Sirtuin 1 (SIRT1) is a class III histone deacetylase that deacetylates histone and nonhistone proteins to regulate gene transcription and protein function. Because SIRT1 regulates very diverse responses such as apoptosis, insulin sensitivity, autophagy, differentiation, and stem cell pluripotency, it has been a challenge to reconcile how it orchestrates such pleiotropic effects. Here we show that SIRT1 serves as an important regulator of Wnt signaling. We demonstrate that SIRT1 loss of function leads to a significant decrease in the levels of all three Dishevelled (Dvl) proteins. Furthermore, we demonstrate that SIRT1 and Dvl proteins complex in vivo and that inhibition of SIRT1 leads to changes in gene expression of Wnt target genes. Finally, we demonstrate that Wnt-stimulated cell migration is inhibited by a SIRT1 inhibitor. Because the three mammalian Dvl proteins serve as key messengers for as many as 19 Wnt ligands, SIRT1-mediated regulation of Dvl proteins may explain the diverse physiological responses observed in different cellular contexts. Previously, SIRT1 had only been shown to mediate the epigenetic silencing of Wnt antagonists. In contrast, here we report that SIRT1 regulates Dvl protein levels and Wnt signaling in several cellular contexts. These findings demonstrate that SIRT1 is a regulator of transient and constitutive Wnt signaling.+ -dependent histone deacetylase (HDAC) that regulates a very broad and complex array of physiological processes. As such, it has been the source of some controversy, as it has been difficult to reconcile the role it plays in the coordination of cellular responses and gene expression in both normal and pathophysiological settings. For example, SIRT1 has been shown to inhibit the maturation of preadipocytes (1, 2), antagonize p53-dependent apoptosis in response to stress (3, 4), and promote chemoresistance to conventional chemotherapeutic agents (5, 6), and is associated with microsatellite instability and CpG island methylator phenotype in human colorectal cancer (7). Furthermore, reports demonstrate that SIRT1 coordinates diverse metabolic responses to changes in nutrient availability (8), regulates autophagy (9), and controls key stages of spermatogenesis and germ stem cell proliferation and function (10, 11). Given the complex influence of SIRT1 on cell-fate decisions in multiple physiological settings, it is reasonable to anticipate that SIRT1 regulates one or more signaling networks recognized for their influence on these diverse cellular and organismal responses.It is well-established that Wnt signaling, likewise, regulates diverse processes such as adipogenesis (12), tumorigenesis (13), and stem cell pluripotency (14, 15). When Wnt ligands are present, they transmit signals through specific Frizzled (Fzd) or Fzd/LRP5/6 coreceptor complexes (16). This signal is then propagated via Dishevelled (Dvl) proteins that will direct canonical (β-catenindependent) or noncanonical (β-catenin-independent) signaling (17). Most of the mechanistic insights into Wnt signaling...

Methyl-CpG-binding protein-2 (MeCP2) regulates gene expression by recruiting SWI/SNF DNA helicase/ATPase (ATRX) and Histone Deacetylase-1 (HDAC1) to methylated gene regions and modulates heterochromatin association by interacting with Heterochromatin protein-1. As MeCP2 contributes to tumor suppressor gene silencing and its mutation causes Rett Syndrome, we investigated how novel post-translational-modification contributes to its function. Herein we report that upon pharmacological inhibition of SIRT1 in RKO colon and MCF-7 breast cancer cells, endogenous MeCP2 is acetylated at sites critical for binding to DNA and transcriptional regulators. We created an acetylation mimetic mutation in MeCP2 and found it to possess decreased binding to ATRX and HDAC1. Conditions inducing MeCP2 acetylation do not alter its promoter occupancy at a subset of target genes analyzed, but do cause decreased binding to ATRX and HDAC1. We also report here that a specific inhibitor of SIRT1, IV, can be used to selectively decrease H3K27me3 repressive marks on a subset of repressed target gene promoters analyzed. Lastly, we show that RKO cells over-expressing MeCP2 mutant show reduced proliferation compared to those over-expressing MeCP2-wildtype. Our study demonstrates the importance of acetylated lysine residues and suggests their key role in regulating MeCP2 function and its ability to bind transcriptional regulators.

Background Group B Streptococcus (GBS) remains a significant cause of neonatal infection, but the maternal risk factors for GBS colonization remain poorly defined. We hypothesized that there may be an association between antibiotic exposure during pregnancy and GBS colonization and/or the presence of inducible clindamycin resistance (iCLI-R) in GBS isolates from GBS-colonized pregnant women. Methods A retrospective cohort study was performed at Louisiana State University Health Sciences Center – Shreveport including demographic and clinical data from 1513 pregnant women who were screened for GBS between July 1, 2009 and December 31, 2010. Results Among 526 (34.8%) women who screened positive for GBS, 124 (23.6%) carried GBS strains with iCLI-R (GBS-iCLI-R). While antibiotic exposure, race, sexually-transmitted infection (STI) in pregnancy, GBS colonization in prior pregnancy and BMI were identified as risk factors for GBS colonization in univariate analyses, the only independent risk factors for GBS colonization were African–American race (AOR = 2.142; 95% CI = 2.092–3.861) and STI during pregnancy (AOR = 1.309; 95% CI = 1.035–1.653). Independent risk factors for GBS-iCLI-R among women colonized with GBS were non-African–American race (AOR = 2.13; 95% CI = 1.20–3.78) and younger age (AOR = 0.94; 95% CI = 0.91–0.98). Among GBS-colonized women with an STI in the current pregnancy, the only independent risk factor for iCLI-R was Chlamydia trachomatis infection (AOR = 4.31; 95% CI = 1.78–10.41). Conclusions This study identified novel associations for GBS colonization and colonization with GBS-iCLI-R. Prospective studies will improve our understanding of the epidemiology of GBS colonization during pregnancy and the role of antibiotic exposure in alterations of the maternal microbiome.

Cyclohexylamine appears to be a novel termiticide with a previously unreported mechanism of toxicity. Its hydrogen phosphate salts retain the toxic effect and are inexpensive and easily synthesized. © 2017 Society of Chemical Industry.

Tumorigenesis stems from errors incorporated in the genetic code and impaired epigenetic mechanisms involved in tumor suppression. Mutation in methyl-CpG-binding protein 2 (MeCP2) is known to cause a neurological disorder, rett syndrome (RTT), however its role in tumorigenesis remains poorly understood. We wanted to characterize how novel post-translational modifications might contribute to its function. MeCP2 regulates gene expression by recruiting co-repressors and histone deacetylases (such as HDAC1) to methylated gene promoters. MeCP2 modulates heterochromatin association by interacting with heterochromatin protein 1 (HP1). It was shown that MeCP2 interacts with and recruits ATRX, a SWI2/SNF2 DNA helicase/ATPase, to regulate gene expression at a subset of imprinted domains. A recent study showed that overexpression of Sirtuin1 (SIRT1) deacetylase leads to reduced levels of acetylation of ectopically expressed MeCP2. Using mass spectrometry, we report that upon pharmacological inhibition of SIRT1 in colon and breast cancer cell lines, endogenous MeCP2 is acetylated at key sites known to be critical for binding to DNA and transcriptional regulators. We mapped several novel acetylated sites and then created an acetylation mimetic mutation in MeCP2 (K171Q) and found that this mutant shows decreased binding to HDAC1 and ATRX in RKO cells. Similar results were obtained when SIRT1 was pharmacologically inhibited. Herein we show that conditions that induce MeCP2 acetylation in RKO cells do not alter its promoter occupancy at a subset of target genes analyzed but do cause a decreased binding to co-repressors such as HDAC1 and ATRX and also alters ATRX binding at a specific gene promoter. We also demonstrate that RKO cells over-expressing our acetylation mimetic mutant show reduced proliferation as compared to those over-expressing MeCP2-wild type (WT). Citation Format: Somnath Pandey, Glenn E. Simmons Jr., Svitlana Malyarchuk, Tara N. Calhoun, Kevin Pruitt. A novel MECP2 acetylation site regulates binding with ATRX and HDAC1. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A19.