Preferred Label : Transcriptional Repression by DNA Methylation Pathway;
NCIt synonyms : DNA Methylation Pathway;
NCIt related terms : Mechanisms of Transcriptional Repression by DNA Methylation;
Alternative definition : BIOCARTA: Tumorigenesis is known to be a multistep process in which defects in various
cancer genes accumulate. Epigenetic modifications, most importantly DNA methylation
events, are frequently involved in transcriptional changes in both tumor suppressor
genes and oncogenes. Methylation of cytosine at CpG dinucleotides is a common feature
of higher eukaryotic genomes. DNA methylation in the promoter regions of genes is
generally correlated with gene silencing. Two underlying mechanisms have been identified.
First, binding of transcription factors or enhancer blocking elements, such as CTCF,
may be inhibited by DNA methylation. The second and more general mechanism involves
proteins that detect methylated DNA through methyl CpG-binding domains (MBDs). Four
of these proteins-MBD1, MBD2, MBD3, and MeCP2-have been implicated in methylation-dependent
repression of transcription. These proteins mediate recruitment of repressor complexes
that include histone deacetylases (HDACs). HDACs remove acetyl groups from lysine
residues of histones H3 and H4 that results in condensation of chromatin and thus
limit access of transcription factors to promoter regions of genes localized nearby.
Well-studied co-repressor complexes include Sin3A and Mi-2/NuRD. MeCP2, a polypeptide
characterized by an MBD and a transcriptional repression domain that specifically
binds methylated DNA, copurifies with the Sin3A/HDAC corepressor complex. MeCP1 complex
is composed of 10 major polypeptides including MBD2 and all of the known NuRD complex
components. The two protein complexes share four polypeptides: HDAC1, HDAC2, RbAp46,
and RbAp48. In addition, each complex contains unique polypeptides (Sin3A, SAP30,
and SAP18 in the Sin3 complex, and Mi2, MTA1, MTA2 and MBD3 in the NuRD complex).
The NuRD complex possesses nucleosome remodeling activity because of the presence
of Mi2, a member of the SWI2/SNF2 helicase/ATPase family. This complex preferentially
binds, remodels, and deacetylates methylated nucleosomes. MTA1 or MTA2 (metastasis-associated
protein 1 or 2) expression levels are elevated in metastatic cancer cells, MTA2 modulates
the enzymatic activity of the histone deacetylase core complex. (This definition may
be outdated - see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_mbdPathway;
Origin ID : C91331;
UMLS CUI : C2984170;
Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element
