TY - JOUR
T1 - Multi-OMICs analysis reveals metabolic and epigenetic changes associated with macrophage polarization
AU - Sowers, Mark L.
AU - Tang, Hui
AU - Singh, Vipul K.
AU - Khan, Arshad
AU - Mishra, Abhishek
AU - Restrepo, Blanca I.
AU - Jagannath, Chinnaswamy
AU - Zhang, Kangling
N1 - Funding Information:
The authors wish to acknowledge funding support from NIH RO1 AI-122070 (C. J.), AI-138587 (C. J.), AI-161015 and HMRI for support funds. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2022 The Authors
PY - 2022/10
Y1 - 2022/10
N2 - 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 crosstalk between metabolism and epigenetics. However, simultaneous measurements of metabolites, epigenetics, and proteins (phenotype) have 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 ‘proinflammatory M1-’ or ‘anti-inflammatory M2-’ MФs. We report here a complex relationship between arginine, tryptophan, glucose, and the citric acid cycle 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, toward 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 tricarboxylic acid 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 that 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.
AB - 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 crosstalk between metabolism and epigenetics. However, simultaneous measurements of metabolites, epigenetics, and proteins (phenotype) have 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 ‘proinflammatory M1-’ or ‘anti-inflammatory M2-’ MФs. We report here a complex relationship between arginine, tryptophan, glucose, and the citric acid cycle 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, toward 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 tricarboxylic acid 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 that 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.
KW - Macrophage, macrophage polarization, multiomics, histone modifications, epigenetics, metabolism and epigenetics, mass spectrometry
KW - Humans
KW - Epigenesis, Genetic
KW - Macrophages/metabolism
KW - Acetyl Coenzyme A/metabolism
KW - Cell Polarity/genetics
KW - Glucose/metabolism
KW - Kynurenine/metabolism
KW - Histones/genetics
UR - http://www.scopus.com/inward/record.url?scp=85138793533&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85138793533&partnerID=8YFLogxK
U2 - 10.1016/j.jbc.2022.102418
DO - 10.1016/j.jbc.2022.102418
M3 - Article
C2 - 36030823
AN - SCOPUS:85138793533
SN - 0021-9258
VL - 298
SP - 102418
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 10
M1 - 102418
ER -