Motifs in the histone H3 and H4 and chromatin modifying factors are crucial to regulate the multifactorial zinc response pathway in Saccharomyces cerevisiae.

Zinc is a trace element that plays a crucial role in regulating various biological processes. To identify the factors involved in maintaining zinc homeostasis, we analysed the growth of histone mutants and gene deletions of chromatin-modifying factors. Growth assays revealed that specific regions and amino acid residues of histones H3 and H4, along with several chromatin-modifying factors, are essential for survival under zinc stress. Cells lacking certain motifs within H3 and H4 or in absence of chromatin modifiers exhibited hypersensitivity to zinc. ICP-MS analysis and fluorescence microscopy using a zinc-specific probe showed that zinc sensitive histone mutants accumulate higher zinc levels. The fluorescence microscopic analysis suggests that zinc sensitive mutants of chromatin modifying factors also contain more intracellular zinc. qRT-PCR analysis revealed that zinc-sensitive mutants exhibit upregulation of ZRT1, a high-affinity zinc transporter. Chromatin immunoprecipitation (ChIP) experiments further demonstrated constitutive recruitment of TBP at the ZRT1 promoter in zinc sensitive histone mutants in zinc untreated condition. Supplementation with amino acids, glutathione, and iron alleviated the zinc sensitivity, indicating a potential interplay between zinc toxicity and metabolic or redox imbalance. Notably, iron supplementation suppressed zinc-induced growth defects, implying disrupted iron homeostasis in the mutants. In summary, our findings provide evidence that specific regions of the H3 and H4 histones and chromatin-modifying factors are critical for regulating the cellular response to zinc. The mutations in histones and chromatin modifiers probably exhibit altered chromatin structure, leading to disruption in zinc metabolism.