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

• 成果类型: Article
• 署名作者: Sternisha, Alex C.; Li, Haocheng; Gajendra, Kumar; Xiao, Yi; Zhao, Xin; Traylor, Jeffrey I.; Guo, Lei; Jun, Ji Hyung; Fleishman, Morgan; Shipman, Tracey; Puliyappadamba, Vinesh T.; Kaphle, Pranita; Ouyang, Qing; Schmidt, Michael; Shi, Diana D.; Savani, Milan R.; Tsai, Alexander C. -Y.; Lee, Joyce H.; Gordillo, Ruth; Garcia-Bermudez, Javier; Kim, Yoon Jung; Tso, Shih-Chia; Brautigam, Chad A.; Zacharias, Lauren G.; Mathews, Thomas P.; Xu, Lin; Doench, John G.; Koduri, Vidyasagar; Abdullah, Kalil G.; Agathocleous, Michalis; Banaszynski, Laura A.; DeBerardinis, Ralph J.; Morrow, Eric M.; McBrayer, Samuel K.
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Brown University; Brown University; Brown University; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Mass General Brigham; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adx8675
• 发表日期: 2026-07-16
• 页码: eadx8675
• 关键词: GLUTAMINE-SYNTHETASE; nuclear-localization; DEPENDENT HISTONE; NITROGEN CONTROL; motor-neurons; acetyl-coa; gene; mutations; differentiation; 2-OXOGLUTARATE

摘要

The metabolite alpha-ketoglutarate (alpha KG) is required for chromatin demethylation, but mechanisms that control alpha KG abundance in the nucleus are poorly defined. We designed a biosensor to monitor this metabolite pool in human cells using an alpha KG-responsive cyanobacterial transcription factor, NtcA, and used it to identify genes that regulate alpha KG 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 alpha KG. 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 alpha KG counteracted these changes and promoted mouse fitness. Our work provides a tool to directly monitor nuclear alpha KG and reveals nuclear alpha KG depletion as a key pathogenic mechanism underlying GPT2 deficiency.