A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin
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.
Authors
- Gajendra Kumar (ORCID: https://orcid.org/0000-0002-7437-6743)
- Alex Sternisha (ORCID: https://orcid.org/0000-0003-0771-6725)
- Eric M. Morrow (ORCID: https://orcid.org/0000-0003-3430-3520)
- Lei Guo (ORCID: https://orcid.org/0000-0002-1167-5463)
- Samuel K. McBrayer (ORCID: https://orcid.org/0000-0001-9361-675X)
- Michalis Agathocleous (ORCID: https://orcid.org/0000-0002-3427-1023)
- Ji Hyung Jun (ORCID: https://orcid.org/0000-0002-2563-4144)
- Milan R. Savani (ORCID: https://orcid.org/0000-0003-1776-451X)
- Jeffrey I. Traylor (ORCID: https://orcid.org/0000-0003-1749-8143)
- Diana D. Shi (ORCID: https://orcid.org/0000-0002-6626-5277)
- Thomas P. Mathews (ORCID: https://orcid.org/0000-0002-9355-8243)
- Ruth Gordillo (ORCID: https://orcid.org/0000-0001-6533-2493)
- Qing Ouyang (ORCID: https://orcid.org/0000-0001-8729-1290)
- John G. Doench (ORCID: https://orcid.org/0000-0002-3707-9889)
- M. Yu. Fleishman (ORCID: https://orcid.org/0000-0002-9337-2801)
- M Schmidt (ORCID: https://orcid.org/0000-0002-7990-033X)
- Laura A. Banaszynski (ORCID: https://orcid.org/0000-0002-5189-8848)
- Lauren G. Zacharias (ORCID: https://orcid.org/0009-0007-7413-6460)
- Vidyasagar Koduri (ORCID: https://orcid.org/0000-0002-9700-8169)
- Kalil G. Abdullah (ORCID: https://orcid.org/0000-0002-5662-0829)
- Yi Xiao (ORCID: https://orcid.org/0000-0002-3817-3471)
- Yoon Jung Kim (ORCID: https://orcid.org/0000-0002-2942-294X)
- Lin Xu (ORCID: https://orcid.org/0000-0002-2153-4840)
- Xin Zhao (ORCID: https://orcid.org/0000-0002-2001-1343)
- Joyce H. Lee (ORCID: https://orcid.org/0000-0003-4635-0199)
- Ralph J. DeBerardinis
- H. Li (ORCID: https://orcid.org/0009-0003-1487-5940)
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Children's Medical Center (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- University of Pittsburgh (US)
- Brown University (US)
- Massachusetts General Hospital (US)
- Southwestern Medical Center (US)
- Dana-Farber Cancer Institute (US)
- University of Pittsburgh Medical Center (US)
- Center for Cancer Research (US)
- Neurological Surgery (US)
- Massachusetts Institute of Technology (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Science
- Published
- 2026-07-16
- DOI
- https://doi.org/10.1126/science.adx8675
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Howard Hughes Medical Institute
- American Cancer Society
- Burroughs Wellcome Fund
- Pew Charitable Trusts
- Welch Foundation
- Human Frontier Science Program
- Cancer Prevention and Research Institute of Texas
- Sontag Foundation
- National Institutes of Health