A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin
Abstract
The metabolite α-ketoglutarate (αKG) is required for chromatin demethylation, but mechanisms that control αKG abundance in the nucleus are poorly defined. We designed a biosensor to monitor this metabolite pool in human cells using an αKG-responsive cyanobacterial transcription factor, NtcA, and used it to identify genes that regulate αKG 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 αKG. 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 αKG counteracted these changes and promoted mouse fitness. Our work provides a tool to directly monitor nuclear αKG and reveals nuclear αKG depletion as a key pathogenic mechanism underlying GPT2 deficiency.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (34)
Alex C. Sternisha
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Haocheng Li
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Kumar Gajendra
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.
Yi Xiao
Xin Zhao
Jeffrey I. Traylor
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Lei Guo
Quantitative Biomedical Research Center, Department of Health Science & Biostatistics, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Ji Hyung Jun
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Morgan Fleishman
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.
Tracey Shipman
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Vinesh T. Puliyappadamba
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Pranita Kaphle
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Qing Ouyang
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.
Michael Schmidt
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.
Diana D. Shi
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Milan R. Savani
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Alexander C.-Y. Tsai
Department of Radiation Oncology, Mass General Brigham, Harvard Medical School, Boston, MA, USA.
Joyce H. Lee
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Ruth Gordillo
Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Javier Garcia-Bermudez
Yoon Jung Kim
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Shih-Chia Tso
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Chad A. Brautigam
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Lauren G. Zacharias
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Thomas P. Mathews
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Lin Xu
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
John G. Doench
Vidyasagar Koduri
Division of Hematology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.
Kalil G. Abdullah
Department of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Michalis Agathocleous
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Laura A. Banaszynski
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Ralph J. DeBerardinis
Eric M. Morrow
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.
Samuel K. McBrayer