In nonhuman primates, we previously demonstrated that a maternal high-fat diet (MHFD) induces fetal nonalcoholic fatty liver disease (NAFLD) and alters the fetal metabolome. These changes are accompanied by altered acetylation of histone H3 (H3K14ac). However, the mechanism behind this alteration in acetylation remains unknown. As SIRT1 is both a lysine deacetylase and a crucial sensor of cellular metabolism, we hypothesized that SIRT1 may be involved in fetal epigenomic alterations. Here we show that in utero exposure to a MHFD, but not maternal obesity per se, increases fetal H3K14ac with concomitant decreased SIRT1 expression and diminished in vitro protein and histone deacetylase activity. MHFD increased H3K14ac and DBC1-SIRT1 complex formation in fetal livers, both of which were abrogated with diet reversal despite persistent maternal obesity. Moreover, MHFD was associated with altered expression of known downstream effectors deregulated in NAFLD and modulated by SIRT1 (e.g., PPARΑ, PPARG, SREBF1, CYP7A1, FASN, and SCD). Finally, ex vivo purified SIRT1 retains deacetylase activity on an H3K14ac peptide substrate with preferential activity toward acetylated histone H3; mutagenesis of the catalytic domain of SIRT1 (H363Y) abrogates H3K14ac deacetylation. Our data implicate SIRT1 as a likely molecular mediator of the fetal epigenome and metabolome under MHFD conditions.-Suter, M. A., Chen, A., Burdine, M. S., Choudhury, M., Harris, R. A., Lane, R. H., Friedman, J. E., Grove, K. L., Tackett, A. J., Aagaard, K. M. A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates.
"It is now well appreciated that the intra-uterine environment can induce heritable alterations that may be retained over generations (Aiken and Ozanne, 2014; Goodspeed et al., 2015; Ng et al., 2010). In non-human primates, a maternal high-fat diet supplemented with calorically dense treats leading to obesity has been shown to epigenetically alter chromatin structure in their progeny via SIRT1-mediated covalent modifications of histones (Aagaard-Tillery et al., 2008; Suter et al., 2012). "
"The metabolic and endocrine function of adipocytes correlates to the dynamics of adipocytes, that is, adipocyte size and numbers . Plasticity of the adipocytes seems to be dictated by chromatin remodeling and transcriptional networks in response to environmental effectors such as diet  . Currently, little is known about the regulatory role of dietary polyphenols on epigenetic remodeling in adipocytes. "
[Show abstract][Hide abstract] ABSTRACT: Chromatin remodeling is a key mechanism in adipocyte differentiation. However, it is unknown whether dietary polyphenols are epigenetic effectors for adiposity control. Ellagic acid (EA) is a naturally occurring polyphenol in numerous fruits and vegetables. Recently, EA-containing foods have been reported to reduce adiposity. In the present study, we sought to determine whether EA inhibits adipogenesis by modifying chromatin remodeling in human adipogenic stem cells (hASCs). qPCR microarray of chromatin modification enzymes revealed that 10 μmol/L of EA significantly inhibits histone deacetylase (HDAC) 9 down-regulation. In addition, EA was associated with up-regulation of HDAC activity and a marked reduction of histone acetylation levels. However, chemical inhibition of HDAC activity or depletion of HDAC9 by siRNA were not sufficient to reverse the anti-adipogenic effects of EA. Intriguingly, EA treatment was also associated with reduced histone 3 arginine 17 methylation levels (H3R17me2), implying the inhibitory role of EA in coactivator-associated arginine methyltransferase 1 (CARM) 1 activity during adipogenesis. Boosting CARM1 activity by delivering cell-penetrating peptides of CARM1 (CPP-CARM1) not only recovered H3R17me2, but also restored adipogenesis evidenced by H3 acetylation at lysine 9 (H3K9Ac), HDAC9 down-regulation, PPARγ expression, and triglyceride accumulation. Taken together, our data suggest that reduced CARM1 activity by EA results in a decrease of H3R17me2 levels, which may interrupt consecutive histone remodeling steps for adipocyte differentiation including histone acetylation and HDAC9 dissociation from chromatin. Our work provides the mechanistic insights into how EA, a polyphenol ubiquitously found in fruits and vegetables, attenuates human adipocyte differentiation by altering chromatin remodeling.
The Journal of nutritional biochemistry 09/2014; 25(9). DOI:10.1016/j.jnutbio.2014.04.008 · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Women are using estrogens for many purposes, such as to prevent pregnancy or miscarriage, or to treat menopausal symptoms. Estrogens also have been used to treat breast cancer which seems puzzling, since there is convincing evidence to support a link between high lifetime estrogen exposure and increased breast cancer risk. In this review, we discuss the findings that maternal exposure to the synthetic estrogen diethylstilbestrol during pregnancy increases breast cancer risk in both exposed mothers and their daughters. In addition, we review data regarding the use of estrogens in oral contraceptives and as postmenopausal hormone therapy and discuss the opposing effects on breast cancer risk based upon timing of exposure. We place particular emphasis on studies investigating how maternal estrogenic exposures during pregnancy increase breast cancer risk among daughters. New data suggest that these exposures induce epigenetic modifications in the mammary gland and germ cells, thereby causing an inheritable increase in breast cancer risk for multiple generations.
Journal of Mammary Gland Biology and Neoplasia 02/2013; 18(1). DOI:10.1007/s10911-013-9274-8 · 4.53 Impact Factor
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