A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin

IF 47.3 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2026-07-16 DOI:10.1126/science.adx8675

Alex C. Sternisha, Haocheng Li, Kumar Gajendra, Yi Xiao, Xin Zhao, Jeffrey I. Traylor, Lei Guo, Ji Hyung Jun, Morgan Fleishman, Tracey Shipman, Vinesh T. Puliyappadamba, Pranita Kaphle, Qing Ouyang, Michael Schmidt, Diana D. Shi, Milan R. Savani, Alexander C.-Y. Tsai, Joyce H. Lee, Ruth Gordillo, Javier Garcia-Bermudez, Yoon Jung Kim, Shih-Chia Tso, Chad A. Brautigam, Lauren G. Zacharias, Thomas P. Mathews, Lin Xu, John G. Doench, Vidyasagar Koduri, Kalil G. Abdullah, Michalis Agathocleous, Laura A. Banaszynski, Ralph J. DeBerardinis, Eric M. Morrow, Samuel K. McBrayer

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Abstract

The metabolite α-ketoglutarate (αKG) is required for chromatin demethylation, but mechanisms that control αKG abundance in the nucleus are poorly defined. We designed a biosensor to monitor this metabolite pool in human cells using an αKG-responsive cyanobacterial transcription factor, NtcA, and used it to identify genes that regulate αKG in the nucleus. We defined an interorganelle pathway in which sequential mitochondrial activities of glutamic-pyruvic transaminase 2 (GPT2) and the SLC25A11 transporter supply nuclear αKG. In a mouse model of GPT2 deficiency, an inborn error of metabolism, Gpt2 loss caused histone hypermethylation in the brain and dysregulated neurodevelopmental genes. Restoring αKG counteracted these changes and promoted mouse fitness. Our work provides a tool to directly monitor nuclear αKG and reveals nuclear αKG depletion as a key pathogenic mechanism underlying GPT2 deficiency.

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转录生物传感器揭示α-酮戊二酸向染色质信号传导的机制

代谢物α-酮戊二酸（αKG）是染色质去甲基化所必需的，但控制细胞核中αKG丰度的机制尚不清楚。我们设计了一种生物传感器来监测人类细胞中αKG-响应蓝藻转录因子NtcA的代谢物池，并利用它来鉴定细胞核中调节αKG的基因。我们定义了一个细胞器间通路，其中谷丙转氨酶2 （GPT2）和SLC25A11转运体的线粒体序列活性提供核αKG。在GPT2缺失（一种先天性代谢错误）的小鼠模型中，GPT2缺失导致大脑组蛋白超甲基化和神经发育基因失调。恢复αKG可以抵消这些变化，提高小鼠的适应性。我们的工作提供了直接监测核αKG的工具，揭示了核αKG缺失是GPT2缺乏的关键致病机制。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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