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

Abstract Alpha-ketoglutarate (αKG) is required for chromatin demethylation but mechanisms controlling αKG abundance in the nucleus are poorly defined. Therefore, we designed a biosensor system to monitor this metabolite pool in human cells using an αKG-responsive cyanobacterial transcription factor, NtcA. We then coupled this system with a genetic screen to identify genes that regulate αKG in the nucleus, defining an inter-organelle pathway in which sequential mitochondrial activities of the GPT2 transaminase and SLC25A11 transporter supply nuclear αKG. 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 αKG signaling to chromatin and a framework for leveraging forward genetics to study nuclear metabolite pools.