Siavash K. Kurdistani

Background: Cells adapt to nutrient fluctuations through both signaling and epigenetic mechanisms. While amino acid (AA) deprivation is known to suppress protein synthesis via mTORC1 inactivation, the epigenetic pathways that support cellular adaptation and recovery remain poorly understood. We investigated how chromatin and transcriptional changes contribute to maintaining translational capacity during AA restriction and priming cells for growth upon AA repletion. Methods: Human cells were cultured under amino acid-replete or -depleted conditions, and global histone methylation levels were assessed by Western blotting and ChIP-seq. RNA-seq and chromatin-associated RNA-seq (chromRNA-seq) were used to evaluate gene expression and transcriptional output. Ribosome profiling and [³⁵S]-methionine/cysteine or O-propargyl-puromycin (OPP) incorporation assays measured protein synthesis. Functional contributions of SETD8 and MYC were tested through knockdown and overexpression experiments. Results: AA deprivation induced a selective, genome-wide loss of H4K20me1, particularly from gene bodies, and led to increased MYC expression and binding at promoter regions. These changes were most pronounced at genes encoding ribosomal proteins and translation initiation factors. Although overall protein synthesis declined during AA restriction, these cells showed increased translational capacity evidenced by accumulation of monomeric ribosomes and enhanced translation upon AA repletion. Loss of H4K20me1 was independent of mTORC1 signaling and partly driven by SETD8 protein downregulation. While MYC overexpression alone was insufficient to upregulate translation-related genes, its combination with SETD8 knockdown in nutrient-rich conditions was both necessary and sufficient to induce expression of these genes and enhance protein synthesis. Conclusions: Our findings reveal a chromatin-based mechanism by which cells integrate metabolic status with transcriptional regulation to adapt to amino acid limitation. Loss of H4K20me1 and increased MYC activity act in parallel to prime the translational machinery during AA deprivation, enabling rapid recovery of protein synthesis upon nutrient restoration. This mechanism may help explain how cells maintain competitive growth potential under fluctuating nutrient conditions and has implications for understanding MYC-driven cancer progression.

The discovery of histone H3 copper reductase activity provides a novel metabolic framework for understanding the functions of core histone residues, which, unlike N-terminal residues, have remained largely unexplored. We previously demonstrated that histone H3 cysteine 110 (H3C110) contributes to cupric (Cu ²⁺ ) ion binding and its reduction to the cuprous (Cu ¹⁺ ) form. However, this residue is absent in Saccharomyces cerevisiae , raising questions about its evolutionary and functional significance. Here, we report that H3C110 has been lost in many fungal lineages despite near-universal conservation across eukaryotes. Introduction of H3C110 into S. cerevisiae increased intracellular Cu ¹⁺ levels and ameliorated the iron homeostasis defects caused by inactivation of the Cup1 metallothionein or glutathione depletion. Enhanced histone copper reductase activity also extended replicative life span under oxidative growth conditions but reduced it under fermentative conditions. Our findings suggest that a trade-off between histone copper reductase activity, iron metabolism, and life span may underlie the loss or retention of H3C110 across eukaryotes.

Perez and Sarkies uncover histones as methyl group repositories in normal and cancer human cells, shedding light on an intriguing function of histone methylation in optimizing the cellular methylation potential independently of gene regulation.

The histone H3-H4 tetramer is a copper reductase enzyme, facilitating the production of cuprous (Cu ¹⁺ ) ions for distribution to copper-dependent enzymes. It was, however, unknown if this enzymatic activity occurred within nucleosomes. To investigate this, we obtained native nucleosomes from Saccharomyces cerevisiae using micrococcal nuclease digestion of chromatin in isolated nuclei and ion-exchange chromatographic purification. The purified nucleosomal fragments robustly reduced Cu ²⁺ to Cu ¹⁺ ions, with the optimal activity dependent on the presence of zinc ions. Mutation of the histone H3 histidine 113 (H3H113) residue at the active site substantially reduced the enzymatic activity of nucleosomes, underscoring the catalytic role of histone H3. Consistently, limiting zinc ions reduced intracellular Cu ¹⁺ levels and compromised growth, phenotypes that were mitigated by genetically enhancing the copper reductase activity of histone H3. These results indicate that yeast nucleosomes possess copper reductase activity, suggesting that the fundamental unit of eukaryotic chromatin is an enzyme complex.

Reduction of Cu ¹⁺ production by histone H3 restores cellular deficiencies caused by insufficient supply of iron-sulfur clusters.

Disruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. An underappreciated source of damage to Fe-S clusters are cuprous (Cu ¹⁺ ) ions. Since histone H3 enzymatically produces Cu ¹⁺ to support copper-dependent functions, we asked whether this activity could become detrimental to Fe-S clusters. Here, we report that histone H3-mediated Cu ¹⁺ toxicity is a major determinant of cellular Fe-S cluster quotient. Inadequate Fe-S cluster supply, either due to diminished assembly as occurs in Friedreich’s Ataxia or defective distribution, causes severe metabolic and growth defects in S. cerevisiae . Decreasing Cu ¹⁺ abundance, through attenuation of histone cupric reductase activity or depletion of total cellular copper, restored Fe-S cluster-dependent metabolism and growth. Our findings reveal a novel interplay between chromatin and mitochondria in Fe-S cluster homeostasis, and a potential pathogenic role for histone enzyme activity and Cu ¹⁺ in diseases with Fe-S cluster dysfunction. Teaser: Reduction of Cu ¹⁺ production by histone H3 restores cellular deficiencies caused by insufficient supply of iron-sulfur clusters.

Enzymatic activity of histones: Eukaryotic histones serve as structural elements to package DNA. However, they contain a copper-binding site for which the biological relevance is unknown. Copper homeostasis is critical for several fundamental eukaryotic processes, including mitochondrial respiration. Attar et al. hypothesized that histones may play a critical role in cellular copper utilization (see the Perspective by Rudolph and Luger). Using a multifaceted approach ranging from in vitro biochemistry to in vivo genetic and molecular analyses, they found that the histone H3-H4 tetramer is an oxidoreductase enzyme that catalyzes reduction of cupric ions, thereby providing biologically usable cuprous ions for various cellular processes. This work opens a new front for chromatin biology, with implications for eukaryotic evolution and human biology and disease. Science , this issue p. 59 ; see also p. 33

Some (re)programming notes on cancer: Epithelial cancers develop resistance to targeted therapies in a number of different ways. Several cancer types do so by undergoing phenotypic conversion to a highly aggressive cancer called small cell neuroendocrine carcinoma (SCNC). Whether distinct cancer types accomplish this “reprogramming” through the same mechanism has been unclear. Park et al. show that the same set of oncogenic factors transforms both normal lung and normal prostate epithelial cells into SCNCs that resemble clinical samples (see the Perspective by Kareta and Sage). This convergence of molecular pathways could potentially simplify the development of new therapies for SCNC, which is currently untreatable. Science , this issue p. 91 ; see also p. 30