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Our review last year reported progress towards elucidating the biological importance of transcriptional repression as revealed by studies of human diseases.
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Gabellini D., Tupler R., Green M.R. Transcriptional derepression as a cause of genetic diseases. Curr Opin Genet Dev. 13:2003;239-245 Our review last year reported progress towards elucidating the biological importance of transcriptional repression as revealed by studies of human diseases.
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This review summarizes new findings on how presenilin-1-mediated proteolysis of several cell-surface receptors initiates a signaling cascade in which the intracellular domain of the receptor is liberated by intramembrane cleavage and translocates to the nucleus where it regulates gene expression.
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Fortini M.E. Gamma-secretase-mediated proteolysis in cell-surface- receptor signalling. Nat Rev Mol Cell Biol. 3:2002;673-684 This review summarizes new findings on how presenilin-1-mediated proteolysis of several cell-surface receptors initiates a signaling cascade in which the intracellular domain of the receptor is liberated by intramembrane cleavage and translocates to the nucleus where it regulates gene expression.
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Fortini, M.E.1
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A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations
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This paper reports that presenilin 1 promotes the cleavage of N-cadherin to generate the intracellular peptide N-Cad/CTF2. N-Cad/CTF2 promotes the degradation of the transcription factor CBP, and functions as a potent repressor of CBP/CREB-mediated transcription. Importantly, presenilin 1 mutations associated with familial AD cause a gain of transcriptional function by inhibiting production of N-Cad/CTF2. These results raise the possibility that familial AD mutation-induced transcriptional misregulation may play a role in the severity of this form of the disease.
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Marambaud P., Wen P.H., Dutt A., Shioi J., Takashima A., Siman R., Robakis N.K. A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell. 114:2003;635-645 This paper reports that presenilin 1 promotes the cleavage of N-cadherin to generate the intracellular peptide N-Cad/CTF2. N-Cad/CTF2 promotes the degradation of the transcription factor CBP, and functions as a potent repressor of CBP/CREB-mediated transcription. Importantly, presenilin 1 mutations associated with familial AD cause a gain of transcriptional function by inhibiting production of N-Cad/CTF2. These results raise the possibility that familial AD mutation-induced transcriptional misregulation may play a role in the severity of this form of the disease.
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Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP
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Petrij F., Giles R.H., Dauwerse H.G., Saris J.J., Hennekam R.C., Masuno M., Tommerup N., van Ommen G.J., Goodman R.H., Peters D.J., et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature. 376:1995;348-351
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This article shows how overexpression of CBP in Drosophila leads to neurodegeneration.
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Ludlam W.H., Taylor M.H., Tanner K.G., Denu J.M., Goodman R.H., Smolik S.M. The acetyltransferase activity of CBP is required for wingless activation and H4 acetylation in Drosophila melanogaster. Mol Cell Biol. 22:2002;3832-3841 This article shows how overexpression of CBP in Drosophila leads to neurodegeneration.
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This thoughtful review discusses the molecular genetics of RTT. The article focuses on experiments addressing the basic properties of MeCP2 and on mouse models that are starting to yield insights into this disorder.
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Kriaucionis S., Bird A. DNA methylation and Rett syndrome. Hum Mol Genet. 12(2):2003;R221-R227 This thoughtful review discusses the molecular genetics of RTT. The article focuses on experiments addressing the basic properties of MeCP2 and on mouse models that are starting to yield insights into this disorder.
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Guy J., Hendrich B., Holmes M., Martin J.E., Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet. 27:2001;322-326
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Chen R.Z., Akbarian S., Tudor M., Jaenisch R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet. 27:2001;327-331
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Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3
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••] report the generation of animal models for RTT. Significantly, the deficiency of Mecp2 specifically in neurons is sufficient to cause neuronal dysfunction with a symptomatic manifestation similar to RTT. In addition, chromatin architecture is abnormal in mutant mice, providing evidence that gene expression may be misregulated in these RTT models.
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••] report the generation of animal models for RTT. Significantly, the deficiency of Mecp2 specifically in neurons is sufficient to cause neuronal dysfunction with a symptomatic manifestation similar to RTT. In addition, chromatin architecture is abnormal in mutant mice, providing evidence that gene expression may be misregulated in these RTT models.
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Neuron
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Shahbazian, M.1
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Noebels, J.6
Armstrong, D.7
Paylor, R.8
Zoghbi, H.9
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Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain
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Biochemical data suggest that MeCP2 acts as a global transcriptional repressor, predicting that Mecp2 mutant mice should have genome-wide transcriptional deregulation. Here, global transcriptional profiling on brain tissues of wild type and Mecp2-null mice tested this hypothesis. The results revealed no dramatic changes in transcription even in mice displaying overt disease symptoms, suggesting that Mecp2 deficiency leads to subtle gene expression changes in mutant brains.
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Tudor M., Akbarian S., Chen R.Z., Jaenisch R. Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain. Proc Natl Acad Sci USA. 99:2002;15536-15541 Biochemical data suggest that MeCP2 acts as a global transcriptional repressor, predicting that Mecp2 mutant mice should have genome-wide transcriptional deregulation. Here, global transcriptional profiling on brain tissues of wild type and Mecp2-null mice tested this hypothesis. The results revealed no dramatic changes in transcription even in mice displaying overt disease symptoms, suggesting that Mecp2 deficiency leads to subtle gene expression changes in mutant brains.
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Proc Natl Acad Sci USA
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Tudor, M.1
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Chen, R.Z.3
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24
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0043178993
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A mutant form of MeCP2 protein associated with human Rett syndrome cannot be displaced from methylated DNA by notch in Xenopus embryos
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This paper shows that MeCP2 is essential for amphibian development and describes the first bona fide MeCP2-regulated gene, Hairy2a. These results support a model whereby MeCP2 regulates genes involved in cell fate decisions during primary neurogenesis in Xenopus.
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Stancheva I., Collins A.L., Van den Veyver I.B., Zoghbi H., Meehan R.R. A mutant form of MeCP2 protein associated with human Rett syndrome cannot be displaced from methylated DNA by notch in Xenopus embryos. Mol Cell. 12:2003;425-435 This paper shows that MeCP2 is essential for amphibian development and describes the first bona fide MeCP2-regulated gene, Hairy2a. These results support a model whereby MeCP2 regulates genes involved in cell fate decisions during primary neurogenesis in Xenopus.
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Stancheva, I.1
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Calcium regulation of neuronal gene expression
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West A.E., Chen W.G., Dalva M.B., Dolmetsch R.E., Kornhauser J.M., Shaywitz A.J., Takasu M.A., Tao X., Greenberg M.E. Calcium regulation of neuronal gene expression. Proc Natl Acad Sci USA. 98:2001;11024-11031
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Takasu, M.A.7
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Greenberg, M.E.9
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Chen, W.G.1
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27
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0242300612
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DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation
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These papers reveal the existence of another genuine target gene of MeCP2, BDNF, which encodes a secreted protein essential for neural plasticity, learning, and memory. Interestingly, MeCP2 shows a dynamic association with DNA, perhaps regulated by phosphorylation. These new findings reveal unexpected plasticity in the biological interpretation of methylated DNA.
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Martinowich K., Hattori D., Wu H., Fouse S., He F., Hu Y., Fan G., Sun Y.E. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science. 302:2003;890-893 These papers reveal the existence of another genuine target gene of MeCP2, BDNF, which encodes a secreted protein essential for neural plasticity, learning, and memory. Interestingly, MeCP2 shows a dynamic association with DNA, perhaps regulated by phosphorylation. These new findings reveal unexpected plasticity in the biological interpretation of methylated DNA.
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Science
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Martinowich, K.1
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Sun, Y.E.8
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An informative review about the biological mechanisms regulating angiogenesis in health and disease.
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Carmeliet P. Angiogenesis in health and disease. Nat Med. 9:2003;653-660 An informative review about the biological mechanisms regulating angiogenesis in health and disease.
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Klippel M., Trenaunay P. Du naevus variqueux osteohypertrophique. Arch Gen Med Paris. 3:1900;611-672 [Title translation: On osteohypertrophic varicose proliferation.]
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This paper reports the identification of the first gene known to be involved in KTS, a congenital vascular disease. Using an elegant approach, the authors show that increased angiogenesis is a molecular pathogenic mechanism of the disease.
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Tian X.L., Kadaba R., You S.A., Liu M., Timur A.A., Yang L., Chen Q., Szafranski P., Rao S., Wu L., et al. Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome. Nature. 427:2004;640-645 This paper reports the identification of the first gene known to be involved in KTS, a congenital vascular disease. Using an elegant approach, the authors show that increased angiogenesis is a molecular pathogenic mechanism of the disease.
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Tian, X.L.1
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This review summarizes recent advances in understanding the molecular mechanism of FSHD.
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Tupler R., Gabellini D. Molecular basis of facioscapulohumeral muscular dystrophy. Cell Mol Life Sci. 61:2004;557-566 This review summarizes recent advances in understanding the molecular mechanism of FSHD.
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Inappropriate gene activation in FSHD: A repressor complex binds a chromosomal repeat deleted in dystrophic muscle
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In this paper, we establish a role for DNA repetitive elements in regulating gene expression and in causing a human disorder. FSHD is associated with the deletion of repetitive DNA elements, termed D4Z4, located on chromosome 4q35. Gene-expression analysis showed that 4q35 genes located upstream of D4Z4 are inappropriately overexpressed specifically in FSHD-affected muscle. An element within D4Z4 specifically binds a multi-protein complex and mediates transcriptional repression of 4q35 genes. On the basis of these results, a new model for FSHD has been proposed: deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes resulting in disease.
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Gabellini D., Green M.R., Tupler R. Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell. 110:2002;339-348 In this paper, we establish a role for DNA repetitive elements in regulating gene expression and in causing a human disorder. FSHD is associated with the deletion of repetitive DNA elements, termed D4Z4, located on chromosome 4q35. Gene-expression analysis showed that 4q35 genes located upstream of D4Z4 are inappropriately overexpressed specifically in FSHD-affected muscle. An element within D4Z4 specifically binds a multi-protein complex and mediates transcriptional repression of 4q35 genes. On the basis of these results, a new model for FSHD has been proposed: deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes resulting in disease.
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Gabellini, D.1
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0345257778
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This paper reports that deletion of D4Z4 causes hypomethylation at 4q35 in individuals with FSHD. Strikingly, individuals with phenotypic FSHD, who are clinically identical to FSHD1 but have an unaltered D4Z4, also have hypomethylation of D4Z4. These results suggest that hypomethylation of D4Z4 is associated to the cascade of epigenetic events causing FSHD.
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van Overveld P.G., Lemmers R.J., Sandkuijl L.A., Enthoven L., Winokur S.T., Bakels F., Padberg G.W., van Ommen G.J., Frants R.R., van der Maarel S.M. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat Genet. 35:2003;315-317 This paper reports that deletion of D4Z4 causes hypomethylation at 4q35 in individuals with FSHD. Strikingly, individuals with phenotypic FSHD, who are clinically identical to FSHD1 but have an unaltered D4Z4, also have hypomethylation of D4Z4. These results suggest that hypomethylation of D4Z4 is associated to the cascade of epigenetic events causing FSHD.
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Nat Genet
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Van Overveld, P.G.1
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van der Maarel SM: Epigenetic causes of facioscapulohumeral muscular dystrophy (Abstract 90). New Directions in Biology and Disease of Skeletal Muscle; San Diego, CA: 25-27 January, 2004.
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The authors of this review focus on the silencing properties of yeast telomeres and speculate on the role of telomeric position effect in yeasts and other organisms.
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Tham W.H., Zakian V.A. Transcriptional silencing at Saccharomyces telomeres: implications for other organisms. Oncogene. 21:2002;512-521 The authors of this review focus on the silencing properties of yeast telomeres and speculate on the role of telomeric position effect in yeasts and other organisms.
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Lonser R.R., Glenn G.M., Walther M., Chew E.Y., Libutti S.K., Linehan W.M., Oldfield E.H. von Hippel-Lindau disease. Lancet. 361:2003;2059-2067
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Haider N.B., Jacobson S.G., Cideciyan A.V., Swiderski R., Streb L.M., Searby C., Beck G., Hockey R., Hanna D.B., Gorman S., et al. Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat Genet. 24:2000;127-131
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