bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2022‒12‒18
five papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Cell Chem Biol. 2022 Dec 01. pii: S2451-9456(22)00415-9. [Epub ahead of print]
      While it is well known that expression levels of metabolic enzymes regulate the metabolic state of the cell, there is mounting evidence that the converse is also true, that metabolite levels themselves can modulate gene expression via epigenetic modifications and transcriptional regulation. Here we focus on the one-carbon metabolic pathway, which provides the essential building blocks of many classes of biomolecules, including purine nucleotides, thymidylate, serine, and methionine. We review the epigenetic roles of one-carbon metabolic enzymes and their associated metabolites and introduce an interactive computational resource that places enzyme essentiality in the context of metabolic pathway topology. Therefore, we briefly discuss examples of metabolic condensates and higher-order complexes of metabolic enzymes downstream of one-carbon metabolism. We speculate that they may be required to the formation of transcriptional condensates and gene expression control. Finally, we discuss new ways to exploit metabolic pathway compartmentalization to selectively target these enzymes in cancer.
    Keywords:  cancer; chromatin; epigenetics; folate metabolism; metabolic condensates; nuclear condensates; nuclear metabolism; nucleotides; one-carbon metabolism; phase separation; purinergic signaling; transcription regulation; transcriptional condensates
  2. Cancers (Basel). 2022 Nov 29. pii: 5900. [Epub ahead of print]14(23):
      The commonly used therapeutic management of PC involves androgen deprivation therapy (ADT) followed by treatment with AR signaling inhibitors (ARSI). However, nearly all patients develop drug-resistant disease, with a median progression-free survival of less than 2 years in chemotherapy-naïve men. Acetyl-coenzyme A (acetyl-CoA) is a central metabolic signaling molecule with key roles in biosynthetic processes and cancer signaling. In signaling, acetyl-CoA serves as the acetyl donor for acetylation, a critical post-translational modification. Acetylation affects the androgen receptor (AR) both directly and indirectly increasing expression of AR dependent genes. Our studies reveal that PC cells respond to the treatment with ARSI by increasing expression of ATP-citrate lyase (ACLY), a major enzyme responsible for cytosolic acetyl-CoA synthesis, and up-regulation of acetyl-CoA intracellular levels. Inhibition of ACLY results in a significant suppression of ligand-dependent and -independent routes of AR activation. Accordingly, the addition of exogenous acetyl-CoA, or its precursor acetate, augments AR transcriptional activity and diminishes the anti-AR activity of ARSI. Taken together, our findings suggest that PC cells respond to antiandrogens by increasing activity of the acetyl-coA pathway in order to reinstate AR signaling.
    Keywords:  abiraterone; acetyl-coenzyme A; androgen receptor; enzalutamide; prostate cancer
  3. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01697-7. [Epub ahead of print]41(11): 111809
      The gut microbiota influences acetylation on host histones by fermenting dietary fiber into butyrate. Although butyrate could promote histone acetylation by inhibiting histone deacetylases, it may also undergo oxidation to acetyl-coenzyme A (CoA), a necessary cofactor for histone acetyltransferases. Here, we find that epithelial cells from germ-free mice harbor a loss of histone H4 acetylation across the genome except at promoter regions. Using stable isotope tracing in vivo with 13C-labeled fiber, we demonstrate that the microbiota supplies carbon for histone acetylation. Subsequent metabolomic profiling revealed hundreds of labeled molecules and supported a microbial contribution to host fatty acid metabolism, which declined in response to colitis and correlated with reduced expression of genes involved in fatty acid oxidation. These results illuminate the flow of carbon from the diet to the host via the microbiota, disruptions to which may affect energy homeostasis in the distal gut and contribute to the development of colitis.
    Keywords:  CP: Microbiology; colitis; epigenetics; fatty acid metabolism; histone acetylation; host-microbiota interactions
  4. BMC Genomics. 2022 Dec 12. 23(1): 823
      BACKGROUND: Embryonic and fetal development is very susceptible to the availability of nutrients that can interfere with the setting of epigenomes, thus modifying the main metabolic pathways and impacting the health and phenotypes of the future individual. We have previously reported that a 38% reduction of the methyl donor methionine in the diet of 30 female ducks reduced the body weight of their 180 mule ducklings compared to that of 190 ducklings from 30 control females. The maternal methionine-restricted diet also altered plasmatic parameters in 30 of their ducklings when compared to that of 30 ducklings from the control group. Thus, their plasma glucose and triglyceride concentrations were higher while their free fatty acid level and alanine transaminase activity were decreased. Moreover, the hepatic transcript level of 16 genes involved in pathways related to energy metabolism was significantly different between the two groups of ducklings. In the present work, we continued studying the liver of these newly hatched ducklings to explore the impact of the maternal dietary methionine restriction on the hepatic transcript level of 70 genes mostly involved in one-carbon metabolism and epigenetic mechanisms.RESULTS: Among the 12 genes (SHMT1, GART, ATIC, FTCD, MSRA, CBS, CTH, AHCYL1, HSBP1, DNMT3, HDAC9 and EZH2) identified as differentially expressed between the two maternal diet groups (p-value < 0.05), 3 of them were involved in epigenetic mechanisms. Ten other studied genes (MTR, GLRX, MTHFR, AHCY, ADK, PRDM2, EEF1A1, ESR1, PLAGL1, and WNT11) tended to be differently expressed (0.05 < p-value < 0.10). Moreover, the maternal dietary methionine restriction altered the number and nature of correlations between expression levels of differential genes for one-carbon metabolism and epigenetic mechanisms, expression levels of differential genes for energy metabolism, and phenotypic traits of ducklings.
    CONCLUSION: This avian model showed that the maternal dietary methionine restriction impacted both the mRNA abundance of 22 genes involved in one-carbon metabolism or epigenetic mechanisms and the mRNA abundance of 16 genes involved in energy metabolism in the liver of the newly hatched offspring, in line with the previously observed changes in their phenotypic traits.
    Keywords:  Avian; Differentially expressed genes; Duck; Methyl donor; Nutritional programming
  5. Int J Mol Sci. 2022 Nov 23. pii: 14564. [Epub ahead of print]23(23):
      For many years, it has been clear that a Western diet rich in saturated fats and sugars promotes an inflammatory environment predisposing a person to chronic cardiometabolic diseases. In parallel, the emergence of ketogenic diets, deprived of carbohydrates and promoting the synthesis of ketone bodies imitating the metabolic effects of fasting, has been shown to provide a possible nutritional solution to alleviating diseases triggered by an inflammatory environment. The main ketone body, β-hydroxybutyrate (BHB), acts as an alternative fuel, and also as a substrate for a novel histone post-translational modification, β-hydroxybutyrylation. β-hydroxybutyrylation influences the state of chromatin architecture and promotes the transcription of multiple genes. BHB has also been shown to modulate inflammation in chronic diseases. In this review, we discuss, in the pathological context of cardiovascular risks, the current understanding of how ketone bodies, or a ketogenic diet, are able to modulate, trigger, or inhibit inflammation and how the epigenome and chromatin remodeling may be a key contributor.
    Keywords:  cardiovascular diseases; histone PTMs; histone β-hydroxybutyrylation; ketone bodies