MBD2 (methyl CpG binding domain protein 2)

2009-10-01   Heather Owen 

Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Kings Buildings, Mayfield Road, Edinburgh EH9 3JR, UK

Identity

HGNC
LOCATION
18q21.2
LOCUSID
ALIAS
DMTase,NY-CO-41
FUSION GENES

DNA/RNA

Atlas Image
MBD2 is expressed as 2 transcripts. NM_003927.3 coding sequence in blue and NM_015832.3 in red. Boxes represent exons and arrows represent transcriptional start sites.

Description

MBD2 (NM_003927.3) is a gene of 70,583 bp coded by 7 exons from 33,240,260 to 33,169,677 according to NCBI reference sequence NT_010966.14 or 51,751,158 to 51,680,575 according to Genome reference consortium human build 37 GRCh37. There is an alternative transcript for MBD2 (NM_015832.3) of 22,111 bp from 33,240,260 to 33,218,149 on NCBI reference sequence NT_010966.14. This transcript shares the first 2 exons (coding for the methyl binding domain) but differs in the 3rd exon, resulting in a shorter truncated protein.

Transcription

The longer transcript encoded by NM_003927.3, mRNA length of 2584bp, is expressed ubiquitiously (according to symatlas).
The shorter transcript NM_015832.3, mRNA length of 1357bp is expressed in germ cells (according to symatlas).

Proteins

Atlas Image
MBD: methyl binding domain, P: phosphorylation detected.

Description

In somatic tissues MBD2 is expressed from a single transcript, and is detected by western blot as 2 stable proteins at approximately 50 kDa (MBD2a) and 30 kDa (MBD2b). Human MBD2a (Q9UBB5) has 411 amino acids. It is unknown whether MBD2b is due to use of an alternative translation start site (creating protein of 262 amino acids) or due to protein cleavage/processing/degradation.
Human germ cells express a short form of MBD2 from the alternative transcript with an expected length of 302 amino acids.

Expression

MBD2a and MBD2b are expressed in all tissues tested with highest levels in spleen and colon nuclei (non-published observation).

Localisation

MBD2 is a nuclear protein. MBD2-GFP localises to major satellite in mouse ES cells, but not in DNA methylation deficient cells (Hendrich and Bird, 1998).

Function

MBD2 is a methyl binding protein that is thought to repress gene expression as part of the NuRD complex. The NuRD complex was identified independently by four separate groups (Wade et al., 1998; Tong et al., 1998; Xue et al., 1998; Zhang et al., 1998). NuRD consists of a chromatin remodelling ATPase Mi2alpha or beta, histone deacetylase HDAC1/HDAC2, MTA1 or MTA2, RbAp46/RbAp48, p66alpha/beta and can also contain MBD2 or MBD3. TAP tagged MBD2a associates with NuRD with equimolar stoichometry implying that most MBD2a is complexed with NuRD in cells (Le Guezennec et al., 2006). MBD2 is required for repression of methylated reporter genes (Hendrich, 2001) and many endogenous target genes of MBD2 have been reported. However the global genomic targets of MBD2 have not been characterised. MBD2 knock out are viable and fertile, and show only mild physiological defects. These are abnormal maternal behaviour and T helper cell deficiencies (Hendrich, 2001; Hutchins, 2002; Hutchins, 2005).

Homology

MBD2 is a member of the methyl-binding domain proteins (Hendrich and Bird, 1998). Other members of this family are MeCp2, MBD2, MBD3 and MBD4 (Klose and Bird, 2006). These proteins share a region of homology (145-213 of MBD2a), which have been shown to form a stable domain consisting of a beta sheet, an alpha helix and a positioned loop (Ohki et al., 2001). The crystal structure of the MBD of MeCP2 complexed with a methylated CpG containing 20mer of DNA indicates that the protein-DNA interactions are dependent on water molecules (Ho et al., 2008). The protein with closest homology to MBD2 is MBD3, however MBD3 has two crucial amino acid substitutions in the MBD and does not specifically bind to methylated DNA (Hendrich and Tweedie, 2003).

Mutations

Note

MBD2 is mutated only infrequently in human cancer tissues.

Implicated in

Entity name
Intestinal tumorigenesis
Note
MBD2-/- APCmin/+ mice have fewer intestinal tumors and survive longer than MBD2+/+ APCmin/+ mice (Sansom, 2003).
These results imply MBD2 is required for tumorigenesis. Although the mechanism is unknown, possibilities are listed below:
1) MBD2 may repress tumor supressor genes (therefore in the absence of MBD2, tumor repressor expression would be upregulated). In cancer cell lines MBD2 has been found to bind to methylated regions of tumor supressor genes GSTP1, p14 and p16 (Stirzaker, 2004; Le Guezennec, 2006; Martin, 2008).
3) In mice MBD2 is required for normal T cell differentiation and MBD2-/- mice have impaired immune responses. This could contribute to the MBD2 requirement in tumor formation in the APCmin/+ strain (Hutchins, 2002; Hutchins, 2005).
4) Other mechanisms are possible, such as a role of mbd2 in higher order chromatin or silencing of heterochromatin regulating tumorigenesis. However this has not been tested.

Knock down of MBD2 in human cancer cell lines reduced tumor volume when implanted into nude mice (Campbell, 2004).
MBD2 expression levels in human cancer tissues have been analysed in multiple studies with differing results. One study found MBD2 expression was low in colorectal and stomach cancers (Kanai, 1999), whereas other studies found high expression in cancer tissues. These discrepancies are likely due to differences between control genes used as well as differences between cancer tissues.

Bibliography

Pubmed IDLast YearTitleAuthors
127762032003MBD1, MBD2 and CGBP genes at chromosome 18q21 are infrequently mutated in human colon and lung cancers.Bader S et al
162461642005Role of MBD2 in gene regulation and tumorigenesis.Berger J et al
146880292004Methylated DNA-binding protein 2 antisense inhibitors suppress tumourigenesis of human cancer cell lines in vitro and in vivo.Campbell PM et al
127112192003The methyl-CpG binding domain and the evolving role of DNA methylation in animals.Hendrich B et al
183133902008MeCP2 binding to DNA depends upon hydration at methyl-CpG.Ho KL et al
162370472005Cutting edge: a critical role for gene silencing in preventing excessive type 1 immunity.Hutchins AS et al
105440381999Reduced mRNA expression of the DNA demethylase, MBD2, in human colorectal and stomach cancers.Kanai Y et al
164036362006Genomic DNA methylation: the mark and its mediators.Klose RJ et al
164284402006MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties.Le Guezennec X et al
125438082003Methyl-CpG-binding domain protein-2 mediates transcriptional repression associated with hypermethylated GSTP1 CpG islands in MCF-7 breast cancer cells.Lin X et al
189315302008MBD2-mediated transcriptional repression of the p14ARF tumor suppressor gene in human colon cancer cells.Martin V et al
104714991999MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex.Ng HH et al
113713452001Solution structure of the methyl-CpG binding domain of human MBD1 in complex with methylated DNA.Ohki I et al
186448722008Deficiency of Mbd2 attenuates Wnt signaling.Phesse TJ et al
127306932003Deficiency of Mbd2 suppresses intestinal tumorigenesis.Sansom OJ et al
151729962004Transcriptional gene silencing promotes DNA hypermethylation through a sequential change in chromatin modifications in cancer cells.Stirzaker C et al
98044271998Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex.Tong JK et al
96633951998A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase.Wade PA et al
98855721998NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities.Xue Y et al
97905341998The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities.Zhang Y et al

Other Information

Locus ID:

NCBI: 8932
MIM: 603547
HGNC: 6917
Ensembl: ENSG00000134046

Variants:

dbSNP: 8932
ClinVar: 8932
TCGA: ENSG00000134046
COSMIC: MBD2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000134046ENST00000256429Q9UBB5
ENSG00000134046ENST00000398398X6RBL6
ENSG00000134046ENST00000578272J3KSA7
ENSG00000134046ENST00000583046Q9UBB5
ENSG00000134046ENST00000583046A0A024R2B8

Expression (GTEx)

0
10
20
30
40
50
60
70
80

Pathways

PathwaySourceExternal ID
Gene ExpressionREACTOMER-HSA-74160
RNA Polymerase I, RNA Polymerase III, and Mitochondrial TranscriptionREACTOMER-HSA-504046
RNA Polymerase I TranscriptionREACTOMER-HSA-73864
RNA Polymerase I Promoter ClearanceREACTOMER-HSA-73854
RNA Polymerase I Promoter OpeningREACTOMER-HSA-73728
Epigenetic regulation of gene expressionREACTOMER-HSA-212165
Negative epigenetic regulation of rRNA expressionREACTOMER-HSA-5250941
NoRC negatively regulates rRNA expressionREACTOMER-HSA-427413

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
164284402006MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties.147
123887202002Protein interactions targeting the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus to cell chromosomes.122
146100932004Role of human ribosomal RNA (rRNA) promoter methylation and of methyl-CpG-binding protein MBD2 in the suppression of rRNA gene expression.74
233614642013Differential roles for MBD2 and MBD3 at methylated CpG islands, active promoters and binding to exon sequences.47
248138562014Alternative splicing of MBD2 supports self-renewal in human pluripotent stem cells.44
121770482002Promoter-specific activation and demethylation by MBD2/demethylase.42
119609942002Methyl-CpG binding domain protein 2 represses transcription from hypermethylated pi-class glutathione S-transferase gene promoters in hepatocellular carcinoma cells.37
237701332013Decreased levels of miR-224 and the passenger strand of miR-221 increase MBD2, suppressing maspin and promoting colorectal tumor growth and metastasis in mice.37
121834692002Two highly related p66 proteins comprise a new family of potent transcriptional repressors interacting with MBD2 and MBD3.35
257985782015SINE transcription by RNA polymerase III is suppressed by histone methylation but not by DNA methylation.33

Citation

Heather Owen

MBD2 (methyl CpG binding domain protein 2)

Atlas Genet Cytogenet Oncol Haematol. 2009-10-01

Online version: http://atlasgeneticsoncology.org/gene/41309/mbd2