The Minimal Repression Domain of MBD2b Overlaps with the Methyl-CpG-binding Domain and Binds Directly to Sin3A
Journal of Biological ChemistryPublished 1 November 2000Open access
Joern Boeke, Ole Ammerpohl, Simone Kegel, Udo Moehren, Rainer Renkawitz
Citations117
SJR quartileQ1
SJR score1.71
SNIP1.00
Generate an AI Snapshot to get a quick, structured summary of this paper.
Study Snapshot
ObjectiveStudy objective
MethodsResearch methodology
PopulationPopulation studied
Sample sizeSample sizes
OutcomesStudy outcomes here
ResultsStudy results comes here
LimitationsResearch study limitations comes here
A concise AI-generated summary of the paper will appear here once you click Generate AI Snapshot.
TL;DR
A minimal functional domain is identified that confers both transcriptional repression as well as the interaction to Sin3A, the transcriptional repressor of granulocyte/macrophage-specific lysozyme gene.
Abstract
Different mechanisms mediating methylation-dependent repression have been demonstrated. Two of these mechanisms play a role in the context of the granulocyte/macrophage-specific lysozyme gene: direct interference with DNA binding of the transcription factor GA-binding protein and deacetylation of histones. Besides enhancement in the unmethylated state, and transcriptional repression upon DNA methylation, the lysozyme downstream enhancer confers tissue-specific demethylation. Because both demethylation activity and repression ability have been attributed to the methyl-CpG-binding domain-containing protein MBD2, we analyzed this protein. The short form MBD2b binds to the methylated lysozyme enhancer and mediates transcriptional repression. MBD2b is capable of binding to the transcriptional repressor Sin3A. The interaction domain of Sin3A required for binding to MBD2b contains the paired amphipathic helix 3. We identified a minimal functional domain that confers both transcriptional repression as well as the interaction to Sin3A. In contrast to the functionally related proteins MeCP2 and MBD1, the repression domain of MBD2b overlaps with the methyl-CpG-binding domain.
Keywords
Biochemistry, Genetics and Molecular Biology
CellDNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development
6,082 Citations1999Masaki Okano, Daphne W. Bell +2 more
It is demonstrated that two recently identified DNA methyltransferases, DnMT3a and Dnmt3b, are essential for de novo methylation and for mouse development and play important roles in normal development and disease.
CellTargeted mutation of the DNA methyltransferase gene results in embryonic lethality
3,960 Citations1992En Li, Timothy H. Bestor +1 more
Results indicate that while a 3-fold reduction in levels of genomic m5C has no detectable effect on the viability or proliferation of ES cells in culture, a similar reduction of DNA methylation in embryos causes abnormal development and embryonic lethality.
Nature GeneticsMethylated DNA and MeCP2 recruit histone deacetylase to repress transcription
2,728 Citations1998Peter Lloyd Jones, Gert Jan C. Veenstra +6 more
The results establish a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin.
Nature GeneticsCancer-epigenetics comes of age
2,349 Citations1999P A Jones, Peter W. Laird
Current mechanistic understanding of the role of DNA methylation in malignant transformation is reviewed, and it is suggested Knudson's two–hit hypothesis should be expanded to include epigenetic mechanisms of gene inactivation.
CellMethylation-Induced Repression— Belts, Braces, and Chromatin
1,833 Citations1999Adrian Bird, Alan P. Wolffe
Although the signals that cause susceptibility or resistance to methylation are still unknown, genetic approaches in plants are leading the way forward and exciting revelations are expected as the knowledge vacuum in this area is filled over the next few years.
Molecular and Cellular BiologyIdentification and Characterization of a Family of Mammalian Methyl-CpG Binding Proteins
1,344 Citations1998Brian Hendrich, Adrian Bird
CellMeCP2 Is a Transcriptional Repressor with Abundant Binding Sites in Genomic Chromatin
1,291 Citations1997Xinsheng Nan, Francisco J. Campoy +1 more
Transient transfection using fusions with the GAL4 DNA binding domain identified a region of MeCP2 that is capable of long-range repression in vivo and suggest a role as a global transcriptional repressor in vertebrate genomes.
Genes & DevelopmentAnalysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation
1,085 Citations1999Yi Zhang, Huck‐Hui Ng +4 more
A novel polypeptide highly related to the metastasis-associated protein 1, MTA2, and the methyl-CpG-binding domain-containing protein, MBD3, were found to be subunits of the NuRD complex, which may provide a means of gene silencing by DNA methylation.
Nature GeneticsMBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex
939 Citations1999Huck‐Hui Ng, Yi Zhang +7 more
The data suggest that HeLa cells, which lack the known methylation-dependent repressor MeCP2, use an alternative pathway involving MBD2 to silence methylated genes.
Nature GeneticsMi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation
810 Citations1999Paul A. Wade, Anne Gégonne +4 more
The data substantiate the mechanistic link between DNA methylation, histone deacetylation and transcriptional silencing and reveal a similarity to a known methyl CpG-binding protein.
The EMBO JournalCpG methylation, chromatin structure and gene silencing—a three‐way connection
798 Citations1998Aharon Razin
Molecular link between methyl groups on the DNA and the positioning of nucleosomes to form an inactive chromatin configuration was missing and recent experimental data may shed light on this molecular link.
CellDNA methylation inhibits transcription indirectly via a methyl-CpG binding protein
729 Citations1991Joan Boyes, Adrian Bird
Repression of transcription in vitro for four different promoters was shown to be an indirect effect and the mediator of repression had properties indistinguishable from those of a methyl-CpG binding protein (MeCP-1) that has been previously identified.
Annual Review of GeneticsGENOMIC IMPRINTING IN MAMMALS
643 Citations1997Marisa S. Bartolomei, Shirley M. Tilghman
Although the function of imprinting remains a subject of some debate, the process is thought to have an important role in regulating the rate of fetal growth.
Current Opinion in Genetics & DevelopmentDNA methylation and chromatin modification
640 Citations1999Huck‐Hui Ng, Adrian Bird
Data suggest that DNA methylation can pattern chromatin modification, and that inhibition of histone deacetylases by specific inhibitors can reactivate endogenous genes or reporter constructs previously silenced by DNA methylations.
NatureA mammalian protein with specific demethylase activity for mCpG DNA
618 Citations1999Sanjoy K. Bhattacharya, Shyam Ramchandani +2 more
CellHistone Deacetylases and SAP18, a Novel Polypeptide, Are Components of a Human Sin3 Complex
575 Citations1997Yi Zhang, Rabah Iratni +3 more
It is found that the mammalian transcriptional repressor Sin3 (mSin3) exists in a complex with histone deacetylases HDAC1 and HDAC2, and that the mSin3-containing complex includes polypeptides that tether the m Sin3 complex to core histone proteins.
CellModular structure of a chicken lysozyme silencer: Involvement of an unusual thyroid hormone receptor binding site
482 Citations1990Aria Baniahmad, Christof Steiner +2 more
It is shown that the chicken lysozyme silencer S-2.4 kb has many other characteristics in common with enhancer elements, including the fact that the palindromic sequence is inverted.
Nucleic Acids ResearchDnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells
407 Citations1998Mitsuhiro Okano
It is shown that endogenous virus was fully methylated in Dnmt2 -deficient mutant ES cells and newly integrated retrovirus DNA was methylated de novo in infected mutantES cells as efficiently as in wild-type cells.
The EMBO JournalA transferable silencing domain is present in the thyroid hormone receptor, in the v‐erbA oncogene product and in the retinoic acid receptor.
297 Citations1992Aria Baniahmad, Anja Carola Köhne +1 more
Evidence is provided that the silencing function of the oncogene product v‐ERBA or the cellular counterpart, the thyroid hormone receptor (TR, c‐erbA) is located in the C‐terminal part and is transferable to a heterologous DNA binding domain.
Molecular and Cellular BiologyActive Repression of Methylated Genes by the Chromosomal Protein MBD1
249 Citations2000Huck‐Hui Ng, Peter Jeppesen +1 more
The present study established by several experimental criteria that, contrary to a previous report, MBD1 is not a component of the MeCP1 repressor complex, and identified a powerful transcriptional repression domain (TRD) at the C terminus ofMBD1 that can actively repress transcription at a distance.
Molecular and Cellular BiologyThe t4 Activation Domain of the Thyroid Hormone Receptor Is Required for Release of a Putative Corepressor(s) Necessary for Transcriptional Silencing
247 Citations1995Aria Baniahmad, Xiaohua Leng +4 more
This study has identified and characterized several functional domains within the ligand binding domain of the human thyroid hormone receptor (TR beta) conferring transactivation and proposed a general model in which the role of hormone is to induce a conformational change in the receptor that subsequently affects the action of tau 4, leading to both relief of silencing and transcriptional activation.
Nature GeneticsA component of the transcriptional represser MeCP1 shares a motif with DNA methyltransferase and HRX proteins
241 Citations1997Sally H. Cross, Richard R. Meehan +2 more
A poly-clonal antibody raised against the protein was able to ‘supershift’ the native MeCP1 complex from HeLa cells, indicating that PCM1 is a component of mammalian MeCP2, which was expressed in bacteria and shown to bind specifically to methylated DNA.
Molecular and Cellular BiologyMethylation-Mediated Transcriptional Silencing in Euchromatin by Methyl-CpG Binding Protein MBD1 Isoforms
200 Citations1999Naoyuki Fujita, Shin‐ichiro Takebayashi +5 more
Interestingly, MBD1 isoforms v1 and v2 containing three CXXC domains also suppressed unmethylated promoter activities in mammalian cells, suggesting that the MBD 1 isoforms have different roles in methylation-mediated transcriptional silencing in euchromatin.
Molecular and Cellular BiologyAlien, a Highly Conserved Protein with Characteristics of a Corepressor for Members of the Nuclear Hormone Receptor Superfamily
199 Citations1999Uwe Dressel, Dorit Thormeyer +7 more
Drosophila Alien represents a member of a novel class of corepressors specific for selected members of the nuclear hormone receptor superfamily, and reporter assays indicate that Alien increases receptor-mediated silencing and that it harbors an autonomous silencing function.
Nucleic Acids Research<i>Caenorhabditis elegans</i>DNA does not contain 5-methylcytosine at any time during development or aging
179 Citations1986Victoria Simpson, Thomas E. Johnson +1 more
Nucleic Acids ResearchTranscriptional repression by the insulator protein CTCF involves histone deacetylases
157 Citations2000M. Lutz
It is suggested that CTCF driven repression is mediated in part by the recruitment of histone deacetylase activity by SIN3A, a candidate tumor suppressor protein that binds to highly divergent DNA sequences.
Nucleic Acids ResearchMeCP2 driven transcriptional repression in vitro: selectivity for methylated DNA, action at a distance and contacts with the basal transcription machinery
147 Citations2000Nikola Kaludov, Alan P. Wolffe
It is found that the transcriptional repression established by both MeCP2 and the Gal4-TRD fusion protein in vitro also correlates with selective assembly of large nucleoprotein complexes, reflecting a local concentration of DNA-bound transcriptional repressor that may stabilize a state of repression even in the presence of exogenous transcriptional machinery.
Novartis Foundation symposiumGene Silencing by Methyl‐CPG‐Binding Proteins
126 Citations2007Xinsheng Nan, Sally H. Cross +1 more
MeCP2 is a relatively abundant chromosomal protein whose localization in the nucleus is primarily dependent on CpG methylation and is found to be a potent transcriptional repressor with a genome-wide distribution.
Molecular and Cellular BiologyTranscriptional Repression by the SMRT-mSin3 Corepressor: Multiple Interactions, Multiple Mechanisms, and a Potential Role for TFIIB
125 Citations1998Chi-Wai Wong, Martin L. Privalsky
It is reported here, however, that the corepressor complex actually appears to exhibit multiple mechanisms of transcriptional repression, only one of which corresponds with detectable recruitment of the histone deacetylase.
Proceedings of the National Academy of SciencesKindred S thyroid hormone receptor is an active and constitutive silencer and a repressor for thyroid hormone and retinoic acid responses.
111 Citations1992Aria Baniahmad, Sophia Y. Tsai +2 more
It is shown here that the beta form of the human receptor possesses the ability to repress basal-level activity of a target promoter, which suggests that silencing plays an important role in the phenotypic expression of the symptoms in patients with GTHR.
Nucleic Acids ResearchHistone deacetylase-independent transcriptional repression by methyl-CpG-binding protein 2
105 Citations2000Fang Yu
It is demonstrated here that transient transcription from the SV40 enhancer/promoter or the SV 40 promoter is strongly repressed in a histone deacetylase-independent manner, since repression is not alleviated by Trichostatin A (TSA).
Nature GeneticsA bird's eye view of global methylation
61 Citations2000Charis Eng, James G. Herman +1 more
This and other genome-scanning approaches allows the rapid analysis of methylation profiles of thousands of genes in parallel—and promises to identify new genes critical to carcinogenesis and other biological processes.
Biological ChemistryMinireview
58 Citations1998Yehudit Bergman, Raúl Mostoslavsky
Several lines of evidence indicate that methylation serves to silence transcription, mainly through indirect mechanisms involving the assembly of repressive nucleoprotein complexes.
Nucleic Acids ResearchMethylation of the mouse M-lysozyme downstream enhancer inhibits heterotetrameric GABP binding
41 Citations1995Joachim Nickel, Marc L. Short +3 more
It is demonstrated that the nuclear factors binding to MLDE are present in all tested myeloid and non-myeloid mouse cell lines and matched the consensus binding sequences for proteins of the ets gene superfamily.
Nucleic Acids ResearchThe involvement of demethylation in the myeloid-specific function of the mouse M lysozyme gene downstream enhancer
31 Citations1992Sabine Klages, Bettina Möllers +1 more
A positive correlation between undermethylation of the entire 3'-flanking region, the appearance of the HS-3 site, and M lysozyme gene expression during in vitro differentiation of hematopoietic stem cells is demonstrated.
Nucleic Acids ResearchRepression of the mouse M-lysozyme gene involves both hindrance of enhancer factor binding to the methylated enhancer and histone deacetylation
24 Citations1998Ole Ammerpohl, Alexander Schmitz +2 more
It is shown that trans-cription of a methylated and silent mouse M-lysozyme gene can be induced upon the inhibition of histone deacetylases in the absence of demethylation or in vivo transactivating factor binding to the enhancer.
Molecular and Cellular Biologyτ4/τc/AF-2 of the Thyroid Hormone Receptor Relieves Silencing of the Retinoic Acid Receptor Silencer Core Independent of Both τ4 Activation Function and Full Dissociation of Corepressors
23 Citations1997Aria Baniahmad, Dorit Thormeyer +1 more
It is shown that nine amino acids derived from the hTRbeta are sufficient to transform the RAR silencer core into a hormone-dependent activator, and a transactivation function at the C terminus is not required for relief of silencing by the hormone, but it is required for transcriptional activation.
Journal of Biological ChemistryCis-elements Required for the Demethylation of the Mouse M-lysozyme Downstream Enhancer
17 Citations1997Alexander Schmitz, Marc L. Short +4 more
The mouse lysozyme downstream enhancer was previously colocalized with the DNase I-hypersensitive site in the chromatin of mature macrophages, and it was found that in addition to the complete methylated MLDE the hemimethylated form of the lower strand inhibits GABP binding as well, therefore, GABp is unlikely to be the mediator of demethylation.
PubMedIn vivo protein interaction with the mouse M-lysozyme gene downstream enhancer correlates with demethylation and gene expression.
12 Citations1996Marc L. Short, Joachim Nickel +2 more
Analysis of the MLDE methylation state revealed a correlation between demethylation of the single CpG dinucleotide within theMLDE sequence and the in vivo interaction of proteins, suggesting that the process of differentiation results in factor accessibility for the enhancer.