Journal ArticleDOI
Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex
Xinsheng Nan,Huck-Hui Ng,Colin A. Johnson,Carol D. Laherty,Bryan M. Turner,Robert N. Eisenman,Adrian Bird +6 more
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TLDR
The data suggest that two global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis.Abstract:
Cytosine residues in the sequence 5'CpG (cytosine-guanine) are often postsynthetically methylated in animal genomes. CpG methylation is involved in long-term silencing of certain genes during mammalian development and in repression of viral genomes. The methyl-CpG-binding proteins MeCP1 and MeCP2 interact specifically with methylated DNA and mediate transcriptional repression. Here we study the mechanism of repression by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis. MeCP2 binds tightly to chromosomes in a methylation-dependent manner. It contains a transcriptional-repression domain (TRD) that can function at a distance in vitro and in vivo. We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. Transcriptional repression in vivo is relieved by the deacetylase inhibitor trichostatin A, indicating that deacetylation of histones (and/or of other proteins) is an essential component of this repression mechanism. The data suggest that two global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by MeCP2.read more
Citations
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Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals
Rudolf Jaenisch,Adrian Bird +1 more
TL;DR: Advances in the understanding of the mechanism and role of DNA methylation in biological processes are reviewed, showing that epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression.
Journal ArticleDOI
Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.
Ruthie E. Amir,Ignatia B. Van den Veyver,Mimi Wan,Charles Q. Tran,Uta Francke,Huda Y. Zoghbi +5 more
TL;DR: This study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.
Journal ArticleDOI
The epigenomics of cancer.
Peter A. Jones,Stephen B. Baylin +1 more
TL;DR: Recent advances in understanding how epigenetic alterations participate in the earliest stages of neoplasia, including stem/precursor cell contributions, are reviewed and the growing implications of these advances for strategies to control cancer are discussed.
Journal ArticleDOI
Epigenetics in Cancer
TL;DR: The current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies are discussed.
Journal ArticleDOI
Epigenetics in human disease and prospects for epigenetic therapy
TL;DR: Great potential lies in the development of ‘epigenetic therapies’ — several inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, have shown promising anti-tumorigenic effects for some malignancies.
References
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Journal ArticleDOI
Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei
TL;DR: A procedure for preparing extracts from nuclei of human tissue culture cells that directs accurate transcription initiation in vitro from class II promoters, including tRNA and Ad 2 VA, is developed.
Journal ArticleDOI
Histone acetylation in chromatin structure and transcription
TL;DR: The amino termini of histones extend from the nucleosomal core and are modified by acetyltransferases and deacetylases during the cell cycle, which may direct histone assembly and help regulate the unfolding and activity of genes.
Journal ArticleDOI
Role for DNA methylation in genomic imprinting
TL;DR: It is demonstrated that a normal level of DNA methylation is required for controlling differential expression of the paternal and maternal alleles of imprinted genes in mutant mice that are deficient in DNA methyltransferase activity.
Journal ArticleDOI
Purification, sequence, and cellular localization of a novel chromosomal protein that binds to Methylated DNA
Joe D. Lewis,Joe D. Lewis,Richard R. Meehan,Richard R. Meehan,William J. Henzel,Ingrid Maurer-Fogy,Peter Jeppesen,Franz Klein,Adrian Bird,Adrian Bird +9 more
TL;DR: This work reports the identification, purification, and cDNA cloning of a novel MeCP called MeCP2, which unlike MeCP1, the new protein is able to bind to DNA that contains a single methyl-CpG pair.
Journal ArticleDOI
Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase.
Laszlo Nagy,Hung Ying Kao,Debabrata Chakravarti,Richard J. Lin,Christian A. Hassig,Donald E. Ayer,Stuart L. Schreiber,Ronald M. Evans +7 more
TL;DR: A convergence of repression pathways for bHLH-Zip proteins and nuclear receptors is established and suggests this type of regulation may be more widely conserved than previously suspected.