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Non-histone protein acetylation: a regulatory role in cellular processes of inflammation, cellular metabolism, and striated muscle contraction.
AuthorRomanick, Samantha Sue
AdvisorFerguson, Bradley S.
Cell and Molecular Pharmacology and Physiology
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Lysine residues undergo diverse and reversible post-translational modifications. Lysine acetylation has traditionally been studied in the epigenetic regulation of nucleosomal histones that provides an important mechanism for regulating gene expression. However, recent proteomics studies have demonstrated that approximately 4,500 proteins can be acetylated in various tissues; the function of most of these remains unknown. Small molecule histone deacetylase (HDAC) inhibitors have demonstrated efficacy in different medical conditions, such as the treatment and reversal of heart failure, rodent models of inflammation, and are currently being used in clinical trials for certain cancers and muscular dystrophy. In this dissertation, we demonstrate a functional role of lysine acetylation in 1) a model of bovine mammary cell inflammation, 2) diet induced obesity-mediated cardiac remodeling, and 3) striated muscle contractility. Using bovine mammary epithelial (MAC‐T) cells stimulated with tumor necrosis factor α (TNF‐α) as a model for mammary cell inflammation, we report that inhibition of HDACs 1 and 2 (HDAC1/2) attenuated TNF‐α‐mediated inflammatory gene expression. Further suggesting that HDAC1/2‐specific inhibitors may prove efficacious for the treatment of bovine mastitis. Additionally, we examined the impact of obesity on protein lysine acetylation in the left ventricle of male c57BL/6J mice. We report that obesity significantly increased heart enlargement and fibrosis and mass spectral analysis identified 14 acetylated proteins significantly impacted by obesity, one being skeletal muscle alpha actin (ACTA1). Ingenuity Pathway Analysis® (IPA) further demonstrated that these proteins were involved in metabolic dysfunction and cardiac remodeling. These findings suggest a critical role for cardiac acetylation in obesity-mediated remodeling; this has the potential to elucidate novel targets that regulate cardiac pathology. Lastly, we investigated lysine acetylation of ACTA1 and its effects on actomyosin interactions in striated muscle contractility in vitro. We report that ACTA1 acetylation enhanced myosin binding and increased calcium sensitivity, suggesting that ACTA1 acetylation disrupts tropomyosin’s ability to inhibit myosin binding in the absence of calcium. Altogether, these data highlight acetylation as an additional posttranslational modification in the regulation of cellular processes of inflammation, cardiac remodeling and cellular metabolism, and striated muscle contractility.