The flip side of the coin: role of ZRF1 and histone H2A ubiquitination in transcriptional activation.

We have recently reported that the protein ZRF1 specifically binds to monoubiquitinated histone H2A and derepresses Polycomb target genes at the onset of cellular differentiation. Our results suggest that ZRF1 exerts its function in a two-step mechanism, by initially displacing the Polycomb-repressive complex 1 (PRC1) from chromatin and subsequently acting together with histone H2A-specific deubiquitinases to facilitate transcriptional activation of its target genes. These findings demonstrate an ambiguity of the epigenetic monoubiquitin mark at histone H2A.

Dynamics of epigenetic modifications in leukemia.

Chromatin modifications at both histones and DNA are critical for regulating gene expression. Mis-regulation of such epigenetic marks can lead to pathological states; indeed, cancer affecting the hematopoietic system is frequently linked to epigenetic abnormalities. Here, we discuss the different types of modifications and their general impact on transcription, as well as the polycomb group of proteins, which effect transcriptional repression and are often mis-regulated.

Transcriptional activation of polycomb-repressed genes by ZRF1.

Covalent modification of histones is fundamental in orchestrating chromatin dynamics and transcription. One example of such an epigenetic mark is the mono-ubiquitination of histones, which mainly occurs at histone H2A and H2B. Ubiquitination of histone H2A has been implicated in polycomb-mediated transcriptional silencing.

Hepatic cancer stem cells and drug resistance: Relevance in targeted therapies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of most common malignancies in the world. Systemic treatments for HCC, particularly for advanced stages, are limited by the drug resistance phenomenon which ultimately leads to therapy failure. Recent studies have indicated an association between drug resistance and the existence of the cancer stem cells (CSCs) as tumor initiating cells.

HDAC1, a novel marker for benign teratomas.

Histone deacetylases (HDACs) are attractive chemotherapy targets, owing to their pro-proliferative activities. However, the finding that loss of HDAC1 promotes teratoma malignancy calls for caution in the use of HDAC inhibitors as cancer therapeutics.

Is BaF3 bioassay useful to identify patients with bioinactive growth hormone?

We analyzed the ability of the BaF3 cell line bioassay to select patients with biologically inactive GH. We first evaluated the biological response of the Ba/F3-hGHR cells to rhGH additional doses from 10 to 5000 pg/ml. The concentration points corresponding to the linear part of the curve were selected.

A phosphorylation switch regulates the transcriptional activation of cell cycle regulator p21 by histone deacetylase inhibitors.

Histone deacetylase inhibitors induce cell cycle arrest and apoptosis in tumor cells and are, therefore, promising anti-cancer drugs. The cyclin-dependent kinase inhibitor p21 is activated in histone deacetylase (HDAC) inhibitor-treated tumor cells, and its growth-inhibitory function contributes to the anti-tumorigenic effect of HDAC inhibitors. We show here that induction of p21 by trichostatin A involves MAP kinase signaling.

Setting and resetting of epigenetic marks in malignant transformation and development.

Epigenetic modifications, such as DNA methylation and post-translation modifications of histones, have been shown to play an important role in chromatin structure, promoter activity, and cellular reprogramming. Large protein complexes, such as Polycomb and trithorax, often harbor multiple activities which affect histone tail modification. Nevertheless, the mechanisms underlying the deposition of these marks, their propagation during cell replication, and the alteration on their distribution during transformation still require further study.

Approaching the molecular and physiological function of macroH2A variants.

The transition of a cell from one state to another involves large changes in the organization of its chromatin. Indeed, it has become increasingly clear that modifications of the chromatin are the molecular basis of an epigenetic memory that defines cellular identity. Histone variants are likely candidates to contribute to epigenetic regulations.

Systematic review and meta-analysis on the adverse events of rimonabant treatment: considerations for its potential use in hepatology.

Background: The cannabinoid-1 receptor blockers have been proposed in the management of obesity and obesity-related liver diseases (fatty liver as NAFLD or NASH). Due to increasing number of patients to be potentially treated and the need to assess the advantage of this treatment in terms of risk/benefit, we analyze the side events reported during the treatment with rimonabant by a systematic review and meta-analysis of all randomized controlled studies.

Methods: All published randomized controlled trials using rimonabant versus placebo in adult subjects were retrieved.

The histone variant macroH2A is an epigenetic regulator of key developmental genes.

The histone variants macroH2A1 and macroH2A2 are associated with X chromosome inactivation in female mammals. However, the physiological function of macroH2A proteins on autosomes is poorly understood. Microarray-based analysis in human male pluripotent cells uncovered occupancy of both macroH2A variants at many genes encoding key regulators of development and cell fate decisions.

ERalpha as ligand-independent activator of CDH-1 regulates determination and maintenance of epithelial morphology in breast cancer cells.

Estrogen receptor alpha (ERalpha) and E-cadherin are primary markers of luminal epithelial breast cancer cells with E-cadherin being a main caretaker of the epithelial phenotype. E-cadherin repression is needed for cancer cells to acquire motile and invasive properties, and it is known that in ER-positive breast cancer cells, estrogen down-regulate E-cadherin gene transcription. We report here that ERalpha is bound to the E-cadherin promoter in both the presence and the complete absence of estrogen, suggesting an unexpected role for unliganded ERalpha in E-cadherin transcription.

MBD3, a component of the NuRD complex, facilitates chromatin alteration and deposition of epigenetic marks.

In plants, as in mammals, mutations in SNF2-like DNA helicases/ATPases were shown to affect not only chromatin structure but also global methylation patterns, suggesting a potential functional link between chromatin structure and epigenetic marks. The SNF2-like ATPase containing nucleosome remodeling and deacetylase corepressor complex (NuRD) is involved in gene transcriptional repression and chromatin remodeling. We have previously shown that the leukemogenic protein PML-RARa represses target genes through recruitment of DNA methytransferases and Polycomb complex.

Natural course of chronic HCV and HBV infection and role of alcohol in the general population: the Dionysos Study.

Background: Population-based studies of the natural course of chronic viral liver disease that consider comorbidity factors are lacking. Using data from the Dionysos Study, we quantified the burden of chronic viral liver disease and the role of alcohol intake to morbidity and mortality in a representative sample of subjects from the general population of two communities of Northern Italy.

Methods And Findings: We followed up 139 subjects with chronic hepatitis C virus (HCV) infection and 61 with chronic hepatitis B virus (HBV) infection for a median (IQR) time of 8.

K313dup is a recurrent CEBPA mutation in de novo acute myeloid leukemia (AML).

The CEBPA gene codes for a transcription factor that has a pivotal role in controlling proliferation and differentiation of myeloid progenitors. Acquired CEBPA mutations have been found in acute myeloid leukemias (AML) with a good prognosis, and most of these patients have a normal karyotype. In this paper, we report four cases that displayed the same K313dup in the CEBPA gene.

Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor.

The transcriptional factor Snail1 is a repressor of E-cadherin (CDH1) gene expression essential for triggering epithelial-mesenchymal transition. Snail1 represses CDH1, directly binding its promoter and inducing the synthesis of the Zeb1 repressor. In this article, we show that repression of CDH1 by Snail1, but not by Zeb1, is dependent on the activity of Polycomb repressive complex 2 (PRC2).

Elevated expression and polymorphisms of SOCS3 influence patient response to antiviral therapy in chronic hepatitis C.

Background: The response to antiviral therapy of chronic hepatitis C virus (HCV) infection is determined by virological, environmental and genetic factors.

Objective: The hypothesis was tested that the expression of specific genes and their haplotype frequencies can differentiate between non-responders (NRs) and sustained virological responders (SVRs) to antiviral treatment.

Methods: A methodological approach based on molecular marker discovery and validation was used to study the genes influencing the antiviral treatment in lymphoblastoid cell lines from 74 genotype 1b HCV patients (44 from Southern Italy and 30 from Northern Italy) treated with pegylated interferon (IFN) alpha and ribavirin.

Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination.

Methylation of histone H3 lysine 27 (H3K27) is a posttranslational modification that is highly correlated with genomic silencing. Here we show that human UTX, a member of the Jumonji C family of proteins, is a di- and trimethyl H3K27 demethylase. UTX occupies the promoters of HOX gene clusters and regulates their transcriptional output by modulating the recruitment of polycomb repressive complex 1 and the monoubiquitination of histone H2A.

Incidence and natural course of fatty liver in the general population: the Dionysos study.

Unlabelled: Using the general population of the Dionysos Study, we followed up 144 subjects without fatty liver (FL(-)) and 336 with fatty liver (FL(+)) for a median time of 8.5 years. All subjects had suspected liver disease (SLD) defined as altered liver enzymes, high mean corpuscular volume, or low platelet count in the absence of HBV and HCV infection.

Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: Insulin resistance and response to antiviral therapy.

Unlabelled: The response to antiviral therapy is lower in hepatitis C virus (HCV) patients with genotype 1 than in those with genotype 2. Overexpression of the suppressor of cytokine signaling 3 (SOCS3) gene in liver tissue is associated with a poorer treatment outcome in patients with chronic hepatitis C viral genotype 1. Also, insulin resistance has been implicated in nonresponse to an anti-HCV treatment.

Role of the polycomb repressive complex 2 in acute promyelocytic leukemia.

Epigenetic changes are common alterations in cancer cells. Here, we have investigated the role of Polycomb group proteins in the establishment and maintenance of the aberrant silencing of tumor suppressor genes during transformation induced by the leukemia-associated PML-RARalpha fusion protein. We show that in leukemic cells knockdown of SUZ12, a key component of Polycomb repressive complex 2 (PRC2), reverts not only histone modification but also induces DNA demethylation of PML-RARalpha target genes.

Subcellular localization of APE1/Ref-1 in human hepatocellular carcinoma: possible prognostic significance.

APE1/Ref-1, normally localized in the nucleus, is a regulator of the cellular response to oxidative stress. Cytoplasmic localization has been observed in several tumors and correlates with a poor prognosis. Because no data are available on liver tumors, we investigated APE1/Ref-1 subcellular localization and its correlation with survival in 47 consecutive patients undergoing hepatocellular carcinoma (HCC) resection.

Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia.

Alteration of lineage-specific transcriptional programs for hematopoiesis causes differentiation block and promotes leukemia development. Here, we show that AML1/ETO, the most common translocation fusion product in acute myeloid leukemia (AML), counteracts the activity of retinoic acid (RA), a transcriptional regulator of myelopoiesis. AML1/ETO participates in a protein complex with the RA receptor alpha (RARalpha) at RA regulatory regions on RARbeta2, which is a key RA target gene mediating RA activity/resistance in cells.