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

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. Competing Interest Statement S.K.M. receives research funding from Servier Pharmaceuticals. S.K.M. and K.G.A. are co-founders of Gliomet. Subject Area - Biochemistry (17681) - Bioengineering (13890) - Bioinformatics (41929) - Biophysics (21446) - Cancer Biology (18586) - Cell Biology (25492) - Clinical Trials (138) - Developmental Biology (13374) - Ecology (19897) - Epidemiology (2067) - Evolutionary Biology (24308) - Genetics (15606) - Genomics (22497) - Immunology (17736) - Microbiology (40385) - Molecular Biology (17175) - Neuroscience (88584) - Paleontology (666) - Pathology (2831) - Pharmacology and Toxicology (4822) - Physiology (7641) - Plant Biology (15149) - Synthetic Biology (4293) - Systems Biology (9822) - Zoology (2271)