Mi-2/NuRD complex

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In the field of molecular biology, the Mi-2/NuRD (Nucleosome Remodeling Deacetylase) complex, is a group of associated proteins with both ATP-dependent chromatin remodeling and histone deacetylase activities. [1] [2] As of 2007, Mi-2/NuRD was the only known protein complex that couples chromatin remodeling ATPase and chromatin deacetylation enzymatic functions. [3]

Contents

Discovery

In 1998, several independent groups reported the discovery of multi-enzyme complexes conferring both nucleosome remodelling and histone deacetylation activities. [4] [5] [6] [7] Xue et al [1] first described the human complex as the Nucleosome Remodelling and Deacetylase (NuRD) - this name has since been adopted for homologous complexes in most organisms.

Composition

The NuRD complex contains seven subunits: the histone deacetylase core proteins HDAC1 and HDAC2, the histone-binding proteins RbAp46 and RbAp48, the metastasis-associated proteins MTA1 (or MTA2 / MTA3), the methyl-CpG-binding domain protein MBD3 (or MBD2) and the chromodomain-helicase-DNA-binding protein CHD3 (aka Mi-2alpha) or CHD4 (aka Mi-2beta).

NuRD can be subdivided into two discrete subcomplexes which confer neuclosome remodelling or histone deacetylation activity,each of which retains catalytic activity without the presence of the other. [8] The histone deacetylases HDAC1 and HDAC2 and the histone binding proteins RbAp48 and RbAp46 form a core complex shared between NuRD and Sin3-histone deacetylase complexes. [9] [10]

NuRD-independent Mi2/CHD4 activity

Mi-2/CHD4 may confer NuRD independent transcriptional regulation in some organisms and contexts. [11] For example, in the fly, Drosophila melanogaster, the majority of Mi2 biochemically purifies separately from the rest of the NuRD subunits [12] and profiling of NuRD component binding sites indicates that only a minority of loci are co-occupied by both Mi-2 and HDAC. [13] Similar results are reported in mouse embryonic stem cells where CHD4 shares only a minority of binding loci with core NuRD component, MBD3. [14] Independently of histone deacetylase, Mi-2 knockdown in neuronal tissue results in mis-expression of genes that are normally restricted to germline. [13] A similar observation was made in human erythroid cells, in which CHD4 but not Mi-2 is required for suppression of fetal globin genes. [15]

Biological functions of NuRD

NuRD is traditionally thought of as a primarily repressive complex, and in some contexts it is clear that it does confer this function. For example, NuRD is required to silence genes in neuronal differentiation. [16] However, more recent studies have presented a more nuanced picture of NuRD activity in which it is required for fine-tuning of gene expression during stem cell differentiation to ensure appropriate lineage specification. [14] [ dubious – discuss ]

Related Research Articles

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<span class="mw-page-title-main">MBD3</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">CHD4</span> Protein-coding gene in the species Homo sapiens

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References

  1. 1 2 Xue Y, Wong J, Moreno GT, Young MK, Côté J, Wang W (December 1998). "NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities". Molecular Cell. 2 (6): 851–861. doi: 10.1016/S1097-2765(00)80299-3 . PMID   9885572.
  2. ↑ Zhang Y, Yinghua L (2010). "The Expanding Mi-2/NuRD Complexes: A Schematic Glance". Proteomics Insights. 3: 79–109. doi: 10.4137/PRI.S6329 .
  3. ↑ Denslow SA, Wade PA (August 2007). "The human Mi-2/NuRD complex and gene regulation". Oncogene. 26 (37): 5433–5438. doi: 10.1038/sj.onc.1210611 . PMID   17694084. Open Access logo PLoS transparent.svg
  4. ↑ Tong JK, Hassig CA, Schnitzler GR, Kingston RE, Schreiber SL (October 1998). "Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex". Nature. 395 (6705): 917–921. doi:10.1038/27699. PMID   9804427.
  5. ↑ Wade PA, Jones PL, Vermaak D, Wolffe AP (July 1998). "A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase". Current Biology. 8 (14): 843–846. doi: 10.1016/S0960-9822(98)70328-8 . PMID   9663395.
  6. ↑ Xue Y, Wong J, Moreno GT, Young MK, Côté J, Wang W (December 1998). "NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities". Molecular Cell. 2 (6): 851–861. doi: 10.1016/S1097-2765(00)80299-3 . PMID   9885572.
  7. ↑ Zhang Y, LeRoy G, Seelig HP, Lane WS, Reinberg D (October 1998). "The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities". Cell. 95 (2): 279–289. doi: 10.1016/S0092-8674(00)81758-4 .
  8. ↑ Zhang W, Aubert A, Gomez de Segura JM, Karuppasamy M, Basu S, Murthy AS, et al. (July 2016). "The Nucleosome Remodeling and Deacetylase Complex NuRD Is Built from Preformed Catalytically Active Sub-modules". Journal of Molecular Biology. 428 (14): 2931–2942. doi:10.1016/j.jmb.2016.04.025. PMC   4942838 . PMID   27117189.
  9. ↑ Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D (August 1999). "Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation". Genes & Development. 13 (15): 1924–1935. doi:10.1101/gad.13.15.1924. PMC   316920 . PMID   10444591.
  10. ↑ Zhang Y, LeRoy G, Seelig HP, Lane WS, Reinberg D (October 1998). "The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities". Cell. 95 (2): 279–289. doi: 10.1016/S0092-8674(00)81758-4 . PMID   9790534.
  11. ↑ Kunert N, Brehm A (May 2009). "Novel Mi-2 related ATP-dependent chromatin remodelers". Epigenetics. 4 (4): 209–211. doi: 10.4161/epi.8933 . PMID   19535903.
  12. ↑ Kunert N, Wagner E, Murawska M, Klinker H, Kremmer E, Brehm A (March 2009). "dMec: a novel Mi-2 chromatin remodelling complex involved in transcriptional repression". The EMBO Journal. 28 (5): 533–544. doi:10.1038/emboj.2009.3. PMC   2657585 . PMID   19165147.
  13. 1 2 Aughey GN, Forsberg E, Grimes K, Zhang S, Southall TD (April 2023). "NuRD-independent Mi-2 activity represses ectopic gene expression during neuronal maturation". EMBO Reports. 24 (4): e55362. doi:10.15252/embr.202255362. PMC   10074086 . PMID   36722816.
  14. 1 2 Bornelöv S, Reynolds N, Xenophontos M, Gharbi S, Johnstone E, Floyd R, et al. (July 2018). "The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression". Molecular Cell. 71 (1): 56–72.e4. doi:10.1016/j.molcel.2018.06.003. PMC   6039721 . PMID   30008319.
  15. ↑ Amaya M, Desai M, Gnanapragasam MN, Wang SZ, Zu Zhu S, Williams DC, Ginder GD (April 2013). "Mi2β-mediated silencing of the fetal γ-globin gene in adult erythroid cells". Blood. 121 (17): 3493–3501. doi:10.1182/blood-2012-11-466227. PMC   3637018 . PMID   23444401.
  16. ↑ Yamada T, Yang Y, Hemberg M, Yoshida T, Cho HY, Murphy JP, et al. (July 2014). "Promoter decommissioning by the NuRD chromatin remodeling complex triggers synaptic connectivity in the mammalian brain". Neuron. 83 (1): 122–134. doi:10.1016/j.neuron.2014.05.039. PMC   4266462 . PMID   24991957.
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