Browsing by Subject "Histone acetylation"

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    Evaluating the GCN5b bromodomain as a novel therapeutic target against the parasite Toxoplasma gondii
    (Elsevier, 2020-02-28) Hanquier, Jocelyne; Gimeno, Thomas; Jeffers, Victoria; Sullivan, William J., Jr.; Microbiology and Immunology, School of Medicine
    Toxoplasma gondii is a protozoan parasite of great importance in human and veterinary health. The frontline treatment of antifolates suffers a variety of drawbacks, including toxicity and allergic reactions, underscoring the need to identify novel drug targets for new therapeutics to be developed. We previously showed that the Toxoplasma lysine acetyltransferase (KAT) GCN5b is an essential chromatin remodeling enzyme in the parasite linked to the regulation of gene expression. We have previously established that the KAT domain is a liability that can be targeted in the parasite by compounds like garcinol; here, we investigate the potential of the bromodomain as a targetable element of GCN5b. Bromodomains bind acetylated lysine residues on histones, which helps stabilize the KAT complex at gene promoters. Using an inducible dominant-negative strategy, we found that the GCN5b bromodomain is critical for Toxoplasma viability. We also found that the GCN5-family bromodomain inhibitor, L-Moses, interferes with the ability of the GCN5b bromodomain to associate with acetylated histone residues using an in vitro binding assay. Moreover, L-Moses displays potent activity against Toxoplasma tachyzoites in vitro, which can be overcome if parasites are engineered to over-express GCN5b. Collectively, our data support the GCN5b bromodomain as an attractive target for the development of new therapeutics.
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    Imbalance between HDAC and HAT activities drives aberrant STAT1/MyD88 expression in macrophages from type 1 diabetic mice
    (Elsevier, 2017-02) Filgueiras, Luciano Ribeiro; Brandt, Stephanie L.; Oliveira Ramalho, Theresa Raquel de; Jancar, Sonia; Serezani, C. Henrique; Microbiology and Immunology, School of Medicine
    AIMS: To investigate the hypothesis that alteration in histone acetylation/deacetylation triggers aberrant STAT1/MyD88 expression in macrophages from diabetics. Increased STAT1/MyD88 expression is correlated with sterile inflammation in type 1 diabetic (T1D) mice. METHODS: To induce diabetes, we injected low-doses of streptozotocin in C57BL/6 mice. Peritoneal or bone marrow-differentiated macrophages were cultured in 5mM (low) or 25mM (high glucose). ChIP analysis of macrophages from nondiabetic or diabetic mice was performed to determine acetylation of lysine 9 in histone H3 in MyD88 and STAT1 promoter regions. Macrophages from diabetic mice were treated with the histone acetyltransferase inhibitor anacardic acid (AA), followed by determination of mRNA expression by qPCR. RESULTS: Increased STAT1 and MyD88 expression in macrophages from diabetic but not naive mice cultured in low glucose persisted for up to 6days. Macrophages from diabetic mice exhibited increased activity of histone acetyltransferases (HAT) and decreased histone deacetylases (HDAC) activity. We detected increased H3K9Ac binding to Stat1/Myd88 promoters in macrophages from T1D mice and AA in vitro treatment reduced STAT1 and MyD88 mRNA expression. CONCLUSIONS/INTERPRETATION: These results indicate that histone acetylation drives elevated Stat1/Myd88 expression in macrophages from diabetic mice, and this mechanism may be involved in sterile inflammation and diabetes comorbidities.