Erratum to: Detection of Differentially Expressed microRNAs in Serum of Pancreatic Ductal Adenocarcinoma Patients: miR-196a Could Be a Potential Marker for Poor Prognosis.

Dig Dis Sci. 2010 Sep 8;

Authors: Kong X, Du Y, Wang G, Gao J, Gong Y, Li L, Zhang Z, Zhu J, Jing Q, Qin Y, Li Z

PMID: 20824495 [PubMed - as supplied by publisher]

MiRNA Profile Associated with Replicative Senescence, Extended Cell Culture, and Ectopic Telomerase Expression in Human Foreskin Fibroblasts.

PLoS One. 2010;5(9):

Authors: Bonifacio LN, Jarstfer MB

Senescence is a highly regulated process that limits cellular replication by enforcing a G1 arrest in response to various stimuli. Replicative senescence occurs in response to telomeric DNA erosion, and telomerase expression can offset replicative senescence leading to immortalization of many human cells. Limited data exists regarding changes of microRNA (miRNA) expression during senescence in human cells and no reports correlate telomerase expression with regulation of senescence-related miRNAs. We used miRNA microarrays to provide a detailed account of miRNA profiles for early passage and senescent human foreskin (BJ) fibroblasts as well as early and late passage immortalized fibroblasts (BJ-hTERT) that stably express the human telomerase reverse transcriptase subunit hTERT. Selected miRNAs that were differentially expressed in senescence were assayed for expression in quiescent cells to identify miRNAs that are specifically associated with senescence-associated growth arrest. From this group of senescence-associated miRNAs, we confirmed the ability of miR-143 to induce growth arrest after ectopic expression in young fibroblasts. Remarkably, miR-143 failed to induce growth arrest in BJ-hTERT cells. Importantly, the comparison of late passage immortalized fibroblasts to senescent wild type fibroblasts reveals that miR-146a, a miRNA with a validated role in regulating the senescence associated secretory pathway, is also regulated during extended cell culture independently of senescence. The discovery that miRNA expression is impacted by expression of ectopic hTERT as well as extended passaging in immortalized fibroblasts contributes to a comprehensive understanding of the connections between telomerase expression, senescence and processes of cellular aging.

PMID: 20824140 [PubMed - in process]

A Negative Regulatory Loop between MicroRNA and Hox Gene Controls Posterior Identities in Caenorhabditis elegans.

PLoS Genet. 2010;6(9):

Authors: Zhao Z, Boyle TJ, Liu Z, Murray JI, Wood WB, Waterston RH

MicroRNAs (miRNAs) have been found to regulate gene expression across eukaryotic species, but the function of most miRNA genes remains unknown. Here we describe how the analysis of the expression patterns of a well-conserved miRNA gene, mir-57, at cellular resolution for every minute during early development of Caenorhabditis elegans provided key insights in understanding its function. Remarkably, mir-57 expression shows strong positional bias but little tissue specificity, a pattern reminiscent of Hox gene function. Despite the minor defects produced by a loss of function mutation, overexpression of mir-57 causes dramatic posterior defects, which also mimic the phenotypes of mutant alleles of a posterior Hox gene, nob-1, an Abd homolog. More importantly, nob-1 expression is found in the same two posterior AB sublineages as those expressing mir-57 but with an earlier onset. Intriguingly, nob-1 functions as an activator for mir-57 expression; it is also a direct target of mir-57. In agreement with this, loss of mir-57 function partially rescues the nob-1 allele defects, indicating a negative feedback regulatory loop between the miRNA and Hox gene to provide positional cues. Given the conservation of the miRNA and Hox gene, the regulatory mechanism might be broadly used across species. The strategy used here to explore mir-57 function provides a path to dissect the regulatory relationship between genes.

PMID: 20824072 [PubMed - in process]

Prediction of a gene regulatory network linked to prostate cancer from gene expression, microRNA and clinical data.

Bioinformatics. 2010 Sep 15;26(18):i638-i644

Authors: Bonnet E, Michoel T, Van de Peer Y

MOTIVATION: Cancer is a complex disease, triggered by mutations in multiple genes and pathways. There is a growing interest in the application of systems biology approaches to analyze various types of cancer-related data to understand the overwhelming complexity of changes induced by the disease. RESULTS: We reconstructed a regulatory module network using gene expression, microRNA expression and a clinical parameter, all measured in lymphoblastoid cell lines derived from patients having aggressive or non-aggressive forms of prostate cancer. Our analysis identified several modules enriched in cell cycle-related genes as well as novel functional categories that might be linked to prostate cancer. Almost one-third of the regulators predicted to control the expression levels of the modules are microRNAs. Several of them have already been characterized as causal in various diseases, including cancer. We also predicted novel microRNAs that have never been associated to this type of tumor. Furthermore, the condition-dependent expression of several modules could be linked to the value of a clinical parameter characterizing the aggressiveness of the prostate cancer. Taken together, our results help to shed light on the consequences of aggressive and non-aggressive forms of prostate cancer. AVAILABILITY: The complete regulatory network is available as an interactive supplementary web site at the following URL: http://bioinformatics.psb.ugent.be/webtools/pronet/ CONTACT: yves.vandepeer@psb.vib-ugent.be.

PMID: 20823333 [PubMed - in process]

Detection of genomic aberrations in molecularly defined Burkitt lymphoma by array-based high resolution single nucleotide polymorphism analysis.

Haematologica. 2010 Sep 7;

Authors: Scholtysik R, Kreuz M, Klapper W, Burkhardt B, Feller AC, Hummel M, Loeffler M, Rosolowski M, Schwaenen C, Spang R, Stein H, Thorns C, Trumper L, Vater I, Wessendorf S, Zenz T, Siebert R, Kuppers R

Background. For sporadic Burkitt lymphoma few genetic lesions are known besides the pathognomonic IG-MYC translocations. Design and Methods. Thirtynine molecularly-defined Burkitt lymphoma were analyzed with high-resolution single-nucleotide polymorphism chips for genomic imbalances and uniparental disomy. Imbalances were correlated to expression profiles and selected miRNA analysis. Translocations affecting the MYC locus were studied by fluoresence in situ hybridization. Results. We detected 528 copy number changes, defining 29 recurrently imbalanced regions. 518 regions of uniparental disomy were found, but these were rarely recurrent. Combined imbalance mapping and expression profiling revealed a profound correlation between copy number and expression. Several recurrent imbalances affected the MYC pathway: The miRNA-supercluster 17-92 was frequently gained and the transcription factor E2F2 was recurrently deleted. Molecular Burkitt lymphoma lacking MYC translocations showed MYC gains. Amplifications of the polymerase iota gene were associated with increased frequency of aberrant single nucleotide polymorphisms. Conclusions. The present findings suggest that uniparental disomies play no major role in the pathogenesis of Burkitt lymphoma, whereas some genes may contribute to Burkitt lymphoma development through gene dosage effects. Amplifications of the polymerase iota gene may be functionally linked with increased genomic alterations in Burkitt lymphoma. The pattern and rarity of chromosomal changes detectable even at the high resolution employed here, together with aberrations of genes regulating MYC activity, support that deregulation of the MYC pathway is the major force driving Burkitt lymphoma pathogenesis, but show that this deregulation is more complex than previously known.

PMID: 20823134 [PubMed - as supplied by publisher]

Differentially expressed microRNAs regulate plasmacytoid vs. conventional dendritic cell development.

Mol Immunol. 2010 Sep 3;

Authors: Kuipers H, Schnorfeil FM, Brocker T

microRNAs have emerged as a novel layer of regulation of cellular development and function, including cells of the immune system. microRNA expression profiles and function of several microRNAs have been elucidated in granulocyte macrophage colony-stimulating factor derived dendritic cells (GM-CSF DC). In this study we determined the microRNA expression profile from plasmacytoid DC (pDC) and conventional DC (cDC) generated in murine FMS-related tyrosine kinase 3 ligand (Flt3L) bone marrow culture. We observed distinct miRNA expression signatures in these two different DC subsets and found that pDC were closer related to CD4(+) T cells than to cDC. Expression of a selected subset of microRNAs was also compared between cDC and GM-CSF DC. Furthermore, we show that inhibition of two differentially expressed microRNAs, miR-221 and miR-222, during differentiation resulted in skewed pDC/cDC ratios. Among the confirmed or potential targets for miR-221 and miR-222 are c-Kit, p27(kip1) and E2-2. While c-Kit is expressed by DC progenitors and p27(kip1) is a cell cycle regulator, E2-2 does transcriptionally regulate pDC development. Our data demonstrate that microRNAs can influence Flt3-driven DC differentiation.

PMID: 20822813 [PubMed - as supplied by publisher]

MicroRNAs, epigenetics and disease.

Essays Biochem. 2010 Sep 20;48(1):165-85

Authors: Silahtaroglu A, Stenvang J

Epigenetics is defined as the heritable chances that affect gene expression without changing the DNA sequence. Epigenetic regulation of gene expression can be through different mechanisms such as DNA methylation, histone modifications and nucleosome positioning. MicroRNAs are short RNA molecules which do not code for a protein but have a role in post-transcriptional silencing of multiple target genes by binding to their 3' UTRs (untranslated regions). Both epigenetic mechanisms, such as DNA methylation and histone modifications, and the microRNAs are crucial for normal differentiation, development and maintenance of tissue-specific gene expression. These mechanisms also explain how cells with the same DNA content can differentiate into cells with different functions. Changes in epigenetic processes can lead to changes in gene function, cancer formation and progression, as well as other diseases. In the present chapter we will mainly focus on microRNAs and methylation and their implications in human disease, mainly in cancer.

PMID: 20822493 [PubMed - in process]

Epigenetic regulation of cell life and death decisions and deregulation in cancer.

Essays Biochem. 2010 Sep 20;48(1):121-46

Authors: Hajji N, Joseph B

For every cell, there is a time to live and a time to die. It is apparent that cell life and death decisions are taken by individual cells based on their interpretation of physiological or non-physiological stimuli, or their own self-assessment of internal damage or changes in their environment. Apoptosis or programmed cell death is a key regulator of physiological growth control and regulation of tissue homoeostasis. One of the most important advances in cancer research in recent years is the recognition that cell death, mostly by apoptosis, is crucially involved in the regulation of tumour formation and also critically determines treatment response. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. The study of epigenetic mechanisms in cancer, such as DNA methylation, histone modifications and microRNA expression, has revealed a plethora of events that contribute to the neoplastic phenotype through stable changes in the expression of genes critical to cell death pathways. A better understanding of the epigenetic molecular events that regulate apoptosis, together with the reversible nature of epigenetic aberrations, should contribute to the emergence of the promising field of epigenetic therapy.

PMID: 20822491 [PubMed - in process]

Non-Mendelian epigenetic heredity: gametic RNAs as epigenetic regulators and transgenerational signals.

Essays Biochem. 2010 Sep 20;48(1):101-6

Authors: Cuzin F, Rassoulzadegan M

Inheritance of epigenetic variations may account for a significant part of heritability in human and in mammalian models. Heritable epigenetic variations were reported in plants under the name 'paramutation' more than 50 years ago. Reports by E. Whitelaw and her colleagues and by our laboratory now describe a variety of situations resulting in epigenetic inheritance in mouse systems. In the three cases that we have analysed, a transcriptional increase is initiated by RNAs related to the locus, either microRNAs or transcript fragments. RNAs carried by the spermatozoon appear as the transgenerational signals responsible for paternal transmission. Extension from mouse models to human heredity, obviously speculative at present, is encouraged by the high load of RNA in human sperm.

PMID: 20822489 [PubMed - in process]