The Swi-Snf chromatin remodeling complex mediates gene activation through metabolic control [ChIP-seq]

In eukaryotes, ATP-dependent chromatin remodelers regulate gene expression in response to nutritional and metabolic stimuli. The Swi-Snf complex is one such remodeler that has been implicated in disease, where loss of Swi-Snf function leads to dysregulated gene transcription. However, altered transcription of metabolic genes may have consequences for entire pathways that remain poorly understood. In this study, we use genetic and molecular approaches to uncover a role for Swi-Snf as a critical regulator of metabolism. We find that Δsnf mutants are cysteine-deficient, despite growth in nutrient-rich media. This cysteine deficiency causes widespread perturbations in sulfur metabolic gene transcription. This includes global alteration and redistribution of the transcription factor Met4 which senses cysteine deficiency and also has roles in heavy metal stress response and cell cycle progression. Additionally, we show that in its role as a metabolic regulator, Swi-Snf is a critical determinant of survival following oxidative stress. Our findings show how a chromatin remodeler can have a significant impact on a whole metabolic pathway by directly regulating an important gene subset and demonstrate an emerging role for chromatin remodeling complexes as key determinants of metabolic control.在真核生物（eukaryotes）中，ATP依赖型染色质重塑因子（ATP-dependent chromatin remodelers）可响应营养与代谢刺激调控基因表达。Swi-Snf复合物（Swi-Snf complex）即为这类重塑因子之一，其功能异常与疾病发生密切相关：Swi-Snf功能丧失会引发基因转录失调。然而，代谢基因转录的改变可能对整条代谢通路产生尚未被充分阐明的影响。本研究采用遗传与分子生物学方法，揭示了Swi-Snf作为代谢关键调控因子的作用。我们发现，尽管Δsnf突变体（Δsnf mutants）培养于营养丰富的培养基中，却呈现半胱氨酸缺陷表型。这种半胱氨酸缺陷会广泛扰动硫代谢基因的转录过程，包括感知半胱氨酸缺乏的转录因子Met4的全局表达改变与重新分布——该转录因子同时参与重金属应激响应与细胞周期进程调控。此外，我们证实，作为代谢调控因子的Swi-Snf是氧化应激（oxidative stress）后细胞存活的关键决定因素。本研究结果表明，染色质重塑因子（chromatin remodeler）可通过直接调控重要基因子集，对整条代谢通路产生显著影响，并揭示了染色质重塑复合物（chromatin remodeling complexes）作为代谢调控核心决定因子的新兴功能。