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Study Links Food Preservative to Newly Detected Histone Modification

NEW YORK (GenomeWeb) – Researchers from the University of Chicago, University of Hong Kong, and University of Georgia have identified a histone modification that can be introduced by the common food preservative sodium benzoate.

The team used a combination of proteomics, chromatin immunoprecipitation sequencing, RNA sequencing, and other approaches to uncover and describe lysine benzoylation: a histone mark that appears to influence the expression of some signaling and metabolic genes. The results, appearing online today in Nature Communications, indicated that the lysine benzoylation modification is regulated by the NAD+-dependent protein deacetylase enzyme SIRT2 and can induced by sodium benzoate.

"[O]ur study not only discovers an epigenetic and [post-translational modification] pathway but also sheds light on potential mechanisms for the physiological changes induced by [sodium benzoate]," senior author Yingming Zhao, a cancer researcher at the University of Chicago, and his colleagues wrote.

Prior studies have suggested that sodium benzoate is active in mammalian cells, the team noted. For example, the compound has been proposed as a potential treatment for urea cycle disorders such as acute hyperammonemia. The authors suspected that this activity might reflect epigenetic changes introduced by benzoyl-CoA, a metabolite that can come from sodium benzoate or from the degradation of compounds produced by some microbes.

To explore that possibility, the researchers began by using high-performance liquid chromatography and mass spectrometry to assess modifications on core histones from a human cell line. When the peptide patterns pointed to the presence of lysine benzoylation, they generated antibodies to detect the histone mark in human, mouse, and fruit fly cells.

The lysine benzoylation mark turned up at nearly two-dozen loci when the team did additional proteomic profiling on human and mouse cell lines. With the help of metabolic labeling, the investigators found that sodium benzoate can serve as a source of the benzoyl-CoA that gets incorporated into lysine benzoylation.

In their follow-up experiments, including ChIP-seq, ChIP-qPCR, and RNA-seq analyses, the researchers began teasing out lysine benzoylation dynamics in mammalian cell lines exposed to the sodium benzoate food additive, while tracking the histone mark's regulation by SIRT2 and its effects on transcriptional consequences.

On the gene expression side, for example, the team found that the presence of steroidogenesis peaks tended to coincide with shifts in the expression of insulin secretion genes and genes from phospholipase D signaling, glycerophospholipid metabolism, ovarian steroidogenesis, and serotonergic synapse pathways.

These and other findings "confirmed the correlation between histone [lysine benzoylation] dynamics and gene expression," the authors wrote, "supporting potential physiological relevance of histone [lysine benzoylation] and its role in the regulation of gene activity."