Related Experiment Video
Updated: Jun 19, 2026
Global Level Quantification of Histone Post-Translational Modifications in a 3D Cell Culture Model of Hepatic Tissue
Published on: May 5, 2022
Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells
Ana M Cervera1, Jean-Pierre Bayley, Peter Devilee
1Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. acervera@cnic.es
Abstract:
Remodelling of mitochondrial metabolism is a hallmark of cancer. Mutations in the genes encoding succinate dehydrogenase (SDH), a key Krebs cycle component, are associated with hereditary predisposition to pheochromocytoma and paraganglioma, through mechanisms which are largely unknown. Recently, the jumonji-domain histone demethylases have emerged as a novel family of 2-oxoglutarate-dependent chromatin modifiers with credible functions in tumourigenesis. Using pharmacological and siRNA methodologies we show that increased methylation of histone H3 is a general consequence of SDH loss-of-function in cultured mammalian cells and can be reversed by overexpression of the JMJD3 histone demethylase. ChIP analysis revealed that the core promoter of IGFBP7, which encodes a secreted protein upregulated after loss of SDHB, showed decreased occupancy by H3K27me3 in the absence of SDH. Finally, we provide the first evidence that the chief (type I) cell is the major methylated histone-immunoreactive constituent of paraganglioma. These results support the notion that loss of mitochondrial function alters epigenetic processes and might provide a signature methylation mark for paraganglioma.
Insights
Loss of succinate dehydrogenase (SDH) function in cells increases histone H3 methylation, a mark reversed by JMJD3. This epigenetic change is linked to paraganglioma development.
Area of Science:
- Biochemistry
- Epigenetics
- Oncology
Background:
- Mitochondrial metabolism remodelling is characteristic of cancer.
- Mutations in succinate dehydrogenase (SDH) are linked to pheochromocytoma and paraganglioma.
- Jumonji-domain histone demethylases are emerging chromatin modifiers in tumorigenesis.
Purpose of the Study:
- To investigate the epigenetic consequences of SDH loss-of-function.
- To explore the role of histone demethylases in SDH-deficient tumors.
- To identify potential epigenetic biomarkers for paraganglioma.
Main Methods:
- Pharmacological inhibition and siRNA knockdown of SDH in mammalian cells.
- Histone methylation analysis and chromatin immunoprecipitation (ChIP).
- Overexpression of JMJD3 histone demethylase.
Main Results:
- SDH loss-of-function leads to increased histone H3 methylation.
- JMJD3 overexpression reverses the methylation changes.
- Loss of SDHB results in decreased H3K27me3 at the IGFBP7 promoter.
- Chief (type I) cells are the primary methylated histone-immunoreactive cells in paraganglioma.
Conclusions:
- Loss of mitochondrial function due to SDH mutations impacts epigenetic regulation.
- Histone methylation alterations may serve as a diagnostic signature for paraganglioma.
- Epigenetic modifications are implicated in the pathogenesis of SDH-deficient tumors.
Related Concept Videos
02:32Histone Modification
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
02:32Histone Modification
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
02:25Spreading of Chromatin Modifications
Writers
The writer is an enzyme that can...
01:32Chromatin Modification in iPS Cells
Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone...
03:17Inheritance of Chromatin Structures
01:37Epigenetic Regulation
X-chromosome...