Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammalian DNA is methylated at many CpG dinucleotides. The biological consequences of methylation are mediated by a family of methyl-CpG binding proteins. The best characterized family member is MeCP2, a transcriptional repressor that recruits histone deacetylases. Our report concerns MBD2, which can bind methylated DNA in vivo and in vitro and has been reported to actively demethylate DNA (ref. 8). As DNA methylation causes gene silencing, the MBD2 demethylase is a candidate transcriptional activator. Using specific antibodies, however, we find here that MBD2 in HeLa cells is associated with histone deacetylase (HDAC) in the MeCP1 repressor complex. An affinity-purified HDAC1 corepressor complex also contains MBD2, suggesting that MeCP1 corresponds to a fraction of this complex. Exogenous MBD2 represses transcription in a transient assay, and repression can be relieved by the deacetylase inhibitor trichostatin A (TSA; ref. 12). In our hands, MBD2 does not demethylate DNA. Our data suggest that HeLa cells, which lack the known methylation-dependent repressor MeCP2, use an alternative pathway involving MBD2 to silence methylated genes.
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PMID:MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. 1047 84

PU.1, a hematopoietic Ets transcription factor, is required for development of the lymphoid and myeloid lineages. We have previously shown that PU.1 functions as both a transcriptional activator and repressor through complex formation with CBP/p300 and HDAC1/mSin3A/MeCP2, respectively. To determine whether modification of PU.1 is responsible for switching its association between co-activators and co-repressors, we examined whether acetylation regulates the physical and functional activities of PU.1. PU.1 was acetylated in vivo and its repressor activity was reduced when the putative acetylation motifs in the Ets domain were mutated. The mutant cooperated with CBP similar to wild type PU.1, but insufficiently with GATA-1 and mSin3A. Whereas overexpression of wild type PU.1 induced differentiation block, growth inhibition, and apoptotic cell death in MEL erythroleukemia cells as we reported previously, overexpression of the mutant-acetylation motif PU.1 did not. Taken together, our data suggest that acetylation might regulate the biological functions of PU.1 in erythroid cells.
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PMID:Impaired repressor activity and biological functions of PU.1 in MEL cells induced by mutations in the acetylation motifs within the ETS domain. 1609 14

Mutations in the gene encoding the transcriptional repressor methyl-CpG binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome. Loss of function as well as increased dosage of the MECP2 gene cause a host of neuropsychiatric disorders. To explore the molecular mechanism(s) underlying these disorders, we examined gene expression patterns in the hypothalamus of mice that either lack or overexpress MeCP2. In both models, MeCP2 dysfunction induced changes in the expression levels of thousands of genes, but unexpectedly the majority of genes (approximately 85%) appeared to be activated by MeCP2. We selected six genes and confirmed that MeCP2 binds to their promoters. Furthermore, we showed that MeCP2 associates with the transcriptional activator CREB1 at the promoter of an activated target but not a repressed target. These studies suggest that MeCP2 regulates the expression of a wide range of genes in the hypothalamus and that it can function as both an activator and a repressor of transcription.
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PMID:MeCP2, a key contributor to neurological disease, activates and represses transcription. 1851 80

The effects of morphine are mediated mainly through the mu opioid receptor (MOR). Expression of the MOR is up-regulated during neuronal differentiation in P19 embryonal carcinoma cells and epigenetic changes play an important role in MOR up-regulation. This study investigates the basis for differentiation-dependent alterations of MOR chromatin by studying the recruitment or dissociation of several factors to the remodeled chromatin locus. Chromatin immunoprecipitation assays were used to demonstrate the recruitment of the transcriptional activator Sp1 and the chromatin remodeling factors Brg1 and BAF155 to this promoter, as well as the dissociation of repressors [histone deacetylases, mSin3A, Brm, and methyl-CpG-binding protein 2 (MeCP2)]. Histone modifications (acetylation, induction of histone H3-lys4 methylation, and reduction of H3-lys9 methylation) were consistently detected on this promoter. Overexpression of Sp1 strongly enhanced MOR promoter activity, and the histone deacetylase inhibitor trichostatin A also increased promoter activity. In vitro DNA CpG-methylation of the promoter partially blocked binding of the Sp1 factor but induced MeCP2 binding. Coimmunoprecipitation studies also found novel evidence of an endogenous MeCP2 interaction with Sp3 but a weaker interaction with Sp1. Overall, the results suggest that during neuronal differentiation, MeCP2 and DNA methylation mediate remodeling of the MOR promoter by chromatin remodeling factors (Brg1 and BAF155) from a compacted state to a conformation allowing access for transcriptional factors. Subsequent recruitment of the activating transcription factor Sp1 to the remodeled promoter results in MOR up-regulation.
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PMID:Up-regulation of the mu-opioid receptor gene is mediated through chromatin remodeling and transcriptional factors in differentiated neuronal cells. 2038 8

Long interspersed nuclear elements-1 (LINE-1 or L1s) are abundant retrotransposons that comprise approximately 20% of mammalian genomes. Active L1 retrotransposons can impact the genome in a variety of ways, creating insertions, deletions, new splice sites or gene expression fine-tuning. We have shown previously that L1 retrotransposons are capable of mobilization in neuronal progenitor cells from rodents and humans and evidence of massive L1 insertions was observed in adult brain tissues but not in other somatic tissues. In addition, L1 mobility in the adult hippocampus can be influenced by the environment. The neuronal specificity of somatic L1 retrotransposition in neural progenitors is partially due to the transition of a Sox2/HDAC1 repressor complex to a Wnt-mediated T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activator. The transcriptional switch accompanies chromatin remodelling during neuronal differentiation, allowing a transient stimulation of L1 transcription. The activity of L1 retrotransposons during brain development can have an impact on gene expression and neuronal function, thereby increasing brain-specific genetic mosaicism. Further understanding of the molecular mechanisms that regulate L1 expression should provide new insights into the role of L1 retrotransposition during brain development. Here we show that L1 neuronal transcription and retrotransposition in rodents are increased in the absence of methyl-CpG-binding protein 2 (MeCP2), a protein involved in global DNA methylation and human neurodevelopmental diseases. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, we revealed that patients with Rett syndrome (RTT), carrying MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Our data demonstrate that L1 retrotransposition can be controlled in a tissue-specific manner and that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition. Our findings add a new level of complexity to the molecular events that can lead to neurological disorders.
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PMID:L1 retrotransposition in neurons is modulated by MeCP2. 2108 68

Since the discovery of MeCP2, its functions have attracted the interest of generations of molecular biologists. Its function as a transducer of DNA methylation, the major post-biosynthetic modification found throughout genomes, and its association with the neurodevelopmental disease Rett syndrome highlight its central role as a transcriptional regulator, and, at the same time, poses puzzling questions concerning its roles in physiology and pathology. The classical model of the MeCP2 function predicts its role in gene-specific repression through the binding of methylated DNA, via its interaction with the histone deacetylases and co-repressor complexes. This view has been questioned and, intriguingly, new roles for MeCP2 as a splicing modulator and as a transcriptional activator have been proposed. Recent data have demonstrated that MeCP2 is extremely abundant in the neurons, where it reaches the level of histone H1; it is widely distributed, tracking the methylated CpGs, and regulates repetitive elements expression. The role of MeCP2 in maintaining the global chromatin structure is further sustained by its involvement in other biologically relevant phenomena, such as the Line-1 repetitive sequences retrotransposition and the pericentromeric heterochromatin clustering during cellular differentiation. These new concepts renew the old view suggesting a role for DNA methylation in transcriptional noise reduction, pointing to a key role for MeCP2 in the modulation of the genome architecture.
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PMID:MeCP2 as a genome-wide modulator: the renewal of an old story. 2297 3

The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3'UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2 mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3'UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior.
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PMID:Mild expression differences of MECP2 influencing aggressive social behavior. 2464 99

Methyl CpG binding protein 2 (MeCP2) is a multifunctional protein which binds to methylated CpG, mutation of which cause a neurodevelopmental disorder, Rett syndrome. MeCP2 can function as both transcriptional activator and repressor of target gene. MeCP2 regulate gene expression in both neuron and glial cells in central nervous system (CNS). Oligodendrocytes, the myelinating cells of CNS, are required for normal functioning of neurons and are regulated by several transcription factors during their differentiation. In current study, we focused on the role of MeCP2 as transcription regulator of myelin genes in cultured rat oligodendrocytes. We have observed expression of MeCP2 at all stages of oligodendrocyte development. MeCP2 knockdown in cultured oligodendrocytes by small interference RNA (siRNA) has shown increase in myelin genes (myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG), and myelin-associated oligodendrocyte basic protein (MOBP)), neurotrophin (brain-derived neurotrophic factor (BDNF)), and transcriptional regulator (YY1) transcripts level, which are involved in regulation of oligodendrocyte differentiation and myelination. Further, we also found that protein levels of MBP, PLP, DM-20, and BDNF also significantly upregulated in MeCP2 knockdown oligodendrocytes. Our study suggests that the MeCP2 acts as a negative regulator of myelin protein expression.
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PMID:Involvement of MeCP2 in Regulation of Myelin-Related Gene Expression in Cultured Rat Oligodendrocytes. 2614 Aug 54

It has been a long trip from 1992, the year of the discovery of MECP2, to the present day. What is surprising is that some of the pivotal roles of MeCP2 were already postulated at that time, such as repression of inappropriate expression from repetitive elements and the regulation of pericentric heterochromatin condensation. However, MeCP2 performs many more functions. MeCP2 is a reader of epigenetic information contained in methylated (and hydroxymethylated) DNA, moving from the 'classical' CpG doublet to the more complex view addressed by the non-CpG methylation, which is a feature of the postnatal brain. MECP2 is a transcriptional repressor, although when it forms complexes with the appropriate molecules, it can become a transcriptional activator. For all of these aspects, Rett syndrome, which is caused by MECP2 mutations, is considered a paradigmatic example of a 'chromatin disorder'. Even if the hunt for bona-fide MECP2 target genes is far from concluded today, the role of MeCP2 in the maintenance of chromatin architecture appears to be clearly established. Taking a cue from the non-scientific literature, we can firmly attest that MeCP2 is a player with 'a great future behind it'*.*V. Gassmann 'Un grande avvenire dietro le spalle'. TEA Eds.
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PMID:MECP2, a multi-talented modulator of chromatin architecture. 2729 83

Rett syndrome is a neurodevelopmental disorder that primarily affects females and is caused by mutations in the methyl-CpG-binding-protein 2 (MECP2) gene. Initially, MeCP2 had been shown to be a repressor of gene transcription. In their 2008 paper, Chahrour and colleagues (DOI: 10.1126/science.1153252) reported that MeCP2 could also function as a transcriptional activator.
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PMID:MeCP2 as an Activator of Gene Expression. 2940 30


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