The hypoxia response pathway promotes PEP carboxykinase and gluconeogenesis in C. elegans.
The hypoxia response pathway promotes PEP carboxykinase and gluconeogenesis in C. elegans.
复制标题
DOI：
10.1038/s41467-022-33849-x
复制
发表时间：
2022-10-18
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
活跃分裂的细胞，包括一些癌症，依靠有氧糖酵解而不是氧化磷酸化来产生能量，这种现象被称为瓦尔堡效应。缺氧诱导因子（HIF-1）是一种已知介导对缺氧（缺氧）的适应性反应的转录因子，其组成性激活是瓦尔堡效应的标志。HIF-1被认为促进糖酵解并抑制氧化磷酸化。在这里，我们反而表明HIF-1可以促进胚胎发生。利用多组学方法，我们揭示了在C.优雅我们在有氧条件下使用RNA-seq和ChIP-seq来分析缺乏EGL-9的突变体，EGL-9是HIF-1的关键负调节因子。我们整合这些方法，以确定超过200个基因的直接和功能上调的HIF-1，包括PEP羧激酶PCK-1，一种限速介质的新生血管。PCK-1通过HIF-1的这种激活促进了对氧化和缺氧应激的响应的存活。我们的工作确定了HIF-1在体内的功能性直接靶点，全面描述了生物体中HIF-1激活诱导的代谢组。缺氧反应通路可以对抗低氧可利用性引起的病理损伤。在这里，作者采用了多组学方法来显示该途径如何重新编程代谢，使其朝着再生的方向发展，以对抗氧化应激。
Actively dividing cells, including some cancers, rely on aerobic glycolysis rather than oxidative phosphorylation to generate energy, a phenomenon termed the Warburg effect. Constitutive activation of the Hypoxia Inducible Factor (HIF-1), a transcription factor known for mediating an adaptive response to oxygen deprivation (hypoxia), is a hallmark of the Warburg effect. HIF-1 is thought to promote glycolysis and suppress oxidative phosphorylation. Here, we instead show that HIF-1 can promote gluconeogenesis. Using a multiomics approach, we reveal the genomic, transcriptomic, and metabolomic landscapes regulated by constitutively active HIF-1 in C. elegans. We use RNA-seq and ChIP-seq under aerobic conditions to analyze mutants lacking EGL-9, a key negative regulator of HIF-1. We integrate these approaches to identify over two hundred genes directly and functionally upregulated by HIF-1, including the PEP carboxykinase PCK-1, a rate-limiting mediator of gluconeogenesis. This activation of PCK-1 by HIF-1 promotes survival in response to both oxidative and hypoxic stress. Our work identifies functional direct targets of HIF-1 in vivo, comprehensively describing the metabolome induced by HIF-1 activation in an organism. The hypoxia response pathway can counter pathological damage caused by low oxygen availability. Here the authors employ a multiomics approach to show how the pathway reprograms metabolism towards gluconeogenesis to combat oxidative stress.
登录
查看更多内容
影响因子：
14.9
作者：
de Bruin A;A Cornelissen PW;Kirchmaier BC;Mokry M;Iich E;Nirmala E;Liang KH;D Végh AM;Scholman KT;Groot Koerkamp MJ;Holstege FC;Cuppen E;Schulte-Merker S;Bakker WJ
通讯作者：
Bakker WJ
影响因子：
14.9
作者：
Benita Y;Kikuchi H;Smith AD;Zhang MQ;Chung DC;Xavier RJ
通讯作者：
Xavier RJ
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS
影响因子：
10.5
作者：
Iyer, NV;Kotch, LE;Semenza, GL
通讯作者：
Semenza, GL
影响因子：
21.3
作者：
LaGory EL;Giaccia AJ
通讯作者：
Giaccia AJ