The Swi3 protein plays a unique role in regulating respiration in eukaryotes.
The Swi3 protein plays a unique role in regulating respiration in eukaryotes.
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DOI：
10.1042/bsr20160083
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发表时间：
2016-07
影响因子：
4
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Lal S;Alam MM;Hooda J;Shah A;Cao TM;Xuan Z;Zhang L
Swi3是众所周知的SWI-SNF染色质重塑复合体的关键组成部分。在这里，我们发现了一种新的Swi3功能：Swi3及其哺乳动物同源物抑制氧气消耗，并且Swi3以氧依赖的方式调节有氧呼吸基因的表达。最近的实验证据越来越多地表明，细胞生物能量失调与一系列常见的人类疾病有关，包括癌症、神经系统疾病和糖尿病。呼吸为大多数真核细胞提供了重要的细胞能量来源，特别是高能量需求的细胞。然而，对呼吸如何在全球范围内受到调节的理解非常有限。有趣的是，最近的证据表明，Swi3是酵母呼吸基因的重要调节因子。在本报告中，我们进行了一系列生化和遗传实验以及计算分析，以直接评估Swi3及其人类同源物在调节呼吸中的功能。首先，我们通过计算分析和氧气消耗和启动子活性的测量表明，Swi3而不是Swi2调节与呼吸和氧气消耗有关的编码功能的基因。生化分析表明，与亲本细胞相比，Δswi3细胞中线粒体呼吸链复合物的水平显著增加。此外，我们的数据显示，Swi3强烈影响血红素/氧依赖的呼吸基因启动子的激活，而Swi2仅影响这些启动子的基础的、与血红素无关的活性。我们发现有氧表达基因的表达增加与空气中Δswi3细胞的氧气消耗和生长速率增加有关。此外，通过计算分析和RNAi敲除，我们发现哺乳动物Swi3 BAF155和BAF170调节HeLa细胞的呼吸。总之，这些实验和计算数据表明，Swi3及其哺乳动物同源物是调节呼吸的关键调节因子。
Swi3 is a key component of the well-known SWI–SNF chromatin remodelling complex. Here, we discovered a novel Swi3 function: Swi3 and its mammalian homologues suppress oxygen consumption, and Swi3 regulates the expression of aerobic respiration genes in an oxygen-dependent manner. Recent experimental evidence increasingly shows that the dysregulation of cellular bioenergetics is associated with a wide array of common human diseases, including cancer, neurological diseases and diabetes. Respiration provides a vital source of cellular energy for most eukaryotic cells, particularly high energy demanding cells. However, the understanding of how respiration is globally regulated is very limited. Interestingly, recent evidence suggests that Swi3 is an important regulator of respiration genes in yeast. In this report, we performed an array of biochemical and genetic experiments and computational analysis to directly evaluate the function of Swi3 and its human homologues in regulating respiration. First, we showed, by computational analysis and measurements of oxygen consumption and promoter activities, that Swi3, not Swi2, regulates genes encoding functions involved in respiration and oxygen consumption. Biochemical analysis showed that the levels of mitochondrial respiratory chain complexes were substantially increased in Δswi3 cells, compared with the parent cells. Additionally, our data showed that Swi3 strongly affects haem/oxygen-dependent activation of respiration gene promoters whereas Swi2 affects only the basal, haem-independent activities of these promoters. We found that increased expression of aerobic expression genes is correlated with increased oxygen consumption and growth rates in Δswi3 cells in air. Furthermore, using computational analysis and RNAi knockdown, we showed that the mammalian Swi3 BAF155 and BAF170 regulate respiration in HeLa cells. Together, these experimental and computational data demonstrated that Swi3 and its mammalian homologues are key regulators in regulating respiration.