* 603573

METHYL-CpG-BINDING DOMAIN PROTEIN 3; MBD3


HGNC Approved Gene Symbol: MBD3

Cytogenetic location: 19p13.3     Genomic coordinates (GRCh38): 19:1,573,596-1,592,865 (from NCBI)


TEXT

Cloning and Expression

The MECP2 (300005) and MBD1 (156535) proteins bind specifically to methylated DNA via a methyl-CpG-binding domain (MBD). Both proteins can repress transcription and appear to be important in interpreting the signal that methylation of DNA represents. By searching an EST database for proteins containing an MBD-like motif, Hendrich and Bird (1998) identified human and mouse cDNAs encoding the 3 novel proteins MBD2 (603547), MBD3, and MBD4 (603574). The predicted 291-amino acid human MBD3 protein (GenBank AF072247) is 94% identical to mouse Mbd3. MBD3 failed to specifically bind methylated DNA in vitro. A green fluorescence protein (GFP)-MBD3 fusion protein showed diffuse nuclear staining in cells in which it was expressed at low levels, and accumulated in many nuclear foci in cells in which it was expressed at high levels. However, MBD3 did not appear to associate with the highly methylated major satellite DNA in mouse cells. The authors identified cDNAs representing an alternatively spliced mouse Mbd3 mRNA that lacks the coding sequence for the N-terminal half of the MBD. RT-PCR analysis of many mouse tissues indicated that this shorter message constitutes a significant fraction of total Mbd3 transcripts. Northern blot analysis detected Mbd3 transcripts in all mouse tissues tested.


Gene Function

Zhang et al. (1999) showed that MTA2 (MTA1L1; 603947) and the 32-kD MBD3 protein are subunits of the NURD (nucleosome remodeling and histone deacetylase) complex (see MTA1; 603526). Immunoprecipitation analysis showed that MBD3 interacts with HDAC1 (601241), RBBP4 (602923), and RBBP7 (300825), but not with MI2 (CHD4; 603277), suggesting that MBD3 is embedded within the NURD complex. The authors found that MTA2 directs the assembly of an active histone deacetylase complex and that the association of MTA2 with the complex requires MBD3. Gel mobility shift analysis determined that both NURD and MBD3 are unable to bind to methylated DNA in the absence of MBD2. Zhang et al. (1999) proposed that NURD is involved in the transcriptional repression of methylated DNA. Wade et al. (1999) also identified MTA1, MTA1L, and MBD3 as components of the NURD complex, which they referred to as the MI2 complex.

Aguilera et al. (2011) demonstrated that unphosphorylated, but not N-terminally phosphorylated, c-Jun (165160) interacts with MBD3 and thereby recruits the NuRD repressor complex. MBD3 depletion in colon cancer cells increased histone acetylation at AP1-dependent promoters, which resulted in increased target gene expression. The intestinal stem cell marker LGR5 (606667) was identified as a novel target gene controlled by c-Jun/MBD3. Gut-specific conditional deletion of Mbd3 in mice stimulated c-Jun activity and increased progenitor cell proliferation. In response to inflammation, Mbd3 deficiency resulted in colonic hyperproliferation, and Mbd3 gut-null mice showed markedly increased susceptibility to colitis-induced tumorigenesis. Aguilera et al. (2011) noted that concomitant inactivation of a single allele of c-Jun reverted physiologic and pathologic hyperproliferation, as well as the increased tumorigenesis in Mbd3 gut-null mice. Thus, the transactivation domain of c-Jun recruits MBD3/NuRD to AP1 target genes to mediate gene repression, and this repression is relieved by JNK (601158)-mediated c-Jun N-terminal phosphorylation.

Rais et al. (2013) showed that depleting MBD3, a core member of the MBD3/NURD repressor complex, together with OSKM (OCT4, 164177; SOX2, 184429; KLF4, 602253; and MYC, 190080) transduction and reprogramming in naive pluripotency-promoting conditions, result in deterministic and synchronized induced pluripotent stem (iPS) cell reprogramming (nearly 100% efficiency within 7 days from mouse and human cells). Rais et al. (2013) stated that their findings uncovered a dichotomous molecular function for the reprogramming factors, serving to reactivate endogenous pluripotency networks while simultaneously directly recruiting the MBD3/NURD repressor complex that potently restrains the reactivation of OSKM downstream target genes. Subsequently, the latter interactions, which are largely depleted during early preimplantation development in vivo, lead to a stochastic and protracted reprogramming trajectory toward pluripotency in vitro. Rais et al. (2013) concluded that their deterministic reprogramming approach offered a novel platform for the dissection of molecular dynamics leading to establishing pluripotency at unprecedented flexibility and resolution.


Gene Structure

By genomic sequence analysis, Hendrich et al. (1999) determined that the MBD3 gene contains 7 exons and spans more than 16 kb. The MBD is encoded within exons 1 and 2.


Mapping

Rasooly (1999) noted that the human MBD3 gene was contained within a genomic clone from chromosomal region 19p13.3 (GenBank AC005943). Using PCR on a hybrid panel and sequence analysis of a mapped cosmid, Hendrich et al. (1999) mapped the MBD3 gene to chromosome 19p13. They mapped the murine gene to chromosome 10.


REFERENCES

  1. Aguilera, C., Nakagawa, K., Sancho, R., Chakraborty, A., Hendrich, B., Behrens, A. c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex. Nature 469: 231-235, 2011. [PubMed: 21196933, related citations] [Full Text]

  2. 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, related citations] [Full Text]

  3. Hendrich, B., Bird, A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Molec. Cell. Biol. 18: 6538-6547, 1998. [PubMed: 9774669, images, related citations] [Full Text]

  4. Rais, Y., Zviran, A., Geula, S., Gafni, O., Chomsky, E., Viukov, S., Mansour, A. A., Caspi, I., Krupalnik, V., Zerbib, M., Maza, I., Mor, N., and 14 others. Deterministic direct reprogramming of somatic cells to pluripotency. Nature 502: 65-70, 2013. Note: Erratum: Nature 520: 710 only, 2015. [PubMed: 24048479, related citations] [Full Text]

  5. Rasooly, R. S. Personal Communication. Baltimore, Md. 2/23/1999.

  6. Wade, P. A., Gegonne, A., Jones, P. L., Ballestar, E., Aubry, F., Wolffe, A. P. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nature Genet. 23: 62-66, 1999. [PubMed: 10471500, related citations] [Full Text]

  7. Zhang, Y., Ng, H.-H., Erdjument-Bromage, H, Tempst, P., Bird, A., Reinberg, D. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13: 1924-1935, 1999. [PubMed: 10444591, images, related citations] [Full Text]


Ada Hamosh - updated : 12/05/2013
Ada Hamosh - updated : 1/28/2011
Paul J. Converse - updated : 1/11/2002
Creation Date:
Rebekah S. Rasooly : 2/22/1999
carol : 08/11/2016
alopez : 12/05/2013
alopez : 2/4/2011
terry : 1/28/2011
mgross : 11/3/2010
mgross : 1/11/2002
mgross : 1/11/2002
mgross : 1/11/2002
psherman : 2/24/1999
psherman : 2/23/1999

* 603573

METHYL-CpG-BINDING DOMAIN PROTEIN 3; MBD3


HGNC Approved Gene Symbol: MBD3

Cytogenetic location: 19p13.3     Genomic coordinates (GRCh38): 19:1,573,596-1,592,865 (from NCBI)


TEXT

Cloning and Expression

The MECP2 (300005) and MBD1 (156535) proteins bind specifically to methylated DNA via a methyl-CpG-binding domain (MBD). Both proteins can repress transcription and appear to be important in interpreting the signal that methylation of DNA represents. By searching an EST database for proteins containing an MBD-like motif, Hendrich and Bird (1998) identified human and mouse cDNAs encoding the 3 novel proteins MBD2 (603547), MBD3, and MBD4 (603574). The predicted 291-amino acid human MBD3 protein (GenBank AF072247) is 94% identical to mouse Mbd3. MBD3 failed to specifically bind methylated DNA in vitro. A green fluorescence protein (GFP)-MBD3 fusion protein showed diffuse nuclear staining in cells in which it was expressed at low levels, and accumulated in many nuclear foci in cells in which it was expressed at high levels. However, MBD3 did not appear to associate with the highly methylated major satellite DNA in mouse cells. The authors identified cDNAs representing an alternatively spliced mouse Mbd3 mRNA that lacks the coding sequence for the N-terminal half of the MBD. RT-PCR analysis of many mouse tissues indicated that this shorter message constitutes a significant fraction of total Mbd3 transcripts. Northern blot analysis detected Mbd3 transcripts in all mouse tissues tested.


Gene Function

Zhang et al. (1999) showed that MTA2 (MTA1L1; 603947) and the 32-kD MBD3 protein are subunits of the NURD (nucleosome remodeling and histone deacetylase) complex (see MTA1; 603526). Immunoprecipitation analysis showed that MBD3 interacts with HDAC1 (601241), RBBP4 (602923), and RBBP7 (300825), but not with MI2 (CHD4; 603277), suggesting that MBD3 is embedded within the NURD complex. The authors found that MTA2 directs the assembly of an active histone deacetylase complex and that the association of MTA2 with the complex requires MBD3. Gel mobility shift analysis determined that both NURD and MBD3 are unable to bind to methylated DNA in the absence of MBD2. Zhang et al. (1999) proposed that NURD is involved in the transcriptional repression of methylated DNA. Wade et al. (1999) also identified MTA1, MTA1L, and MBD3 as components of the NURD complex, which they referred to as the MI2 complex.

Aguilera et al. (2011) demonstrated that unphosphorylated, but not N-terminally phosphorylated, c-Jun (165160) interacts with MBD3 and thereby recruits the NuRD repressor complex. MBD3 depletion in colon cancer cells increased histone acetylation at AP1-dependent promoters, which resulted in increased target gene expression. The intestinal stem cell marker LGR5 (606667) was identified as a novel target gene controlled by c-Jun/MBD3. Gut-specific conditional deletion of Mbd3 in mice stimulated c-Jun activity and increased progenitor cell proliferation. In response to inflammation, Mbd3 deficiency resulted in colonic hyperproliferation, and Mbd3 gut-null mice showed markedly increased susceptibility to colitis-induced tumorigenesis. Aguilera et al. (2011) noted that concomitant inactivation of a single allele of c-Jun reverted physiologic and pathologic hyperproliferation, as well as the increased tumorigenesis in Mbd3 gut-null mice. Thus, the transactivation domain of c-Jun recruits MBD3/NuRD to AP1 target genes to mediate gene repression, and this repression is relieved by JNK (601158)-mediated c-Jun N-terminal phosphorylation.

Rais et al. (2013) showed that depleting MBD3, a core member of the MBD3/NURD repressor complex, together with OSKM (OCT4, 164177; SOX2, 184429; KLF4, 602253; and MYC, 190080) transduction and reprogramming in naive pluripotency-promoting conditions, result in deterministic and synchronized induced pluripotent stem (iPS) cell reprogramming (nearly 100% efficiency within 7 days from mouse and human cells). Rais et al. (2013) stated that their findings uncovered a dichotomous molecular function for the reprogramming factors, serving to reactivate endogenous pluripotency networks while simultaneously directly recruiting the MBD3/NURD repressor complex that potently restrains the reactivation of OSKM downstream target genes. Subsequently, the latter interactions, which are largely depleted during early preimplantation development in vivo, lead to a stochastic and protracted reprogramming trajectory toward pluripotency in vitro. Rais et al. (2013) concluded that their deterministic reprogramming approach offered a novel platform for the dissection of molecular dynamics leading to establishing pluripotency at unprecedented flexibility and resolution.


Gene Structure

By genomic sequence analysis, Hendrich et al. (1999) determined that the MBD3 gene contains 7 exons and spans more than 16 kb. The MBD is encoded within exons 1 and 2.


Mapping

Rasooly (1999) noted that the human MBD3 gene was contained within a genomic clone from chromosomal region 19p13.3 (GenBank AC005943). Using PCR on a hybrid panel and sequence analysis of a mapped cosmid, Hendrich et al. (1999) mapped the MBD3 gene to chromosome 19p13. They mapped the murine gene to chromosome 10.


REFERENCES

  1. Aguilera, C., Nakagawa, K., Sancho, R., Chakraborty, A., Hendrich, B., Behrens, A. c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex. Nature 469: 231-235, 2011. [PubMed: 21196933] [Full Text: https://doi.org/10.1038/nature09607]

  2. 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]

  3. Hendrich, B., Bird, A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Molec. Cell. Biol. 18: 6538-6547, 1998. [PubMed: 9774669] [Full Text: https://doi.org/10.1128/MCB.18.11.6538]

  4. Rais, Y., Zviran, A., Geula, S., Gafni, O., Chomsky, E., Viukov, S., Mansour, A. A., Caspi, I., Krupalnik, V., Zerbib, M., Maza, I., Mor, N., and 14 others. Deterministic direct reprogramming of somatic cells to pluripotency. Nature 502: 65-70, 2013. Note: Erratum: Nature 520: 710 only, 2015. [PubMed: 24048479] [Full Text: https://doi.org/10.1038/nature12587]

  5. Rasooly, R. S. Personal Communication. Baltimore, Md. 2/23/1999.

  6. Wade, P. A., Gegonne, A., Jones, P. L., Ballestar, E., Aubry, F., Wolffe, A. P. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nature Genet. 23: 62-66, 1999. [PubMed: 10471500] [Full Text: https://doi.org/10.1038/12664]

  7. Zhang, Y., Ng, H.-H., Erdjument-Bromage, H, Tempst, P., Bird, A., Reinberg, D. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13: 1924-1935, 1999. [PubMed: 10444591] [Full Text: https://doi.org/10.1101/gad.13.15.1924]


Contributors:
Ada Hamosh - updated : 12/05/2013
Ada Hamosh - updated : 1/28/2011
Paul J. Converse - updated : 1/11/2002

Creation Date:
Rebekah S. Rasooly : 2/22/1999

Edit History:
carol : 08/11/2016
alopez : 12/05/2013
alopez : 2/4/2011
terry : 1/28/2011
mgross : 11/3/2010
mgross : 1/11/2002
mgross : 1/11/2002
mgross : 1/11/2002
psherman : 2/24/1999
psherman : 2/23/1999