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

Alex C. Sternisha; Haocheng Li; Kumar Gajendra; Yi Xiao; Xin Zhao; Jeffrey Isaac 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

doi:10.1126/science.adx8675

Synthetic BiologyScienceJul 16, 2026

Peer-reviewed journal article

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

Alex C. Sternisha iD, Haocheng Li iD, Kumar Gajendra, Yi Xiao iD, Xin Zhao, Jeffrey Isaac Traylor iD, Lei Guo iD, Ji Hyung Jun iD, Morgan Fleishman, Tracey Shipman iD, Vinesh T. Puliyappadamba iD, Pranita Kaphle iD, Qing Ouyang iD, Michael Schmidt iD, Diana D. Shi iD, Milan R. Savani iD, Alexander C.-Y. Tsai, Joyce H. Lee iD, Ruth Gordillo iD, Javier Garcia-Bermudez iD, Yoon Jung Kim iD, Shih-Chia Tso, Chad A. Brautigam iD, Lauren G. Zacharias iD, Thomas P. Mathews iD, , Samuel K. McBrayer iD

Abstract

Alpha-ketoglutarate (KG) is required for chromatin demethylation but mechanisms controlling KG abundance in the nucleus are poorly defined. Therefore, we designed a biosensor system to monitor this metabolite pool in human cells using an KG-responsive cyanobacterial transcription factor, NtcA. We then coupled this system with a genetic screen to identify genes that regulate KG in the nucleus, defining an inter-organelle pathway in which sequential mitochondrial activities of the GPT2 transaminase and SLC25A11 transporter supply nuclear KG. Using a mouse model of GPT2 deficiency, a human inborn error of metabolism, we found that this pathway controls chromatin methylation in the developing brain. Our work provides a tool to assess KG signaling to chromatin and a framework for leveraging forward genetics to study nuclear metabolite pools.

PDF DOI