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