bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2022‒09‒04
four papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. J Biol Chem. 2022 Aug 25. pii: S0021-9258(22)00861-4. [Epub ahead of print] 102418
      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.
  2. Commun Biol. 2022 Aug 27. 5(1): 882
      Chromatin metabolism is frequently altered in cancer cells and facilitates cancer development. While cancer cells produce large amounts of histones, the protein component of chromatin packaging, during replication, the potential impact of histone density on cancer biology has not been studied systematically. Here, we show that altered histone density affects global histone acetylation, histone deactylase inhibitor sensitivity and altered mitochondrial proteome composition. We present estimates of nuclear histone densities in 373 cancer cell lines, based on Cancer Cell Line Encyclopedia data, and we show that a known histone regulator, HMGB1, is linked to histone density aberrations in many cancer cell lines. We further identify an E3 ubiquitin ligase interactor, DCAF6, and a mitochondrial respiratory chain assembly factor, CHCHD4, as histone modulators. As systematic characterization of histone density aberrations in cancer cell lines, this study provides approaches and resources to investigate the impact of histone density on cancer biology.
  3. Sci Adv. 2022 Sep 02. 8(35): eabq5206
      Nucleic acid and histone modifications critically depend on the tricarboxylic acid (TCA) cycle for substrates and cofactors. Although a few TCA cycle enzymes have been reported in the nucleus, the corresponding pathways are considered to operate in mitochondria. Here, we show that a part of the TCA cycle is operational also in the nucleus. Using 13C-tracer analysis, we identified activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes in the nuclei of HeLa cells. Proximity labeling mass spectrometry revealed a spatial vicinity of the involved enzymes with core nuclear proteins. We further show nuclear localization of aconitase 2 and 2-oxoglutarate dehydrogenase in mouse embryonic stem cells. Nuclear localization of the latter enzyme, which produces succinyl-CoA, changed from pluripotency to a differentiated state with accompanying changes in the nuclear protein succinylation. Together, our results demonstrate operation of an extended metabolic pathway in the nucleus, warranting a revision of the canonical view on metabolic compartmentalization.
  4. Front Oncol. 2022 ;12 969563
      The methionine cycle comprises a series of reactions that catabolizes and regenerates methionine. This process is crucial to many cellular functions, including polyamine synthesis, DNA synthesis, redox balance, and DNA and histone methylation. In response to antigens, T cells activate the methionine cycle to support proliferation and differentiation, indicating the importance of the methionine cycle to T cell immunity. In cancer, T cells serve as important effectors of adaptive immunity by directly killing cancerous cells. However, the tumor microenvironment can induce a state of T cell exhaustion by regulating the methionine metabolism of T cells, posing a barrier to both endogenous T cell responses and T cell immunotherapy. Here we review the role of methionine cycle metabolites in regulating the activation and effector function of T cells and explore the mechanism by which tumor cells exploit the methionine pathway as a means of immune evasion. Finally, we discuss new perspectives on reprogramming the methionine cycle of T cells to enhance anti-tumor immunotherapy.
    Keywords:  T cells; cancer; cancer immunotherapy; immunemetabolism; metabolism; the methionine cycle