Mi-2/NuRD complex explained

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], Mi-2/NuRD was the only known protein complex that couples chromatin remodeling ATPase and chromatin deacetylation enzymatic functions.[3]

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 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. 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]

Notes and References

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

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