Mi-2/NuRD complex

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]

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]

Overexpression of Mbd3, a subunit of NuRD, inhibits induction of iPSCs. Depletion of Mbd3, on the other hand, improves reprogramming efficiency only in fibroblast,[17][18] that results in deterministic and synchronized iPS cell reprogramming (near 100% efficiency within seven days from mouse and human cells).[19]

References
  1. 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
  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. 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. 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.
  17. Luo M, Ling T, Xie W, Sun H, Zhou Y, Zhu Q, et al. (July 2013). "NuRD blocks reprogramming of mouse somatic cells into pluripotent stem cells". Stem Cells. 31 (7): 1278–1286. doi:10.1002/stem.1374. hdl:10397/18487. PMID 23533168.
  18. Drozd AM, Walczak MP, Piaskowski S, Stoczynska-Fidelus E, Rieske P, Grzela DP (June 2015). "Generation of human iPSCs from cells of fibroblastic and epithelial origin by means of the oriP/EBNA-1 episomal reprogramming system". Stem Cell Research & Therapy. 6 (1): 122. doi:10.1186/s13287-015-0112-3. PMC 4515927. PMID 26088261.
  19. Rais Y, Zviran A, Geula S, Gafni O, Chomsky E, Viukov S, et al. (October 2013). "Deterministic direct reprogramming of somatic cells to pluripotency". Nature. 502 (7469): 65–70. doi:10.1038/nature12587. PMID 24048479.
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