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Antibodies from IMGENEX: DNA Methylation & Repair
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). 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. Recently, a MBD2-binding zinc finger protein (MIZF) has been identified that represses transcription by associating with MBD2 and a histone deacetylase complex.

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).

Reference
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]
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.
 
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Cat.No Description Format Species Clone Application Publications
IMG-261A Dnmt1 Purified H, M, Zf 60B1220.1 ChIP, IHC (p), IP, WB pricing
IMG-268A Dnmt3a Purified H, M 64B1446 ChIP, IF/ICC, IHC (p), WB pricing
IMG-184A Dnmt3b Purified H, M 52A1018 ChIP, IF/ICC, IHC (p), IP, WB pricing
IMG-246 p73 Purified H, M 5B429 ChIP, IF/ICC, IHC (frozen), IHC (p), IP, WB pricing
IMG-259A p73 (Alpha, Beta, Gamma, Delta Isoforms) Purified H, M 5B1288 ChIP, IF/ICC, IP, WB pricing
IMG-5410-1 AID/AICDA Purified, Peptide Affinity H, M N/A IF/ICC, WB pricing
IMG-5410-2 AID/AICDA Purified, Peptide Affinity H, M N/A IF/ICC, WB pricing
IMG-5658 AIF Sera C, D, H, M, R N/A IHC (frozen), IHC (p), IP, WB pricing
IMG-30020 AIF1/IBA1 (isoform 3) Purified, Peptide Affinity H N/A WB pricing
IMG-80164 Androgen Receptor Purified H AR 441 IHC (frozen), IHC (p), WB pricing
IMG-392 APE Purified H N/A IHC-P, WB pricing
IMG-3470 APE1/APEX1 Purified, Peptide Affinity H N/A  IHC (p), WB pricing
IMG-466 APEXL2 Purified H N/A WB pricing
IMG-4114 Artemis Purified H N/A WB pricing
IMG-311 ATF2 Purified H N/A WB pricing
IMG-3435 ATF2 Purified, Peptide Affinity H N/A  WB pricing
IMG-5040 ATF2 (Ser490/498) Purified, Peptide Affinity H N/A   IHC (frozen), WB pricing
IMG-350A ATF2 (Thr71) Purified H, M 103C411.2 WB pricing
IMG-90221-1 ATM (Ser1981) Purified, Peptide Affinity H, M N/A IHC (p) pricing
IMG-4115 BACH1 Purified H N/A WB pricing
IMG-90537-2 BRCA1 (Ab-1423) Purified, Peptide Affinity H N/A IHC (p), WB pricing
IMG-90307-1 BRCA1 (Ser1423) Purified, Peptide Affinity H N/A IHC (p), WB pricing
IMG-90218-1 BRCA1 (Ser1524) Purified, Peptide Affinity H N/A IHC (p) pricing
IMG-477 CGBP Purified H N/A WB pricing
IMG-336A Chk2 Purified H, M 73C175.1.1 WB pricing
IMG-3353 CLLD8/SETDB2 Purified, Peptide Affinity H N/A WB pricing
IMG-30130 COMT Purified, Peptide Affinity H N/A WB pricing
IMG-6142A DMAP1 Purified Chp, C, D, H, M, R N/A IHC (p), WB pricing
IMG-90496-2 DNA PKcs (Ab-2609) Purified, Peptide Affinity H N/A WB pricing
IMG-90259-1 DNA PKcs (Thr2609) Purified, Peptide Affinity H N/A WB pricing
IMG-281 Dnmt2 Purified H, M N/A WB pricing
IMG-374 Dnmt2 Purified H, M 102B1259.2 WB pricing
IMG-266A Dnmt3a Purified H, M 64B814.1 IF/ICC, WB pricing
IMG-266B Dnmt3a Biotin H, M 64B814.1 Peptide ELISA pricing
IMG-6465A Dnmt3a Purified, Peptide Affinity Chp, H, RH N/A WB pricing
IMG-6466A Dnmt3a Purified, Peptide Affinity Ca, Ch, Chp, C, Hs, H, M N/A WB pricing
IMG-6831A Dnmt3a Purified H    WB pricing
IMG-465 DUT-N Purified H N/A WB pricing
IMG-31152 ERCC1 Purified, Peptide Affinity H N/A Peptide ELISA, WB pricing
IMX-6576 EZH2 Purified Ch, C, H, M, R N/A Peptide ELISA pricing
IMX-6560 EZH2 Sera H, Mk, M, R N/A Peptide ELISA pricing
IMG-6395A Furin Purified Chp, C, D, Hs, H, M, R, RH N/A IHC (p) pricing
IMG-30126 GPX4 Purified, Peptide Affinity H N/A IHC (p), WB pricing
IMG-4145 HDAC-10 Purified H N/A WB pricing
IMG-5027 HDAC-11 Purified H, M, R N/A WB pricing
IMG-339 HDAC-5 Purified H, M N/A ChIP, IP, WB pricing
IMX-5932 HDAC-7 Purified, Peptide Affinity Chp, C, D, H, Mk, M, R N/A Peptide ELISA pricing
IMX-5933 HDAC-7 Purified, Peptide Affinity Chp, C, D, Hs, H, Mk, Zf N/A Peptide ELISA pricing
IMG-6125A HDAC-7 (Ser155) Purified, Peptide Affinity Chp, C, D, H, Mk, M, R N/A WB pricing
IMG-359 Histone H2B Purified Ch, D, Ds, H, M, M, R, Zf N/A IHC (p), WB pricing
 

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