bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2022‒05‒29
seven papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Cell Death Differ. 2022 May 25.
      Metabolic switch is critical for cell fate determination through metabolic functions, epigenetic modifications, and gene expression. However, the mechanisms underlying these alterations and their functional roles remain unclear. Here, we show that Plin2-mediated moderate lipid hydrolysis is critical for pluripotency of embryonic stem cells (ESCs). Upon exit from pluripotency, lipid droplet (LD)-associated protein Plin2 is recognized by Hsc70 and degraded via chaperone-mediated autophagy to facilitate LD mobilization. Enhancing lipid hydrolysis by Plin2 knockout promotes pluripotency exit, which is recovered by ATGL inhibition. Mechanistically, excessive lipid hydrolysis induces a dramatic lipidomic remodeling characterized by decreased cardiolipin and phosphatidylethanolamine, which triggers defects in mitochondrial cristae and fatty acid oxidation, resulting in reduced acetyl-CoA and histone acetylation. Our results reveal how LD mobilization is regulated and its critical role in ESC pluripotency, and indicate the mechanism linking LD homeostasis to mitochondrial remodeling and epigenetic regulation, which might shed light on development and diseases.
  2. Biochem Biophys Res Commun. 2022 May 13. pii: S0006-291X(22)00730-6. [Epub ahead of print]613 187-192
      Histone lysine crotonylation (Kcr) is a novel hydrophobic histone acylation modification, and we recently report its crucial roles in neural differentiation. However, it is still unclear how histone Kcr involve in early neural commitment. Here, we systematically investigate the H3K9cr landscapes during neuroectodermal differentiation of pluripotent P19 embryonal carcinoma cells (ECCs). We reveal that the genome-wide changes in H3K9cr favor neural fate specification, and identify potential co-factors binding H3K9cr. We also uncover that H3K9cr collaborates with H3K9ac to regulate gene expression changes. Our results provide novel insights into the epigenetic mechanisms underlying neural commitment.
    Keywords:  Epigenetics; Gene expression; H3K9cr; Histone crotonylation; Neural commitment
  3. Nat Metab. 2022 May 23.
      Regulatory T (Treg) cells are critical for maintaining immune homeostasis and preventing autoimmunity. Here, we show that the non-oxidative pentose phosphate pathway (PPP) regulates Treg function to prevent autoimmunity. Deletion of transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in Treg cells causes a fatal autoimmune disease in mice, with impaired Treg suppressive capability despite regular Treg numbers and normal Foxp3 expression levels. Mechanistically, reduced glycolysis and enhanced oxidative stress induced by TKT deficiency triggers excessive fatty acid and amino acid catabolism, resulting in uncontrolled oxidative phosphorylation and impaired mitochondrial fitness. Reduced α-KG levels as a result of reductive TCA cycle activity leads to DNA hypermethylation, thereby limiting functional gene expression and suppressive activity of TKT-deficient Treg cells. We also find that TKT levels are frequently downregulated in Treg cells of people with autoimmune disorders. Our study identifies the non-oxidative PPP as an integrator of metabolic and epigenetic processes that control Treg function.
  4. Oxid Med Cell Longev. 2022 ;2022 5216786
      Changes to macrophage polarization affect the local microenvironment of the placenta, resulting in pathological pregnancy diseases such as recurrent spontaneous abortion (RSA). Macrophages are in close contact with trophoblasts during placental development, and trophoblast-derived cytokines are important regulators of macrophage polarization and function. Histone acetylation can affect the expression and secretion of cytokines, and ATP citrate lyase (ACLY) is an important factor that regulates histone acetylation. The aim of this study was to investigate the effect of ACLY expression differences in trophoblast on macrophage polarization and its mechanism. Our data demonstrate that ACLY level in placental villi of patients with RSA is decreased, which may lead to the inhibition of histone acetylation in trophoblasts, thereby reducing the secretion of IL-10. Reduced IL-10 secretion activates endoplasmic reticulum stress in macrophages, thus inhibiting their M2 polarization.
  5. Sci Transl Med. 2022 May 25. 14(646): eabn4772
      Organic acidemias such as methylmalonic acidemia (MMA) are a group of inborn errors of metabolism that typically arise from defects in the catabolism of amino and fatty acids. Accretion of acyl-CoA species is postulated to underlie disease pathophysiology, but the mechanism(s) remain unknown. Here, we surveyed hepatic explants from patients with MMA and unaffected donors, in parallel with samples from various mouse models of methylmalonyl-CoA mutase deficiency. We found a widespread posttranslational modification, methylmalonylation, that inhibited enzymes in the urea cycle and glycine cleavage pathway in MMA. Biochemical studies and mouse genetics established that sirtuin 5 (SIRT5) controlled the metabolism of MMA-related posttranslational modifications. SIRT5 was engineered to resist acylation-driven inhibition via lysine to arginine mutagenesis. The modified SIRT5 was used to create an adeno-associated viral 8 (AAV8) vector and systemically delivered to mutant and control mice. Gene therapy ameliorated hyperammonemia and reduced global methylmalonylation in the MMA mice.
  6. J Cell Sci. 2022 May 27. pii: jcs.259811. [Epub ahead of print]
      Acetyl-CoA participates in post-translational modification of proteins, central carbon and lipid metabolism in several cell compartments. In mammals, the acetyl-CoA transporter 1 (AT1) facilitates the flux of cytosolic acetyl-CoA into the endoplasmic reticulum (ER), enabling the acetylation of proteins of the secretory pathway, in concert with dedicated acetyltransferases including NAT8. However, the implication of the ER acetyl-CoA pool in acetylation of ER-transiting proteins in Apicomplexa is unknown. We identify homologues of AT1 and NAT8 in Toxoplasma gondii and Plasmodium berghei. Proteome-wide analyses revealed widespread N-terminal acetylation marks of secreted proteins in both parasites. Such acetylation profile of N-terminally processed proteins was never observed so far in any other organisms. AT1 deletion resulted in a considerable reduction of parasite fitness. In P. berghei, AT1 is important for growth of asexual blood stages and production of female gametocytes and male gametocytogenesis impaling its requirement for transmission. In the absence of AT1, the lysine and N-terminal acetylation sites remained globally unaltered, suggesting an uncoupling between the role of AT1 in development and active acetylation occurring along the secretory pathway.
    Keywords:  Acetyl-CoA transporter; Acetylation; Endoplasmic Reticulum; Plasmodium berghei; Secretory pathway; Toxoplasma gondii
  7. Biochem Biophys Res Commun. 2022 May 13. pii: S0006-291X(22)00726-4. [Epub ahead of print]615 31-35
      Osteoblast cells tend to metabolize glucose to lactate via aerobic glycolysis during osteogenic differentiation. However, the function of lactate in this process is still elusive. As a newly discovered protein posttranslational modification, lactate-derived histone lactylation has been found to play important roles in gene regulation and have profound effects on diverse biological processes. Here, we found that the expression of lactate dehydrogenase A (LDHA), intracellular lactate, and histone lactylation levels were all gradually increased during osteogenic differentiation. Knockdown of LDHA impaired the formation of mineralized nodules and ALP activity. RNA-sequencing and subsequent validation experiments showed that JunB expression was decreased in LDHA knockdown cells. Mechanistically, knockdown of LDHA decreased histone lactylation mark enrichment on JunB promoter, and exogenous lactate treatment rescued this effect. Our study revealed a non-canonical function of lactate during osteogenic differentiation.
    Keywords:  Histone lactylation; LDHA; Lactate; Osteogenic differentiation