School of Medicine Publications and Presentations
Document Type
Article
Publication Date
8-25-2022
Abstract
Macrophages (MФ) are an essential immune cell for defense and repair that travel to different tissues and adapt based on local stimuli. A critical factor that may govern their polarization is the cross-talk between metabolism and epigenetics. However, simultaneous measurements of metabolites, epigenetics, and proteins (phenotype) has been a major technical challenge. To address this, we have developed a novel triomics approach using mass spectrometry to comprehensively analyze metabolites, proteins, and histone modifications, in a single sample. To demonstrate this technique, we investigated the metabolic-epigenetic-phenotype axis following polarization of human blood-derived monocytes into either 'pro-inflammatory M1'- or 'anti-inflammatory M2-' MФs. We report here a complex relationship between arginine, tryptophan, glucose, and the citric acid cycle (TCA) metabolism, protein and histone post-translational modifications, and human macrophage polarization that was previously not described. Surprisingly, M1-MФs had globally reduced histone acetylation levels but high levels of acetylated amino acids. This suggests acetyl-CoA was diverted, in part, towards acetylated amino acids. Consistent with this, stable isotope tracing of glucose revealed reduced usage of acetyl-CoA for histone acetylation in M1-MФs. Furthermore, isotope tracing also revealed MФs uncoupled glycolysis from the TCA cycle, as evidenced by poor isotope enrichment of succinate. M2-MФs had high levels of kynurenine and serotonin which are reported to have immune-suppressive effects. Kynurenine is upstream of de novo NAD+ metabolism which is a necessary cofactor for Sirtuin-type histone deacetylases. Taken together, we demonstrate a complex interplay between metabolism and epigenetics that may ultimately influence cell phenotype.
Recommended Citation
Sowers, M. L., Tang, H., Singh, V. K., Khan, A., Mishra, A., Restrepo, B. I., Jagannath, C., & Zhang, K. (2022). Multi-OMICs analysis reveals metabolic and epigenetic changes associated with macrophage polarization. The Journal of biological chemistry, 102418. Advance online publication. https://doi.org/10.1016/j.jbc.2022.102418
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Publication Title
Journal of Biological Chemistry
DOI
10.1016/j.jbc.2022.102418
Academic Level
faculty
Mentor/PI Department
Office of Human Genetics
Comments
© 2022 The Authors. Published by Elsevier Inc. All rights reserved.