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HGNC Approved Gene Symbol: MBD1
Cytogenetic location: 18q21.1 Genomic coordinates (GRCh38): 18:50,266,885-50,281,767 (from NCBI)
Attempts to understand how DNA methylation prevents transcription have centered on 2 alternative mechanisms: direct interference of site-specific methylation with the binding of essential transcription factors, and indirect interference of promoter-proximal methylation with transcription via a protein that binds to methylated DNA. Methyl-CpG-binding protein-1 (MECP1) binds to a variety of methylated sequences in vitro, provided they contain at least 12 symmetrically methylated CpGs. MECP1 has been detected in crude nuclear extracts. Boyes and Bird (1991) and Levine et al. (1991) presented evidence suggesting that the MECP1 protein is a mediator of repression.
Methylation of cytosines within the sequence CpG is essential for mouse development and has been linked to transcriptional suppression in vertebrate systems. Methyl-CpG-binding proteins MECP1 and MECP2 (300005) bind preferentially to methylated DNA and can inhibit transcription. The rat Mecp2 gene was cloned by Nan et al. (1993) and its methyl-CpG-binding domain (MBD) defined. By searching DNA sequence databases with the MBD sequence, Cross et al. (1997) identified a human cDNA with potential to encode an MBD-like region. Sequencing of the complete cDNA revealed that the open reading frame also encodes 2 cysteine-rich domains that were found in animal DNA methyltransferases (see DNMT; 126375) and in the mammalian HRX protein, also known as MLL and ALL-1 (159555). They designated the protein PCM1 for 'protein containing MBD.' Expressed in bacteria, it showed specific binding to methylated DNA. PCM1 also repressed transcription in vitro in a methylation-dependent manner. A polyclonal antibody raised against the protein was able to bind the native MECP1 complex from HeLa cells, indicating that PCM1 is a component of mammalian MECP1.
Ohki et al. (2001) reported the solution structure of the conserved MBD of human MBD1 bound to methylated DNA. DNA binding causes a loop in MBD1 to fold into a major and novel DNA-binding interface. Recognition of the methyl groups and CG sequence at the methylation site is due to 5 highly conserved residues that form a hydrophobic patch. The authors concluded that the structure indicates how MBD may access nucleosomal DNA without encountering steric interference from core histones, and provides a basis to interpret mutations linked to Rett syndrome in MECP2.
Using yeast 2-hybrid analysis, reciprocal immunoprecipitation analysis, and protein pull-down assays, Fujita et al. (2003) showed that MBD1 interacted directly with MCAF (ATF7IP; 613644). Deletion analysis revealed that the C-terminal transcriptional repressor domain (TRD) of MBD1 interacted with a conserved C-terminal domain of MCAF. Reporter gene assays showed that MCAF increased the repressive function of the isolated TRD of MBD1 against SP1 (189906). Chromatin immunoprecipitation analysis revealed that MBD1 linked MCAF to methylated promoters.
Uchimura et al. (2006) found that MBD1 was multiply sumoylated in HeLa cells. Sumoylation did not alter the intracellular localization of MBD1 at nuclear foci in C-33A human cervical cancer cells. However, knockdown of endogenous SUMO1 (601912) or SUMO2 (603042)/SUMO3 (602231) disrupted association of MCAF1 with MBD1. SUMO knockdown also disrupted the association of MBD1 with several factors required for heterochromatin assembly, including HP1-beta (CBX1; 604511) and HP1-gamma (CBX3; 604477), but not HP1-alpha (CBX5; 604478), and caused delocalization of trimethylated histone H3 (see 602810) lys9 (H3K9). Uchimura et al. (2006) concluded that sumoylation of MBD1 is critical for anchoring MCAF1, methylation of H3K9, and targeting of HP1-beta and HP1-gamma to MBD1-containing heterochromatin.
The PML (102578)-RARA (180240) fusion gene product induces a block on hematopoietic differentiation and acute promyelocytic leukemia by inactivating target genes via its ability to recruit histone deacetylases and DNA methyltransferases. Villa et al. (2006) found that MBD1 cooperated with PML-RARA in transcriptional repression and cellular transformation in human cell lines. PML-RARA recruited MBD1 to its target promoter through an HDAC3 (605166)-mediated mechanism. Binding of HDAC3 and MBD1 was not confined to the target promoter, but was instead spread over the locus. Knockdown of HDAC3 expression by RNA interference in acute promyelocytic leukemia cells alleviated PML-RARA-induced promoter silencing. Furthermore, retroviral expression of dominant-negative mutants of MBD1 in human hematopoietic precursors interfered with PML-RARA-induced repression and restored cell differentiation. Villa et al. (2006) concluded that PML-RARA recruits an HDAC3-MBD1 complex to target promoters to establish and maintain chromatin silencing.
By genomic sequence analysis, Hendrich et al. (1999) determined that the murine Mbd1 gene contains 15 exons spanning more than 14 kb. The MBD is encoded by exons 2 and 3. They found that the human MBD1 gene has a similar structure, except that exons 9 and 15 are each split into 2 exons in human (9A and 9B, and 15A and 15B).
Using PCR on a hybrid panel and FISH, Hendrich et al. (1999) mapped the MBD1 gene to chromosome 18q21, 2.1 cM distal to MBD2 (603547). They mapped the murine gene to chromosome 18.
Allan et al. (2008) had previously found that Mbd1 deletion led to reduced hippocampal neurogenesis in mice. They found that Mbd1 -/- mice had normal motor activity, but they showed several deficits associated with autism, including reduced social interaction, hippocampal- and amygdala-dependent learning deficits, anxiety, defective sensory motor gating, depression, and abnormal brain serotonin activity. Mbd1 directly regulated expression of the serotonin receptor Htr2c (312861) in wildtype mice, and deletion of Mbd1 resulted in elevated Htr2c expression and serotonin binding in Mbd1 -/- medial frontal cortex.
Allan, A. M., Liang, X., Luo, Y., Pak, C., Li, X., Szulwach, K. E., Chen, D., Jin, P., Zhao, X. The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits. Hum. Molec. Genet. 17: 2047-2057, 2008. [PubMed: 18385101] [Full Text: https://doi.org/10.1093/hmg/ddn102]
Boyes, J., Bird, A. DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein. Cell 64: 1123-1134, 1991. [PubMed: 2004419] [Full Text: https://doi.org/10.1016/0092-8674(91)90267-3]
Cross, S. H., Meehan, R. R., Nan, X., Bird, A. A component of the transcriptional repressor MeCP1 shares a motif with DNA methyltransferase and HRX proteins. Nature Genet. 16: 256-259, 1997. [PubMed: 9207790] [Full Text: https://doi.org/10.1038/ng0797-256]
Fujita, N., Watanabe, S., Ichimura, T., Ohkuma, Y., Chiba, T., Saya, H., Nakao, M. MCAF mediates MBD1-dependent transcriptional repression. Molec. Cell. Biol. 23: 2834-2843, 2003. [PubMed: 12665582] [Full Text: https://doi.org/10.1128/MCB.23.8.2834-2843.2003]
Hendrich, B., Abbott, C., McQueen, H., Chambers, D., Cross, S., Bird, A. Genomic structure and chromosomal mapping of the murine and human Mbd1, Mbd2, Mbd3, and Mbd4 genes. Mammalian Genome 10: 906-912, 1999. [PubMed: 10441743] [Full Text: https://doi.org/10.1007/s003359901112]
Levine, A., Cantoni, G. L., Razin, A. Inhibition of promoter activity by methylation: possible involvement of protein mediators. Proc. Nat. Acad. Sci. 88: 6515-6518, 1991. [PubMed: 1650472] [Full Text: https://doi.org/10.1073/pnas.88.15.6515]
Nan, X., Meehan, R. R., Bird, A. Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. Nucleic Acids Res. 21: 4886-4892, 1993. [PubMed: 8177735] [Full Text: https://doi.org/10.1093/nar/21.21.4886]
Ohki, I., Shimotake, N., Fujita, N., Jee, J.-G., Ikegami, T., Nakao, M., Shirakawa, M. Solution structure of the methyl-CpG binding domain of human MBD1 in complex with methylated DNA. Cell 105: 487-497, 2001. Note: Erratum: Cell 105: 815 only, 2001. [PubMed: 11371345] [Full Text: https://doi.org/10.1016/s0092-8674(01)00324-5]
Uchimura, Y., Ichimura, T., Uwada, J., Tachibana, T., Sugahara, S., Nakao, M., Saitoh, H. Involvement of SUMO modification in MBD1- and MCAF1-mediated heterochromatin formation. J. Biol. Chem. 281: 23180-23190, 2006. [PubMed: 16757475] [Full Text: https://doi.org/10.1074/jbc.M602280200]
Villa, R., Morey, L., Raker, V. A., Buschbeck, M., Gutierrez, A., De Santis, F., Corsaro, M., Varas, F., Bossi, D., Minucci, S., Pelicci, P. G., Di Croce, L. The methyl-CpG binding protein MBD1 is required for PML-RAR-alpha function. Proc. Nat. Acad. Sci. 103: 1400-1405, 2006. [PubMed: 16432238] [Full Text: https://doi.org/10.1073/pnas.0509343103]