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| DNA Methylation And Transcriptional Repression |
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Transcriptional repression is an essential
mechanism in the precise control of gene expression. Transcriptional repressor proteins
associate with their target genes either directly through a DNA-binding domain or
indirectly by interacting with other DNA-bound proteins. To inhibit transcription in a
selective manner, a repressor protein can (1) mask a transcriptional activation domain,
(2) block interaction of an activator with other components of the transcription
machinery, or (3) displace an activator from the DNA. Furthermore, DNA response elements
can exert allosteric effects on transcriptional regulators, such that regulators may
activate transcription in the context of one gene, yet repress transcription in another
(Ref.1).
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The most direct mechanism by which DNA
methylation can interfere with transcription is to prevent the binding of basal
transcriptional machinery or ubiquitous TF (Transcription Factors) that require contact
with cytosine (C) in the major groove of the double helix. Transcriptionally active
chromatin is predominantly unmethylated and has high levels of acetylated histone tails.
Most mammalian TFs have GC-rich binding sites and many have CpGs in their DNA recognition
elements. Binding by several of these factors is impeded or abolished by methylation of
CpG (Ref.2). Methylation at CpG dinucleotides is carried out by one of the three known
human DNA methyltransferases (DNMT1, DNMT3a and DNMT3b), resulting in DNA with high levels
of CpG methylation, but still containing predominantly acetylated histone tails. CpG
methylation induces histone deacetylation, chromatin remodeling and gene silencing through
a transcription repressor complex that includes SMRT (Silencing Mediator of Retinoid and
Thyroid Receptors), mSin3a, RbAp46/48 and the two histone deacetylases HDAC1 and HDAC2
formed around mSin3a. This complex is assembled by interaction of mSin3a with the
methyl-binding protein MeCP2 and SAP18/30 (Sin3-Associated Polypeptides 18/30), which are
found associated with large protein complexes such as the NURD complex (Methyl-CpG Binding
Domain proteins: MBD2, MBD3). MECP2 acts as a shuttle interlocking DNA methylation and
core histone deacetylation in inducing gene silencing. This methyl-binding protein tethers
the repression multiprotein complex that includes the corepressor protein, mSin3a, HDAC1
and HDAC2 (Ref.3). The deacetylase activity, which accompanies the MeCP2-bound mSin3a
render the promoter of the gene inaccessible to TFs by deacetylating histone H3 and H4. To
reverse such a silenced status of a gene, demethylation takes place and an activating
complex, which carries the capacity of acetylating histones H3 and H4, replaces the
repression complex. This modification of core histones results in a chromatin structure,
which is accessible to TFs. Alternatively, the methyl-directed repression can be
alleviated by a methylation-overriding effect that is exerted by a strong activation
complex ultimately resulting in effective acetylation of histones H3 and H4. In addition
to MBD, a TRD (Transcriptional Repressor Domain) overlaps with a region that interacts
directly with the corepressor mSin3a (Ref.4). HDAC1 and HDAC2 and chromatin-remodeling
activities (Mi-2 and mSin3a) within these complexes result in alterations in chromatin
structure, producing chromatin that is refractory to transcriptional activation.
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The repression mechanism is significantly
different when the number of methylated sites is increased and reaches the threshold that
leads to diffusion of gene silencing on the DNA fiber. Hypomethylation contributes to
chromosomal instability and possibly to increased expression of some proto-oncogenes. CpG
island methylation is capable of silencing tumor suppressor genes and also increases the
possibility of mutations, which can occur frequently in these regions. DNA methylation at
the 5-position of cytosine within CpG dinucleotides in mammals is essential for important
functions, such as cell differentiation, imprinting and X-inactivation. Several genetic
diseases are caused by defects within the methylation machinery, like the Rett Syndrome,
Fragile X Syndrome and ICF (Immunodeficiency-Centromeric Instability-Facial Anomalies
Syndrome).
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REFERENCES:
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Maldonado E, Hampsey M, Reinberg D.
Repression: targeting the heart of the matter.
Cell. 1999 Nov 24; 99(5): 455-8. Review. No abstract available.
PMID: 10589673 [PubMed - indexed for MEDLINE]
Curradi M, Izzo A, Badaracco G, Landsberger N.
Molecular mechanisms of gene silencing mediated by DNA methylation.
Mol Cell Biol. 2002 May; 22(9): 3157-73.
PMID: 11940673 [PubMed - indexed for MEDLINE]
Zlatanova J, Caiafa P, Van Holde K.
Linker histone binding and displacement: versatile mechanism for transcriptional
regulation.
FASEB J. 2000 Sep; 14(12): 1697-704. Review.
PMID: 10973918 [PubMed - indexed for MEDLINE]
Razin A.
CpG methylation, chromatin structure and gene silencing-a three-way connection.
EMBO J. 1998 Sep 1; 17(17): 4905-8. Review.
PMID: 9724627 [PubMed - indexed for MEDLINE] |
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PRIMARY SEARCH:
DNA Methylation, Transcriptional Repression, gene expression, Transcriptional repressor
proteins, transcription, TF, Transcription Factors, cytosine, chromatin, unmethylated,
acetylated histone tails, CpGs, methylation, CpG methylation, CpG dinucleotides, DNA
methyltransferases, DNMT1, DNMT3a, DNMT3b, histone deacetylation, chromatin remodeling,
gene silencing, SMRT, Silencing Mediator of Retinoid and Thyroid Receptors, mSin3A,
RbAp46/48, HDAC1, HDAC2, histone deacetylases, methyl-binding protein, SAP18/30,
Sin3-Associated Polypeptides 18/30, MECP2, NURD complex, Methyl-CpG Binding Domain
protein, MBD2, MBD3, H3, H4, TRD, Transcriptional Repressor Domain, Mi-2, methylated
sites, chromosomal instability, tumor suppressor genes, cell differentiation, imprinting,
Rett Syndrome, Fragile X Syndrome, ICF, Immunodeficiency-Centromeric Instability-Facial
Anomalies Syndrome
SECONDARY SEARCH:
DNA-binding domain, transcriptional activation domain, activator, DNA response elements,
allosteric, transcriptional regulators, GC-rich binding sites, DNA recognition elements,
corepressor protein, hypomethylation, proto-oncogenes, mutations.
CATEGORY:
DNA Maintenance
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