修饰，从而抑制RA对Pax6的诱导。这项研究揭示了一种新的RA诱导的基因抑制机制，该机制调节组蛋白修饰剂LSD1对神经元调节因子Pax6的丰度、酶质量和募集，为RA诱导的神经元分化提供了一种稳态控制。
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