Author: Yamashita, Shohei ; Everett, Eric T. ; Shindo, Satoru ; Mendonca, Melanie ; Brueckner, Susanne ; Gill Dhillon, Navi ; Chang, Chang-Sheng Sam ; Kuriki, Nanako ; Kitamura, Eiko ; Suzuki, Maiko ; Kawai, Toshihisa ; Okamoto, Motoki ; Bartlett, John D. ; Fujiwara, Natsumi ; Cooley, Marion A.

Excessive fluoride ingestion during tooth development can cause dental fluorosis. Previously, we reported that fluoride activates histone acetyltransferase (HAT) to acetylate p53, promoting fluoride toxicity in mouse ameloblast-like LS8 cells. However, the roles of HAT and histone acetylation status in fluoride-mediated gene expression remain unidentified. Here, we demonstrate that fluoride-mediated histone modification causes gene expression alterations in LS8 cells. LS8 cells were treated with or without fluoride followed by ChIP-Seq analysis of H3K27ac. Genes were identified by differential H3K27ac peaks within ±1 kb from transcription start sites. The levels of mRNA of identified genes were assessed using rea-time PCR (qPCR). Fluoride increased H3K27ac peaks associated with Bax, p21, and Mdm2 genes and upregulated their mRNA levels. Fluoride decreased H3K27ac peaks and p53, Bad, and Bcl2 had suppressed transcription. HAT inhibitors (Anacardic acid or MG149) suppressed fluoride-induced mRNA of p21 and Mdm2, while fluoride and the histone deacetylase (HDAC) inhibitor sodium butyrate increased Bad and Bcl2 expression above that of fluoride treatment alone. To our knowledge, this is the first study that demonstrates epigenetic regulation via fluoride treatment via H3 acetylation. Further investigation is required to elucidate epigenetic mechanisms of fluoride toxicity in enamel development.

Scientific Reports

KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy

Article

Author: Plun-Favreau, Helene ; Esteras, Noemi ; Soutar, Marc P M ; de Talhouët, Capucine ; O'Callaghan, Benjamin

AbstractIt has recently been shown that KAT8, a genome-wide association study candidate risk gene for Parkinson’s Disease, is involved in PINK1/Parkin-dependant mitophagy. The KAT8 gene encodes a lysine acetyltransferase and represents the catalytically active subunit of the non-specific lethal epigenetic remodelling complex. In the current study, we show that contrary to KAT5 inhibition, dual inhibition of KAT5 and KAT8 via the MG149 compound inhibits the initial steps of the PINK1-dependant mitophagy process. More specifically, our study shows that following mitochondrial depolarisation induced by mitochondrial toxins, MG149 treatment inhibits PINK1-dependant mitophagy initiation by impairing PINK1 activation, and subsequent phosphorylation of Parkin and ubiquitin. While this inhibitory effect of MG149 on PINK1-activation is potent, MG149 treatment in the absence of mitochondrial toxins is sufficient to depolarise the mitochondrial membrane, recruit PINK1 and promote partial downstream recruitment of the autophagy receptor p62, leading to an increase in mitochondrial delivery to the lysosomes. Altogether, our study provides additional support for KAT8 as a regulator of mitophagy and autophagy processes.

100 Deals associated with MG-149

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Indication	Highest Phase	Country/Location	Organization	Date
Bladder Cancer	Preclinical	CN	Sun Yat-Sen University	06 Apr 2024
Malignant Pleural Mesothelioma	Preclinical	IE	St. Jamess Hospital Foundation Ltd.	30 Oct 2013

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