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Results reveal that the retinoid receptors interaction with circulating hormonal signals MOP4 and CLOCK causes retinoic acid phase shifts in Per2 mRNA and in the smooth muscle cells, leading to a nuclear receptor-mediated hormonal signaling for regulating a peripheral clock in the vasculature.

Research demonstrates the role of inhibitor of acetyltransferases complex (INHAT) in blocking acetylation of histones by binding to histone and preventing access to acetyl transferase substrae. Data show that a multiprotein cellular complex inhibits the histone acetyltransferase activity of p300/CBP and PCAF.

UHRF1 is a key regulator in DNA methylation maintenance. It binds histone H3K9me2/3 and hemi-methylated DNA and recruits DNMT1 to DNA replication forks during S phase. However, the regulatory mechanism of hemi-methylated DNA binding activity of UHRF1 remains unknown. In this study, we reveal that acetylation of UHRF1 is regulated by PCAF and HDAC1. We show that UHRF1 acetylation at K490 attenuates its binding affinity to hemi-methylated DNA. We analyze genome-wide DNA methylation and gene-expression patterns using stable cell lines and discover that cells where the endogenous UHRF1 is replaced with an acetyl-mimetic (UHRF1 K490Q) mutant show deficiencies in inherited DNA methylation and show different gene-expression patterns in genes related to cell survival. These results reveal that precise regulation of UHRF1 acetylation is required to maintain DNA methylation during cell division and control cell survival. • Acetylation of UHRF1 is regulated by PCAF and HDAC1 • PCAF-mediated UHRF1 acetylation disrupts its hemi-methylated DNA binding • Deacetylation by HDAC1 is required for chromatin association of UHRF1 during S phase • Deregulation of UHRF1 acetylation impedes the inheritance of global DNA methylation Hahm et al. describe a regulatory mechanism of UHRF1 in DNA methylation maintenance. UHRF1 acetylation by PCAF at lysine 490 disrupts the binding affinity of UHRF1 to hemi-methylated DNA in nascent DNA. These findings suggest that fine-tuned acetylation of UHRF1 is essential for inheritance of epigenomic information. [ABSTRACT FROM AUTHOR]

Clonorchis sinensis is a carcinogenic human liver fluke. Its infection promotes persistent oxidative stress and chronic inflammation environments in the bile duct and surrounding liver tissues owing to direct contact with worms and their excretory–secretory products (ESPs), provoking epithelial hyperplasia, periductal fibrosis, and cholangiocarcinogenesis. We examined the reciprocal regulation of two ESP-induced redox-active proteins, NF-κB and peroxiredoxin 6 (Prdx6), during C. sinensis infection. Prdx6 overexpression suppressed intracellular free-radical generation by inhibiting NADPH oxidase2 and inducible nitric oxide synthase activation in the ESP-treated cholangiocarcinoma cells, substantially attenuating NF-κB-mediated inflammation. NF-κB overexpression decreased Prdx6 transcription levels by binding to two κB sites within the promoter. This transcriptional repression was compensated for by other ESP-induced redox-active transcription factors, including erythroid 2-related factor 2 (Nrf2), hypoxia inducible factor 1α (HIF1α), and CCAAT/enhancer-binding protein β (C/EBPβ). Distribution of immunoreactive Prdx6 and NF-κB was distinct in the early stages of infection in mouse livers but shared concomitant localization in the later stages. The intensity and extent of their immunoreactive staining in infected mouse livers are proportional to lesion severity and infection duration. The constitutive elevations of Prdx6 and NF-κB during C. sinensis infection may be associated with more severe persistent hepatobiliary abnormalities mediated by clonorchiasis. [ABSTRACT FROM AUTHOR]

Skeletal muscle atrophy results from the net loss of muscular proteins and organelles and is caused by pathologic conditions such as nerve injury, immobilization, cancer, and other metabolic diseases. Recently, ubiquitination-mediated degradation of skeletal-muscle-specific transcription factors was shown to be involved in muscle atrophy, although the mechanisms have yet to be defined. Here we report that ret finger protein (RFP), also known as TRIM27, works as an E3 ligase in Pax7-induced degradation of MyoD. Muscle injury induced by sciatic nerve transection up-regulated RFP and RFP physically interacted with both Pax7 and MyoD. RFP and Pax7 synergistically reduced the protein amounts of MyoD but not the mRNA. RFP-induced reduction of MyoD protein was blocked by proteasome inhibitors. The Pax7-induced reduction MyoD was attenuated by RFP siRNA and by MG132, a proteasome inhibitor. RFPΔR, an RFP construct that lacks the RING domain, failed to reduce MyoD amounts. RFP ubiquitinated MyoD, but RFPΔR failed to do so. Forced expression of RFP, but not RFPΔR, enhanced Pax7-induced ubiquitination of MyoD, whereas RFP siRNA blocked the ubiquitination. Sciatic nerve injury-induced muscle atrophy as well the reduction in MyoD was attenuated in RFP knockout mice. Taken together, our results show that RFP works as a novel E3 ligase in the Pax7-mediated degradation of MyoD in response to skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

Abstract: Loss of gene function is implicated in the emergence of novel phenotypes during organism evolution. Here, we report the inactivation of the MSLNL gene encoding mesothelin-like protein in African great ape evolution. Human MSLNL has a nonsense mutation in exon 10 and two polymorphic mutations: a frameshift in exon 3 and a nonsense codon in exon 8. The gorilla gene also shows multiple deleterious mutations, including a premature stop codon, a deletion, and a splice site mutation. Molecular evolutionary analysis indicated relaxed selection pressure on MSLNL in African great ape lineages, which suggested that MSLNL might have become inactivated before the divergence of human, chimpanzee and gorilla. The mouse Mslnl gene is highly expressed in olfactory epithelium and moderately expressed in several other tissues. We propose that the loss of MSLNL may be associated with the evolution of the olfactory system in African great apes including human. [Copyright &y& Elsevier]

Abstract: Clonorchiasis is an infection associated with bile duct malignancy and subsequent development of cholangiocarcinoma. This disease is mainly caused by Clonorchis sinensis worms and their excretory–secretory products (ESP). However, the precise molecular mechanisms of carcinogenesis remain to be determined. Previously, we established differential gene expression profiles from microarrays containing 23,920 human genes of known function in a human cholangiocarcinoma cell line, HuCCT1, treated with ESP. Among the upregulated genes, we focused on minichromosome maintenance protein 7 (Mcm7), which is implicated in various cancer types, and analyzed transcriptional regulation mediated by ESP to further elucidate its role in cholangiocarcinoma development. Global histone acetylation levels were increased in ESP-treated cells, along with histone acetyltransferase (HAT) protein expression. Detailed promoter analysis using reporter and chromatin immunoprecipitation assays revealed that transcriptional activation of Mcm7 is mediated by HAT recruitment to the promoter region upon C. sinensis ESP treatment. These findings contribute to clarification of the intrinsic mechanism underlying the cellular carcinogenesis process stimulated by Mcm7 in C. sinensis-treated host cells. [Copyright &y& Elsevier]

Skeletal muscle differentiation is well regulated by a series of transcription factors. We reported previously that enhancer of polycombi (Epcl), a chromatin protein, can modulate skeletal muscle differentiation, although the mechanisms of this action have yet to be defined. Here we report that Epcl recruits both serum response factor (SRF) and p300 to induce skeletal muscle differentiation. Epcl interacted physically with SRF. Transfection of Epcl to myoblast cells potentiated the SRF-induced expression of skeletal muscle-specific genes as well as multinucleation. Proximal CArG box in the skeletal α-actin promoter was responsible for the synergistic activation of the promoter-luciferase. Epcl knockdown caused a decrease in the acetylation of histones associated with serum response element (SRE) of the skeletal a-actin promoter. The EpcFSRF complex bound to the SRE, and the knockdown of Epcl resulted in a decrease in SRF binding to the skeletal n-actin promoter. Epcl recruited histone acetyltransferase activity, which was potentiated by cotransfection with p300 but abolished by si-p300. Epcl directly bound to p300 in myoblast cells. Epc1[sup+/-]mice showed distortion of skeletal α-actin, and the isolated myoblasts from the mice had impaired muscle differentiation. These results suggest that Epcl is required for skeletal muscle differentiation by recruiting both SRF and p300 to the SRE of muscle-specific gene promoters. [ABSTRACT FROM AUTHOR]