Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling
- 1Department of Pathology and Laboratory Medicine, College of Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
- 2Molecular Bioinformatics Core and the University of Tennessee Health Science Center Office of Research, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
- 3Department of Biochemistry and Biophysics, and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Abstract
Chromatin is dynamically regulated in response to nutrient flux to promote the transcriptional changes needed for adaptation. The mechanistic target of rapamycin complex 1 (yeast TORC1) kinase integrates nutrient signaling with chromatin regulation, yet whether chromatin signals back to regulate TORC1 remains unclear. We find that a histone H3 lysine 37 to alanine (H3K37A) mutant predicted to disrupt a histone-DNA contact promotes histone degradation, hyperactivates TORC1, and causes cytotoxicity upon TORC1 inhibition. This cytotoxicity is specific to H3K37A, since chromatin instability in wild-type histone H3 (H3WT) cells reduces histone abundance and hyperactivates TORC1 without cytotoxicity upon TORC1 inhibition. Combining H3K37A with these chromatin stability mutants exacerbates histone loss, TORC1 hyperactivity, and lethality during TORC1 inhibition. Transcriptome analysis indicates H3K37A deregulates mitochondrial retrograde signaling, which is exacerbated upon TORC1 inhibition and becomes cytotoxic due in part to defective mitochondrial import of an OXPHOS subunit. Retrograde inactivation, or neutralization of reactive oxygen species (ROS) prevents this toxicity. These findings identify chromatin stability as an upstream restraint on TORC1 signaling, revealing bidirectional communication between chromatin and a major nutrient-responsive pathway. They further show H3K37 has an additional functionality that prevents mitochondrial dysregulation during metabolic stress adaptation. Author summary: The cellular nutrient environment regulates gene expression by signaling through the TORC1 kinase to control chromatin structure and function. However, whether chromatin signals back to regulate TORC1 is unknown. We find that a histone H3 lysine 37 to alanine (H3K37A) mutant promotes histone degradation, hyperactivates TORC1, and causes cell death when TORC1 is inhibited. Surprisingly, in cells with wild-type histone H3 (H3WT), other chromatin-destabilizing mutations also reduce histone abundance and hyperactivate TORC1 without causing cytotoxicity upon TORC1 inhibition. The selective cytotoxic effect in H3K37A cells is linked to deregulated mitochondrial retrograde signaling upon TORC1 inhibition that impairs mitochondrial protein import and causes production of toxic mitochondrial reactive oxygen species (ROS). This H3K37A-dependent cell death is completely prevented by genetic inactivation of the mitochondrial retrograde pathway or by ROS neutralization. Collectively, we provide evidence that chromatin stability restrains TORC1 activity, revealing bidirectional communication between chromatin and a major nutrient-responsive pathway. These effects are separable from the selective cytotoxicity caused by H3K37A, indicating that H3K37 has an additional chromatin functionality required for mitochondrial homeostasis during metabolic stress adaptation.
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BibTeX
@article{sigamani2026chromatin,
title = {{Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling}},
author = {Vinoth Sigamani and Mohd Yousuf and Daniel L Johnson and Brian D Strahl and R Nicholas Laribee},
journal = {PLOS Genetics},
year = {2026},
month = oct,
doi = {10.1371/journal.pgen.1012330},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012330},
note = {CC BY},
}
RIS
TY - JOUR
TI - Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling
AU - Vinoth Sigamani
AU - Mohd Yousuf
AU - Daniel L Johnson
AU - Brian D Strahl
AU - R Nicholas Laribee
PY - 2026
DA - 2026/10/08
JO - PLOS Genetics
DO - 10.1371/journal.pgen.1012330
UR - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012330
AB - Chromatin is dynamically regulated in response to nutrient flux to promote the transcriptional changes needed for adaptation. The mechanistic target of rapamycin complex 1 (yeast TORC1) kinase integrates nutrient signaling with chromatin regulation, yet whether chromatin signals back to regulate TORC1 remains unclear. We find that a histone H3 lysine 37 to alanine (H3K37A) mutant predicted to disrupt a histone-DNA contact promotes histone degradation, hyperactivates TORC1, and causes cytotoxicity upon TORC1 inhibition. This cytotoxicity is specific to H3K37A, since chromatin instability in wild-type histone H3 (H3WT) cells reduces histone abundance and hyperactivates TORC1 without cytotoxicity upon TORC1 inhibition. Combining H3K37A with these chromatin stability mutants exacerbates histone loss, TORC1 hyperactivity, and lethality during TORC1 inhibition. Transcriptome analysis indicates H3K37A deregulates mitochondrial retrograde signaling, which is exacerbated upon TORC1 inhibition and becomes cytotoxic due in part to defective mitochondrial import of an OXPHOS subunit. Retrograde inactivation, or neutralization of reactive oxygen species (ROS) prevents this toxicity. These findings identify chromatin stability as an upstream restraint on TORC1 signaling, revealing bidirectional communication between chromatin and a major nutrient-responsive pathway. They further show H3K37 has an additional functionality that prevents mitochondrial dysregulation during metabolic stress adaptation. Author summary: The cellular nutrient environment regulates gene expression by signaling through the TORC1 kinase to control chromatin structure and function. However, whether chromatin signals back to regulate TORC1 is unknown. We find that a histone H3 lysine 37 to alanine (H3K37A) mutant promotes histone degradation, hyperactivates TORC1, and causes cell death when TORC1 is inhibited. Surprisingly, in cells with wild-type histone H3 (H3WT), other chromatin-destabilizing mutations also reduce histone abundance and hyperactivate TORC1 without causing cytotoxicity upon TORC1 inhibition. The selective cytotoxic effect in H3K37A cells is linked to deregulated mitochondrial retrograde signaling upon TORC1 inhibition that impairs mitochondrial protein import and causes production of toxic mitochondrial reactive oxygen species (ROS). This H3K37A-dependent cell death is completely prevented by genetic inactivation of the mitochondrial retrograde pathway or by ROS neutralization. Collectively, we provide evidence that chromatin stability restrains TORC1 activity, revealing bidirectional communication between chromatin and a major nutrient-responsive pathway. These effects are separable from the selective cytotoxicity caused by H3K37A, indicating that H3K37 has an additional chromatin functionality required for mitochondrial homeostasis during metabolic stress adaptation.
SN - 1553-7404
SN - 1553-7390
ER -