Laboratory of Transcription Biology, Molecular Genetics Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), Kolkata 700032, India.
Department of Endocrinology and Metabolism, Institute of Postgraduate Medical Education & Research (IPGM&R), Kolkata 700020, India.
Proc Natl Acad Sci U S A. 2020 Mar 24;117(12):6509-6520. doi: 10.1073/pnas.1912375117. Epub 2020 Mar 9.
Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis.
在所有超级延伸复合物 (SEC) 组件中，ELL1（也称为 ELL）是唯一真正的延伸因子，它可直接刺激 RNA 聚合酶 II 的转录延伸。然而，ELL1（以下称为 ELL）的功能调节机制（其稳定性）完全未知。在这里，我们报告了人类 DBC1 通过涉及 HDAC3、p300 和 Siah1 的功能来调节 ELL 稳定性的功能。从机制上讲，我们表明 p300 介导的特异性乙酰化增加，而 HDAC3 介导的去乙酰化减少，通过 E3 泛素连接酶 Siah1 的多泛素化增加 ELL 的稳定性。DBC1 与 HDAC3 竞争 ELL 上的相同结合位点，从而增加其乙酰化和稳定性。DBC1 的敲低会降低 ELL 水平和大量基因的表达，包括参与葡萄糖代谢的基因。一致地，2 型糖尿病患者来源的外周血单核细胞显示 DBC1 和 ELL 以及与葡萄糖稳态相关的关键靶基因的表达减少。因此，我们描述了一种调节关键延伸因子 ELL 的稳定性和功能的途径，用于表达包括与 2 型糖尿病发病机制相关的基因在内的各种基因。
