Epigenetic modifications and chromatin loop organization explain the different expression profiles of the Tbrg4, WAP and Ramp3 genes.
By admin | February 29, 2008
Montazer-Torbati MB, Hue-Beauvais C, Droineau S, Ballester M, Coant N, Aujean E, Petitbarat M, Rijnkels M, Devinoy E
Exp Cell Res (Mar 2008)
Whey Acidic Protein (WAP) gene expression is specific to the mammary gland and regulated by lactogenic hormones to peak during lactation. It differs markedly from the more constitutive expression of the two flanking genes, Ramp3 and Tbrg4. Our results show that the tight regulation of WAP gene expression parallels variations in the chromatin structure and DNA methylation profile throughout the Ramp3-WAP-Tbrg4 locus. Three Matrix Attachment Regions (MAR) have been predicted in this locus. Two of them are located between regions exhibiting open and closed chromatin structures in the liver. The third, located around the transcription start site of the Tbrg4 gene, interacts with topoisomerase II in HC11 mouse mammary cells, and in these cells anchors the chromatin loop to the nuclear matrix. Furthermore, if lactogenic hormones are present in these cells, the chromatin loop surrounding the WAP gene is more tightly attached to the nuclear structure, as observed after a high salt treatment of the nuclei and the formation of nuclear halos. Taken together, our results point to a combination of several epigenetic events that may explain the differential expression pattern of the WAP locus in relation to tissue and developmental stages.
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The Hsp90 molecular chaperone: an open and shut case for treatment.
By admin | February 25, 2008
Pearl LH, Prodromou C, Workman P
Biochem J (Mar 2008)
The molecular chaperone Hsp90 (90 kDa heat-shock protein) is a remarkably versatile protein involved in the stress response and in normal homoeostatic control mechanisms. It interacts with ‘client proteins’, including protein kinases, transcription factors and others, and either facilitates their stabilization and activation or directs them for proteasomal degradation. By this means, Hsp90 displays a multifaceted ability to influence signal transduction, chromatin remodelling and epigenetic regulation, development and morphological evolution. Hsp90 operates as a dimer in a conformational cycle driven by ATP binding and hydrolysis at the N-terminus. The cycle is also regulated by a group of co-chaperones and accessory proteins. Here we review the biology of the Hsp90 molecular chaperone, emphasizing recent progress in our understanding of structure-function relationships and the identification of new client proteins. In addition we describe the exciting progress that has been made in the development of Hsp90 inhibitors, which are now showing promise in the clinic for cancer treatment. We also identify the gaps in our current understanding and highlight important topics for future research.
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The power of the word may reside in the power of affect.
By admin | February 25, 2008
Panksepp J
Integr Psychol Behav Sci (Mar 2008)
This commentary on Dan Shanahan’s, A New View of Language, Emotion and the Brain, basically agrees with an emotion-based view of the evolutionary and developmental basis of language acquisition. It provides a supplementary neuroscience perspective that is more deeply affective and epigenetic in the sense that all claims about neocortically-based language modules need to be tempered by the existing genetic evidence as well as the robust neuroscience evidence that the cortex resembles random-access-memory space, a tabula rasa upon which epigenetic and learning processes create functional networks. The transition from non-linguistic creatures to linguistic ones may have required the conjunction of social-affective brain mechanisms, morphological changes in the articulatory apparatus, an abundance of cross-modal cortical processing ability, and the initial urge to communicate in coordinate prosodic gestural and vocal ways, which may have been more poetic and musical than current propositional language. There may be no language instinct that is independent of these evolutionary pre-adaptations.
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Cutting Edge: TGF-{beta}-Induced Expression of Foxp3 in T cells Is Mediated through Inactivation of ERK.
By admin | February 25, 2008
Luo X, Zhang Q, Liu V, Xia Z, Pothoven KL, Lee C
J Immunol (Mar 2008)
The peripheral induction of T regulatory cells can be accomplished by TGF-beta through an epigenetic regulation leading to the expression of Foxp3. However, the exact mechanism of such a TGF-beta-mediated action remains unclear. In the current study, we found that TGF-beta treatment of CD4(+)CD25(-) T cells during T cell activation led to a transient inhibition of the phosphorylation of ERK followed by the induction of Foxp3 expression in these cells. Direct treatment with a specific ERK inhibitor, UO126, during CD4(+)CD25(-) T cell activation also induced Foxp3 expression and conferred a suppressive function to the induced Foxp3(+) T cells. Furthermore, treatment of T cells with either TGF-beta or UO126 significantly down-regulated the expression of DNMTs, a reaction normally elicited by demethylation agents, such as 5-Aza-2′-deoxycytidine. These results indicate that the epigenetic regulation of TGF-beta-induced expression of Foxp3 may be mediated through the inactivation of ERK.
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Epigenetic regulation of telomerase in retinoid-induced differentiation of human leukemia cells.
By admin | February 25, 2008
Love WK, Berletch JB, Andrews LG, Tollefsbol TO
Int J Oncol (Mar 2008)
Changes in the promoter methylation of hTERT, the gene that encodes telomerase, a ribonucleoprotein responsible for replacing telomeric repeats, have been demonstrated in differentiating cells where hTERT is inhibited, suggesting epigenetic regulation of hTERT. All-trans retinoic acid (ATRA) induces differentiation in human leukemia cells and has had significant clinical success treating promyelocytic leukemia in what is termed ‘differentiation therapy’. It is thought that the inhibition of telomerase is a target of retinoids and is closely tied to the differentiated phenotype. This study demonstrates the epigenetic changes associated with ATRA-induced inhibition of telomerase activity, including the hypoacetylation and hypermethylation of the hTERT promoter. Further, we have found changes in the differential expression of the three DNA methyltransferases during ATRA-induced differentiation of HL60 human leukemia cells. These results suggest that alteration of DNA methylation may play a role in the activation of telomerase in cancer cells and that epigenetic mechanisms may represent a target for differentiation therapy mechanisms. We propose that epigenetic changes in the hTERT promoter represent a stable locking mechanism in the retionoid-induced suppression of telomerase acitivity.
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Lyl1 interacts with CREB1 and alters expression of CREB1 target genes.
By admin | February 25, 2008
San-Marina S, Han Y, Suarez Saiz F, Trus MR, Minden MD
Biochim Biophys Acta (Mar 2008)
The basic helix-loop-helix (bHLH) transcription factor family contains key regulators of cellular proliferation and differentiation as well as the suspected oncoproteins Tal1 and Lyl1. Tal1 and Lyl1 are aberrantly over-expressed in leukemia as a result of chromosomal translocations, or other genetic or epigenetic events. Protein-protein and protein-DNA interactions described so far are mediated by their highly homologous bHLH domains, while little is known about the function of other protein domains. Hetero-dimers of Tal1 and Lyl1 with E2A or HEB, decrease the rate of E2A or HEB homo-dimer formation and are poor activators of transcription. In vitro, these hetero-dimers also recognize different binding sites from homo-dimer complexes, which may also lead to inappropriate activation or repression of promoters in vivo. Both mechanisms are thought to contribute to the oncogenic potential of Tal1 and Lyl1. Despite their bHLH structural similarity, accumulating evidence suggests that Tal1 and Lyl1 target different genes. This raises the possibility that domains flanking the bHLH region, which are distinct in the two proteins, may participate in target recognition. Here we report that CREB1, a widely-expressed transcription factor and a suspected oncogene in acute myelogenous leukemia (AML) was identified as a binding partner for Lyl1 but not for Tal1. The interaction between Lyl1 and CREB1 involves the N terminal domain of Lyl1 and the Q2 and KID domains of CREB1. The histone acetyl-transferases p300 and CBP are recruited to these complexes in the absence of CREB1 Ser 133 phosphorylation. In the Id1 promoter, Lyl1 complexes direct transcriptional activation. We also found that in addition to Id1, over-expressed Lyl1 can activate other CREB1 target promoters such as Id3, cyclin D3, Brca1, Btg2 and Egr1. Moreover, approximately 50% of all gene promoters identified by ChIP-chip experiments were jointly occupied by CREB1 and Lyl1, further strengthening the association of Lyl1 with Cre binding sites. Given the newly recognized importance of CREB1 in AML, the ability of Lyl1 to modulate promoter responses to CREB1 suggests that it plays a role in the malignant phenotype by occupying different promoters than Tal1.
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Epigenetic analysis of the human alpha- and beta-globin gene clusters.
By admin | February 23, 2008
Fathallah H, Portnoy G, Atweh GF
Blood Cells Mol Dis ()
K562 erythroleukemia cells have been widely used as a model for the study of globin gene regulation. A number of agents have been shown to activate or suppress globin gene expression in these cells. However, the molecular effects of these agents on the epigenetic configuration of the alpha- and gamma-globin genes that encode HbF are not known. In this report, we investigated the relationship between globin expression and histone acetylation of the human alpha- and beta-globin clusters in the fetal erythroid environment of K562 cells. Our studies suggest that acetylation of histone H3 may be important in regulating developmental stage-specific expression of the different beta-like globin genes while acetylation of both histones H3 and H4 may be important for the regulation of tissue-specific expression of these genes. In contrast, acetylation of both histones H3 and H4 at the alpha-like globin promoters appears to be important for both developmental stage- and tissue-specific expression. Interestingly, butyrate-induced activation of alpha-globin gene expression in K562 cells is associated with significant increase in histone acetylation levels while TPA-induced inhibition is associated with decreased histone acetylation at its promoters. In contrast, changes in histone acetylation and DNA methylation do not appear to be important in the regulation of gamma-globin gene expression by the same agents. These data suggest that the butyrate-mediated induction of the fetal gamma-globin genes in K562 cells is not a direct result of its histone deacetylase inhibitor activity of butyrate on the chromatin of the gamma-globin promoters, while the induction of the alpha-globin genes could be a result of a direct effect of butyrate on chromatin at its promoters. This is another example of the important differences in the molecular mechanisms of regulation of the genes of the alpha- and beta-like globin clusters.
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Effects of early cigarette smoke exposure on early immune development and respiratory disease.
By admin | February 23, 2008
Prescott SL
Paediatr Respir Rev (Mar 2008)
Exposure to tobacco constituents during early development remains a common but avoidable toxic exposure, which has been clearly linked with decreased lung growth and subsequent wheezing illness. There is also now emerging evidence that tobacco smoke can influence early immune function. This includes alterations in cytokine production by the fetoplacental unit, as detected ex vivo in cord blood, as well as in patterns of fetal mononuclear cell responses in vitro. Recent studies also suggest that the newborns of smoking mothers have altered signalling through Toll-like receptors (TLRs) that are essential for innate microbial responses. This may be implicated in the increased predisposition to infection in exposed infants. TLR-mediated innate response pathways are also believed to be important in promoting regulatory pathways that inhibit allergic immune responses. However, although a number of studies have documented associations between early cigarette smoke exposure and subsequent allergic disease, this remains controversial. This review explores the consequences of smoking on these important aspects of early development, including potential mechanisms, interactions with predisposing asthma genes and a potential role in epigenetic regulation. Although parental smoking may not be the primary factor in the changing prevalence of asthma and respiratory disease, we propose that it is an important contributor, with significant potential to interact with other genetic factors and environmental risk factors to influence disease propensity.
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Lyl1 interacts with CREB1 and alters expression of CREB1 target genes.
By admin | February 23, 2008
San-Marina S, Han Y, Suarez Saiz F, Trus MR, Minden MD
Biochim Biophys Acta (Mar 2008)
The basic helix-loop-helix (bHLH) transcription factor family contains key regulators of cellular proliferation and differentiation as well as the suspected oncoproteins Tal1 and Lyl1. Tal1 and Lyl1 are aberrantly over-expressed in leukemia as a result of chromosomal translocations, or other genetic or epigenetic events. Protein-protein and protein-DNA interactions described so far are mediated by their highly homologous bHLH domains, while little is known about the function of other protein domains. Hetero-dimers of Tal1 and Lyl1 with E2A or HEB, decrease the rate of E2A or HEB homo-dimer formation and are poor activators of transcription. In vitro, these hetero-dimers also recognize different binding sites from homo-dimer complexes, which may also lead to inappropriate activation or repression of promoters in vivo. Both mechanisms are thought to contribute to the oncogenic potential of Tal1 and Lyl1. Despite their bHLH structural similarity, accumulating evidence suggests that Tal1 and Lyl1 target different genes. This raises the possibility that domains flanking the bHLH region, which are distinct in the two proteins, may participate in target recognition. Here we report that CREB1, a widely-expressed transcription factor and a suspected oncogene in acute myelogenous leukemia (AML) was identified as a binding partner for Lyl1 but not for Tal1. The interaction between Lyl1 and CREB1 involves the N terminal domain of Lyl1 and the Q2 and KID domains of CREB1. The histone acetyl-transferases p300 and CBP are recruited to these complexes in the absence of CREB1 Ser 133 phosphorylation. In the Id1 promoter, Lyl1 complexes direct transcriptional activation. We also found that in addition to Id1, over-expressed Lyl1 can activate other CREB1 target promoters such as Id3, cyclin D3, Brca1, Btg2 and Egr1. Moreover, approximately 50% of all gene promoters identified by ChIP-chip experiments were jointly occupied by CREB1 and Lyl1, further strengthening the association of Lyl1 with Cre binding sites. Given the newly recognized importance of CREB1 in AML, the ability of Lyl1 to modulate promoter responses to CREB1 suggests that it plays a role in the malignant phenotype by occupying different promoters than Tal1.
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Global DNA methylation is influenced by smoking behaviour.
By admin | February 23, 2008
Hillemacher T, Frieling H, Moskau S, Muschler MA, Semmler A, Kornhuber J, Klockgether T, Bleich S, Linnebank M
Eur Neuropsychopharmacol (Apr 2008)
The level of epigenetic DNA methylation is an important factor in the pathogenesis of various human diseases. As smoking may influence DNA methylation, we investigated the effect of smoking habits on global DNA methylation in 298 genomic DNA samples (73 fathers, 69 mothers and 156 offspring). We did not find a direct effect of smoking on global DNA methylation. However, there was an association of the offspring’s DNA methylation with paternal DNA methylation that was strongest if both had never smoked (R(2)(corr)=0.41, Beta=0.68, p=0.02) and completely vanished if the offspring smoked or had ever smoked. These findings suggest an association between smoking behaviour and global DNA methylation, which may be of importance for a wide range of diseases.
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Offspring of Women Exposed In Utero to Diethylstilbestrol (DES): A Preliminary Report of Benign and Malignant Pathology in the Third Generation.
By admin | February 23, 2008
Titus-Ernstoff L, Troisi R, Hatch EE, Hyer M, Wise LA, Palmer JR, Kaufman R, Adam E, Noller K, Herbst AL, Strohsnitter W, Cole BF, Hartge P, Hoover RN
Epidemiology (Mar 2008)
BACKGROUND:: Animal studies suggest that prenatal exposure to the synthetic estrogen diethylstilbestrol (DES) causes epigenetic changes that may be transmitted to the next generation. Specifically, these studies show an elevated incidence of reproductive tumors in the female offspring of prenatally-exposed mice. METHODS:: We assessed cancer and benign pathology diagnoses occurring in the offspring of women whose prenatal exposure to DES (or lack of exposure) was verified by medical record. Our data arose from 2 sources: the mothers’ reports of cancers occurring in 8216 sons and daughters, and pathology-confirmed cancers and benign diagnoses self-reported by a subset of 793 daughters. RESULTS:: Although statistical power is limited, our data are consistent with no overall increase of cancer in the sons or daughters of women exposed in utero to DES. Based on pathology-confirmed diagnoses reported by the daughters, we saw no association between DES and risk of benign breast disease or reproductive tract conditions. Based on 3 cases, the incidence of ovarian cancer was higher than expected in the daughters of women exposed prenatally to DES. CONCLUSIONS:: Our data do not support an overall increase of cancer risk in the sons or daughters of women exposed prenatally to DES, but the number of ovarian cancer cases was greater than expected. While preliminary, this finding supports continued monitoring of these daughters.
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Epigenetic memory loss in aging oligodendrocytes in the corpus callosum.
By admin | February 23, 2008
Shen S, Liu A, Li J, Wolubah C, Casaccia-Bonnefil P
Neurobiol Aging (Mar 2008)
In this study, we address the hypothesis that aging modifies the intrinsic properties of oligodendrocytes, the myelin-forming cells of the brain. According to our model, an “epigenetic memory” is stored in the chromatin of the oligodendrocyte lineage cells and is responsible for the maintenance of a mature phenotype, characterized by low levels of expression of transcriptional inhibitors. We report here an age-related decline of histone deacetylation and methylation, the molecular mechanisms responsible for the establishment and maintenance of this “epigenetic memory” of the differentiated state. We further show that lack of histone methylation and increased acetylation in mature oligodendrocytes are associated with global changes in gene expression, that include the re-expression of bHLH inhibitors (i.e. Hes5 and Id4) and precursor markers (i.e. Sox2). These changes characteristic of the “aging” oligodendrocytes can be recapitulated in vitro, by treating primary oligodendrocyte cultures with histone deacetylase inhibitors. Thus, we conclude that the “epigenetic memory loss” detected in white matter tracts of older mice induces global changes of gene expression that modify the intrinsic properties of aged oligodendrocytes and may functionally modulate the responsiveness of these cells to external stimuli.
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DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function.
By admin | February 23, 2008
Jin B, Tao Q, Peng J, Soo HM, Wu W, Ying J, Fields CR, Delmas AL, Liu X, Qiu J, Robertson KD
Hum Mol Genet (Mar 2008)
Genome-wide DNA methylation patterns are established and maintained by the coordinated action of three DNA methyltransferases (DNMTs), DNMT1, DNMT3A and DNMT3B. DNMT3B hypomorphic germline mutations are responsible for two-thirds of immunodeficiency, centromere instability, facial anomalies (ICF) syndrome cases, a rare recessive disease characterized by immune defects, instability of pericentromeric satellite 2-containing heterochromatin, facial abnormalities and mental retardation. The molecular defects in transcription, DNA methylation and chromatin structure in ICF cells remain relatively uncharacterized. In the present study, we used global expression profiling to elucidate the role of DNMT3B in these processes using cell lines derived from ICF syndrome and normal individuals. We show that there are significant changes in the expression of genes critical for immune function, development and neurogenesis that are highly relevant to the ICF phenotype. Approximately half the upregulated genes we analyzed were marked with low-level DNA methylation in normal cells that was lost in ICF cells, concomitant with loss of repressive histone modifications, particularly H3K27 trimethylation, and gains in transcriptionally active H3K9 acetylation and H3K4 trimethylation marks. In addition, we consistently observed loss of binding of the SUZ12 component of the PRC2 polycomb repression complex and DNMT3B to derepressed genes, including a number of homeobox genes critical for immune system, brain and craniofacial development. We also observed altered global levels of certain histone modifications in ICF cells, particularly ubiquitinated H2AK119. Therefore, this study provides important new insights into the role of DNMT3B in modulating gene expression and chromatin structure and reveals new connections between DNMT3B and polycomb-mediated repression.
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Poorly differentiated colorectal adenocarcinomas show higher rates of microsatellite instability and promoter methylation of p16 and hMLH1: A study matched for T classification and tumor location.
By admin | February 23, 2008
Kazama Y, Watanabe T, Kanazawa T, Tanaka J, Tanaka T, Nagawa H
J Surg Oncol (Mar 2008)
BACKGROUND: Extensive genetic and epigenetic analysis of poorly differentiated colorectal adenocarcinomas (Por) has been difficult, as the number of cases is too small. METHODS: We investigated genetic and epigenetic alterations of 53 cases of Por and 53 cases of well-differentiated colorectal adenocarcinomas (WD) to clarify their differences. The cases of WD were matched with the cases of Por for T classification and tumor location, which influence genetic and epigenetic alterations. We evaluated microsatellite instability (MSI) status and loss of heterozygosity (LOH) of four loci (2p, 5q, 17p, 18q), and defined “MSI tumors” as those that showed MSI-H, and “chromosomal instability (CIN) tumors” as those that showed LOH but not MSI-H. Further, we evaluated the methylation status of the hMLH1 and p16 promoter region. RESULTS: MSI tumors were significantly more frequent in Por (22.6%) than in WD (3.8%; P = 0.0041). CIN tumors were significantly less frequent in Por (64.2%) than in WD (83.0%; P = 0.046). Further, methylation of the p16 and hMLH1 promoter region was significantly more frequent in Por than in WD (P = 0.037, P = 0.047, respectively). CONCLUSIONS: Our results indicate that Por tumorigenesis strongly correlates with MSI and methylation of the p16 and hMLH1 promoter region. J. Surg. Oncol. 2008;97:278-283. (c) 2007 Wiley-Liss, Inc.
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Non-coding RNAs in imprinted gene clusters.
By admin | February 23, 2008
Royo H, Cavaill J
Biol Cell (Mar 2008)
Imprinted ncRNA (non-coding RNA) genes represent a family of untranslated transcripts that are mono-allelically expressed in a parent-of-origin manner (their expression is restricted to either the maternal or the paternal allele). Although the expression of a few long imprinted ncRNAs act as cis-acting silencers in the epigenetic regulation of chromatin at imprinted gene clusters, many of them fall into the growing class of small regulatory RNAs, namely C/D small nucleolar RNAs, microRNAs and also likely piRNAs (Piwi-interacting RNAs), which are known to act as antisense trans-acting regulators of gene expression (for example, site-specific RNA modifications and RNA-mediated gene silencing). Although their biological functions remain elusive, recent studies have pointed to their functional importance in development, in brain plasticity and also perhaps in some pathological situations, such as cancers or Prader-Willi syndrome. In this review, we summarize our current understanding of the molecular and biological roles of these ncRNAs, both in terms of their contribution to genomic imprinting control, as well as in terms of cellular RNA targets they might interact with.
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