Plasticity of gene expression in the nervous system by exposure to environmental odorants that inhibit HDACs

Reviewer #1 (Public Review):

Yamanaka et al.'s research investigates into the impact of volatile organic compounds (VOCs), particularly diacetyl, on gene expression changes. By inhibiting histone acetylase (HDACs) enzymes, the authors were able to observe changes in the transcriptome of various models, including cell lines, flies, and mice. The study reveals that HDAC inhibitors not only reduce cancer cell proliferation but also provide relief from neurodegeneration in fly Huntington's disease models. Although the findings are intriguing, the research falls short in providing a thorough analysis of the underlying mechanisms.

HDAC inhibitors have been previously shown to induce gene expression changes as well as control cell division and demonstrated to work on disease models. The authors demonstrate diacetyl as a prominent HDAC inhibitor. Though the demonstration of diacetyl is novel, several similar molecules have been used before.

Reviewer #2 (Public Review):

Sachiko et al. study presents strong evidence that implicates environmental volatile odorants, particularly diacetyl, in an alternate role as an inhibitors HDAC proteins and gene expression. HDACs are histone deacetylases that generally have repressive role in gene expression. In this paper the authors test the hypothesis that diacetyl, which is a compound emitted by rotting food sources, can diffuse through blood-brain-barrier and cell membranes to directly modulate HDAC activity to alter gene expression in a neural activity independent manner. This work is significant because the authors also link modulation of HDAC activity by diacetyl exposure to transcriptional and cellular responses to present it as a potential therapeutic agent for neurological diseases, such as inhibition of neuroblastoma and neurodegeneration.

The authors first demonstrate that exposure to diacetyl, and some other odorants, inhibits deacetylation activity of specific HDAC proteins using in vitro assays, and increases acetylation of specific histones in cultured cells. Consistent with a role for diacetyl in HDAC inhibition, the authors find dose dependent alterations in gene expression in different fly and mice tissues in response to diacetyl exposure. In flies they first identify a decrease in the expression of chemosensory receptors in olfactory neurons after exposure to diacetyl. Subsequently, they also observe large gene expression changes in the lungs, brain, and airways in mice. In flies, some of the gene expression changes in response to diacetyl are partially reversable and show an overlap with genes that alter expression in response to treatment with other HDAC inhibitors. Given the use of HDAC inhibitors as chemotherapy agents and treatment methods for cancers and neurodegenerative diseases, the authors hypothesize that diacetyl as an HDAC inhibitor can also serve similar functions. Indeed, they find that exposure of mice to diacetyl leads to a decrease in the brain expression of many genes normally upregulated in neuroblastomas, and selectively inhibited proliferation of cell lines which are driven from neuroblastomas. To test the potential for diacetyl in treatment of neurodegenerative diseases, the authors use the fly Huntington's disease model, utilizing the overexpression of Huntingtin protein with expanded poly-Q repeats in the photoreceptor rhabdomeres which leads to their degeneration. Exposing these flies to diacetyl significantly decreases the loss of rhabdomeres, suggesting a potential for diacetyl as a therapeutic agent for neurodegeneration.

The findings are very intriguing and highlight environmental chemicals as potent agents which can alter gene expression independent of their action through chemosensory receptors.