Key Points
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The nucleosome remodelling and histone deacetylase (NuRD; also known as Mi-2) complex is a multisubunit chromatin remodelling complex that contains two core subunits (chromodomain-helicase-DNA-binding protein 3 (CHD3; also known as Mi-2α) and CHD4 (also known as Mi-2β), and histone deacetylase 1 (HDAC1) and HDAC2) with enzymatic functions. CHD3 and CHD4 catalyse ATP-dependent chromatin remodelling, and HDAC1 and HDAC2 mediate histone and protein deacetylation.
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All subunits of the complex are encoded by multiple gene paralogues. Combinatorial assembly of these paralogues contributes to the targeting and function of the complex.
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The metastasis-associated gene 1 (MTA1) subunit is widely overexpressed in many types of cancer and is associated with poor prognosis.
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Unlike other chromatin remodelling complexes with well-defined roles in cancer, the NuRD complex can promote or suppress tumorigenesis depending on context.
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NuRD complex recruitment to specific loci is mediated by multiple mechanisms, including recruitment by transcription factors and direct interaction with methylated DNA.
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Emerging evidence suggests non-transcriptional roles of the NuRD complex in the maintenance of genome stability, including DNA replication, chromatin assembly and DNA repair.
Abstract
The nucleosome remodelling and histone deacetylase (NuRD; also known as Mi-2) complex regulates gene expression at the level of chromatin. The NuRD complex has been identified — using both genetic and molecular analyses — as a key determinant of differentiation in mouse embryonic stem cells and during development in various model systems. Similar to other chromatin remodellers, such as SWI/SNF and Polycomb complexes, NuRD has also been implicated in the regulation of transcriptional events that are integral to oncogenesis and cancer progression. Emerging molecular details regarding the recruitment of NuRD to specific loci during development, and the modulation of these events in cancer, are used to illustrate how the inappropriate localization of the complex could contribute to tumour biology.
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References
Clapier, C. R. & Cairns, B. R. The biology of chromatin remodeling complexes. Annu. Rev. Biochem. 78, 273–304 (2009).
Denslow, S. A. & Wade, P. A. The human Mi-2/NuRD complex and gene regulation. Oncogene 26, 5433–5438 (2007).
Tong, J. K., Hassig, C. A., Schnitzler, G. R., Kingston, R. E. & Schreiber, S. L. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395, 917–921 (1998).
Wade, P. A., Jones, P. L., Vermaak, D. & Wolffe, A. P. A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. Curr. Biol. 8, 843–846 (1998).
Xue, Y. et al. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol. Cell 2, 851–861 (1998).
Zhang, Y., LeRoy, G., Seelig, H. P., Lane, W. S. & Reinberg, D. The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell 95, 279–289 (1998).
Wang, Y. et al. LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 138, 660–672 (2009).
Wade, P. A. et al. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nature Genet. 23, 62–66 (1999).
Brackertz, M., Boeke, J., Zhang, R. & Renkawitz, R. Two highly related p66 proteins comprise a new family of potent transcriptional repressors interacting with MBD2 and MBD3. J. Biol. Chem. 277, 40958–40966 (2002).
Feng, Q. et al. Identification and functional characterization of the p66/p68 components of the MeCP1 complex. Mol. Cell. Biol. 22, 536–546 (2002).
Marhold, J., Brehm, A. & Kramer, K. The Drosophila methyl-DNA binding protein MBD2/3 interacts with the NuRD complex via p55 and MI-2. BMC Mol. Biol. 5, 20 (2004).
Loyola, A. & Almouzni, G. Histone chaperones, a supporting role in the limelight. Biochim. Biophys. Acta 1677, 3–11 (2004).
Brackertz, M., Gong, Z., Leers, J. & Renkawitz, R. p66α and p66β of the Mi-2/NuRD complex mediate MBD2 and histone interaction. Nucleic Acids Res. 34, 397–406 (2006).
Hendrich, B. & Bird, A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol. Cell. Biol. 18, 6538–6547 (1998).
Fujita, N. et al. MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation. Cell 119, 75–86 (2004). This study is the first to demonstrate the association of the MTA subunit to a tissue-specific transcription factor for mediating transcriptional repression.
Le Guezennec, X. et al. MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties. Mol. Cell. Biol. 26, 843–851 (2006). This study demonstrates that MBD2 and MBD3 form mutually exclusive NuRD complexes.
Saito, M. & Ishikawa, F. The mCpG-binding domain of human MBD3 does not bind to mCpG but interacts with NuRD/Mi2 components HDAC1 and MTA2. J. Biol. Chem. 277, 35434–35439 (2002).
Hendrich, B. & Tweedie, S. The methyl-CpG binding domain and the evolving role of DNA methylation in animals. Trends Genet. 19, 269–277 (2003).
Aguilera, C. et al. c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex. Nature 469, 231–235 (2011). This study demonstrates the protein–protein interaction property of the MBD domain within MBD3.
Hendrich, B., Guy, J., Ramsahoye, B., Wilson, V. A. & Bird, A. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. 15, 710–723 (2001).
Yang, X. J. & Seto, E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nature Rev. Mol. Cell Biol. 9, 206–218 (2008).
You, A., Tong, J. K., Grozinger, C. M. & Schreiber, S. L. CoREST is an integral component of the CoREST- human histone deacetylase complex. Proc. Natl Acad. Sci. USA 98, 1454–1458 (2001).
Zhang, Y., Iratni, R., Erdjument-Bromage, H., Tempst, P. & Reinberg, D. Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex. Cell 89, 357–364 (1997).
Ramirez, J. & Hagman, J. The Mi-2/NuRD complex: a critical epigenetic regulator of hematopoietic development, differentiation and cancer. Epigenetics 4, 532–536 (2009).
Yoshida, T. et al. The role of the chromatin remodeler Mi-2β in hematopoietic stem cell self-renewal and multilineage differentiation. Genes Dev. 22, 1174–1189 (2008). This study investigated the function of the NuRD complex in haematopoietic stem cells using CHD4-conditional knockout mice.
Li, X., Jia, S., Wang, S., Wang, Y. & Meng, A. Mta3-NuRD complex is a master regulator for initiation of primitive hematopoiesis in vertebrate embryos. Blood 114, 5464–5472 (2009).
Gao, H. et al. Opposing effects of SWI/SNF and Mi-2/NuRD chromatin remodeling complexes on epigenetic reprogramming by EBF and Pax5. Proc. Natl Acad. Sci. USA 106, 11258–11263 (2009).
Williams, C. J. et al. The chromatin remodeler Mi-2β is required for CD4 expression and T cell development. Immunity 20, 719–733 (2004).
Naito, T., Gomez-Del Arco, P., Williams, C. J. & Georgopoulos, K. Antagonistic interactions between Ikaros and the chromatin remodeler Mi-2β determine silencer activity and Cd4 gene expression. Immunity 27, 723–734 (2007).
Hong, W. et al. FOG-1 recruits the NuRD repressor complex to mediate transcriptional repression by GATA-1. EMBO J. 24, 2367–2378 (2005).
Gao, Z. et al. FOG-1-mediated recruitment of NuRD is required for cell lineage re-enforcement during haematopoiesis. EMBO J. 29, 457–468 (2010).
Cismasiu, V. B. et al. BCL11B functionally associates with the NuRD complex in T lymphocytes to repress targeted promoter. Oncogene 24, 6753–6764 (2005).
Grabarczyk, P. et al. Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells. Oncogene 26, 3797–3810 (2007).
Cobb, B. S. et al. Targeting of Ikaros to pericentromeric heterochromatin by direct DNA binding. Genes Dev. 14, 2146–2160 (2000).
Kaji, K. et al. The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nature Cell Biol. 8, 285–292 (2006).
Zhu, D., Fang, J., Li, Y. & Zhang, J. Mbd3, a component of NuRD/Mi-2 complex, helps maintain pluripotency of mouse embryonic stem cells by repressing trophectoderm differentiation. PLoS ONE 4, e7684 (2009).
Pencil, S. D., Toh, Y. & Nicolson, G. L. Candidate metastasis-associated genes of the rat 13762NF mammary adenocarcinoma. Breast Cancer Res. Treat. 25, 13165–13174 (1993).
Nicolson, G. L. et al. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer cell invasion, proliferation and nuclear regulation. Clin. Exp. Metastasis 20, 19–24 (2003).
Zhang, X. Y. et al. Metastasis-associated protein 1 (MTA1) is an essential downstream effector of the c-MYC oncoprotein. Proc. Natl Acad. Sci. USA 102, 13968–13973 (2005).
Toh, Y. & Nicolson, G. L. The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications. Clin. Exp. Metastasis 26, 215–227 (2009).
Fujita, N. et al. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell 113, 207–219 (2003). This paper demonstrates that MTA family members form distinct NuRD complexes.
Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).
Mazumdar, A. et al. Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nature Cell Biol. 3, 30–37 (2001). This paper shows that MTA1 expression can be upregulated by the heregulin–ERBB2 pathway in breast cancer cells and represses ER activity.
Molli, P. R., Singh, R. R., Lee, S. W. & Kumar, R. MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene. Oncogene 27, 1971–1980 (2008).
Kumar, R. Another tie that binds the MTA family to breast cancer. Cell 113, 142–143 (2003).
Zhang, H., Stephens, L. C. & Kumar, R. Metastasis tumor antigen family proteins during breast cancer progression and metastasis in a reliable mouse model for human breast cancer. Clin. Cancer Res. 12, 1479–1486 (2006). This paper demonstrates the opposing expression pattern of MTA1 and MTA3 during breast cancer progression.
Reisman, D., Glaros, S. & Thompson, E. A. The SWI/SNF complex and cancer. Oncogene 28, 1653–1668 (2009).
Bracken, A. P. & Helin, K. Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nature Rev. Cancer 9, 773–784 (2009).
Jaye, D. L. et al. The BCL6-associated transcriptional co-repressor, MTA3, is selectively expressed by germinal centre B cells and lymphomas of putative germinal centre derivation. J. Pathol. 213, 106–115 (2007).
Kusam, S. & Dent, A. Common mechanisms for the regulation of B cell differentiation and transformation by the transcriptional repressor protein BCL-6. Immunol. Res. 37, 177–186 (2007).
Satterwhite, E. et al. The BCL11 gene family: involvement of BCL11A in lymphoid malignancies. Blood 98, 3413–3420 (2001).
Liu, P. et al. Bcl11a is essential for normal lymphoid development. Nature Immunol. 4, 525–532 (2003).
Wakabayashi, Y. et al. Bcl11b is required for differentiation and survival of αβ T lymphocytes. Nature Immunol. 4, 533–539 (2003).
Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).
Peinado, H., Olmeda, D. & Cano, A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nature Rev. Cancer 7, 415–428 (2007).
Fu, J. et al. The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis. Cell Res. 21, 275–289 (2011).
Morey, L. et al. MBD3, a component of the NuRD complex, facilitates chromatin alteration and deposition of epigenetic marks. Mol. Cell. Biol. 28, 5912–5923 (2008).
Srinivasan, R., Mager, G. M., Ward, R. M., Mayer, J. & Svaren, J. NAB2 represses transcription by interacting with the CHD4 subunit of the nucleosome remodeling and deacetylase (NuRD) complex. J. Biol. Chem. 281, 15129–15137 (2006).
Adamson, E. D. & Mercola, D. Egr1 transcription factor: multiple roles in prostate tumor cell growth and survival. Tumour Biol. 23, 93–102 (2002).
Abdulkadir, S. A. et al. Frequent and early loss of the EGR1 corepressor NAB2 in human prostate carcinoma. Hum. Pathol. 32, 935–939 (2001).
Sancho, R. et al. JNK signalling modulates intestinal homeostasis and tumourigenesis in mice. EMBO J. 28, 1843–1854 (2009).
Li, R. et al. ZIP: a novel transcription repressor, represses EGFR oncogene and suppresses breast carcinogenesis. EMBO J. 28, 2763–2776 (2009).
Yoo, Y. G., Kong, G. & Lee, M. O. Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1α protein by recruiting histone deacetylase 1. EMBO J. 25, 1231–1241 (2006).
Luo, J., Su, F., Chen, D., Shiloh, A. & Gu, W. Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 408, 377–381 (2000). This paper was the first to demonstrate that the NuRD complex can regulate tumour suppressors via post-translational modifications.
Moon, H. E., Cheon, H. & Lee, M. S. Metastasis-associated protein 1 inhibits p53-induced apoptosis. Oncol. Rep. 18, 1311–1314 (2007).
Gururaj, A. E. et al. MTA1, a transcriptional activator of breast cancer amplified sequence 3. Proc. Natl Acad. Sci. USA 103, 6670–6675 (2006).
Ohshiro, K. et al. Acetylation-dependent oncogenic activity of metastasis-associated protein 1 co-regulator. EMBO Rep. 11, 691–697 (2010). This paper shows that post-translational modification of MTA1 is important for its oncogenic activities.
Balasenthil, S. et al. Identification of Pax5 as a target of MTA1 in B-cell lymphomas. Cancer Res. 67, 7132–7138 (2007).
Polo, S. E., Kaidi, A., Baskcomb, L., Galanty, Y. & Jackson, S. P. Regulation of DNA-damage responses and cell-cycle progression by the chromatin remodelling factor CHD4. EMBO J. 29, 3130–3139 (2010). This paper demonstrates poly(ADP-ribose)-dependent recruitment of the NuRD complex to sites of DNA damage and shows that NuRD has a role in G1/S transition during the cell cycle by modulating p53 function.
Olsen, J. V. et al. Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci. Signal 3, ra3 (2010).
Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840 (2009).
Howard, G., Eiges, R., Gaudet, F., Jaenisch, R. & Eden, A. Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice. Oncogene 27, 404–408 (2008).
Costello, J. F. et al. Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nature Genet. 24, 132–138 (2000).
McCabe, M. T., Brandes, J. C. & Vertino, P. M. Cancer DNA methylation: molecular mechanisms and clinical implications. Clin. Cancer Res. 15, 3927–3937 (2009).
Zhang, Y. et al. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13, 1924–1935 (1999).
Sansom, O. J., Maddison, K. & Clarke, A. R. Mechanisms of disease: methyl-binding domain proteins as potential therapeutic targets in cancer. Nature Clin. Pract. Oncol. 4, 305–315 (2007).
Magdinier, F. & Wolffe, A. P. Selective association of the methyl-CpG binding protein MBD2 with the silent p14/p16 locus in human neoplasia. Proc. Natl Acad. Sci. USA 98, 4990–4995 (2001).
Sansom, O. J. et al. Deficiency of Mbd2 suppresses intestinal tumorigenesis. Nature Genet. 34, 145–147 (2003).
Helbling Chadwick, L., Chadwick, B. P., Jaye, D. L. & Wade, P. A. The Mi-2/NuRD complex associates with pericentromeric heterochromatin during S phase in rapidly proliferating lymphoid cells. Chromosoma 118, 445–457 (2009).
Chou, D. M. et al. A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage. Proc. Natl Acad. Sci. USA 107, 18475–18480 (2010). This paper also demonstrates poly(ADP-ribose)-dependent recruitment of NuRD complex to sites of DNA damage. It further suggests a role of the NuRD complex in repressing transcription at sites of DNA damage.
Smeenk, G. et al. The NuRD chromatin-remodeling complex regulates signaling and repair of DNA damage. J. Cell Biol. 190, 741–749 (2010).
Brehm, A. et al. The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth. EMBO J. 18, 2449–2458 (1999).
Xu, G. L. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187–191 (1999).
Hansen, R. S. et al. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc. Natl Acad. Sci. USA 96, 14412–14417 (1999).
Blanco-Betancourt, C. E. et al. Defective B-cell-negative selection and terminal differentiation in the ICF syndrome. Blood 103, 2683–2690 (2004).
Larsen, D. H. et al. The chromatin-remodeling factor CHD4 coordinates signaling and repair after DNA damage. J. Cell Biol. 190, 731–740 (2010).
Li, D. Q. et al. MTA1 coregulator regulates p53 stability and function. J. Biol. Chem. 284, 34545–34552 (2009).
Li, D. Q. et al. E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1. Proc. Natl Acad. Sci. USA 106, 17493–17498 (2009).
Bantscheff, M. et al. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nature Biotech. 29, 255–265 (2011).
Krivtsov, A. V. & Armstrong, S. A. MLL translocations, histone modifications and leukaemia stem-cell development. Nature Rev. Cancer 7, 823–833 (2007).
Pegoraro, G. et al. Ageing-related chromatin defects through loss of the NURD complex. Nature Cell Biol. 11, 1261–1267 (2009).
Kim, M. S., Chung, N. G., Kang, M. R., Yoo, N. J. & Lee, S. H. Genetic and expressional alterations of CHD genes in gastric and colorectal cancers. Histopathology 58, 660–668 (2011).
Bader, S. et al. MBD1, MBD2 and CGBP genes at chromosome 18q21 are infrequently mutated in human colon and lung cancers. Oncogene 22, 3506–3510 (2003).
Zhu, Y., Harrison, D. J. & Bader, S. A. Genetic and epigenetic analyses of MBD3 in colon and lung cancer. Br. J. Cancer 90, 1972–1975 (2004).
Ropero, S. et al. A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. Nature Genet. 38, 566–569 (2006).
Musselman, C. A. et al. Binding of the CHD4 PHD2 finger to histone H3 is modulated by covalent modifications. Biochem. J. 423, 179–187 (2009).
Mansfield, R. E. et al. Plant homeodomain (PHD) fingers of CHD4 are histone H3-binding modules with preference for unmodified H3K4 and methylated H3K9. J. Biol. Chem. 286, 11779–11791 (2011).
Bouazoune, K. et al. The dMi-2 chromodomains are DNA binding modules important for ATP-dependent nucleosome mobilization. EMBO J. 21, 2430–2440 (2002).
Durr, H., Flaus, A., Owen-Hughes, T. & Hopfner, K. P. Snf2 family ATPases and DExx box helicases: differences and unifying concepts from high-resolution crystal structures. Nucleic Acids Res. 34, 4160–4167 (2006).
Pazin, M. J. & Kadonaga, J. T. SWI2/SNF2 and related proteins: ATP-driven motors that disrupt protein-DNA interactions? Cell 88, 737–740 (1997).
Becker, P. B. & Horz, W. ATP-dependent nucleosome remodeling. Annu. Rev. Biochem. 71, 247–273 (2002).
Thiagalingam, S. et al. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann. N. Y Acad. Sci. 983, 84–100 (2003).
Jones, P. L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genet. 19, 187–191 (1998).
Nan, X., Campoy, F. J. & Bird, A. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88, 471–481 (1997).
Oliver, A. W. et al. Crystal structure of the proximal BAH domain of the polybromo protein. Biochem. J. 389, 657–664 (2005).
Humphrey, G. W. et al. Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J. Biol. Chem. 276, 6817–6824 (2001).
Roche, A. E. et al. The zinc finger and C-terminal domains of MTA proteins are required for FOG-2-mediated transcriptional repression via the NuRD complex. J. Mol. Cell. Cardiol. 44, 352–360 (2008).
Murzina, N. V. et al. Structural basis for the recognition of histone H4 by the histone-chaperone RbAp46. Structure 16, 1077–1085 (2008).
Acknowledgements
The authors would like to thank members of the Wade laboratory for critical comments and suggestions for this manuscript. They apologize to those whose work is not cited owing to space limitations. The authors' research is funded by the Intramural Research Program of the US National Institute of Environmental Health Sciences, NIH (Project number Z01ES101965 to P.A.W.).
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Lai, A., Wade, P. Cancer biology and NuRD: a multifaceted chromatin remodelling complex. Nat Rev Cancer 11, 588–596 (2011). https://doi.org/10.1038/nrc3091
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DOI: https://doi.org/10.1038/nrc3091
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