An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation

Abstract

We have previously described a multiprotein complex termed the BHC or BRAF–HDAC complex, which is required for the repression of neuronal-specific genes1. We have shown that the BHC complex is recruited by a neuronal silencer, REST (RE1-silencing transcription factor), and mediates the repression of REST-responsive genes1. BHC is a multiprotein complex consisting of two enzymatic activities: a histone deacetylase (HDAC1 or 2) and a recently described histone demethylase (BHC110, also known as LSD1 or AOF2)1,2,3. Here we show that BHC110-containing complexes show a nearly fivefold increase in demethylation of histone H3 lysine 4 (H3K4) compared to recombinant BHC110. Furthermore, recombinant BHC110 is unable to demethylate H3K4 on nucleosomes, but BHC110-containing complexes readily demethylate nucleosomes. In vitro reconstitution of the BHC complex using recombinant subunits reveals an essential role for the REST corepressor CoREST, not only in stimulating demethylation on core histones but also promoting demethylation of nucleosomal substrates. We find that nucleosomal demethylation is the result of CoREST enhancing the association between BHC110 and nucleosomes. Depletion of CoREST in in vivo cell culture results in de-repression of REST-responsive gene expression and increased methylation of H3K4. Together, these results highlight an essential role for CoREST in demethylation of H3K4 both in vitro and in vivo.

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Figure 1: Mutation in a conserved lysine residue abrogates demethylation activity of BHC110-containing complexes.
Figure 2: Demethylation of nucleosomes by BHC110 complexes.
Figure 3: CoREST promotes nucleosomal demethylation in vitro.
Figure 4: CoREST mediates the association of BHC110 with nucleosomes.

References

  1. 1

    Hakimi, M. A. et al. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc. Natl Acad. Sci. USA 99, 7420–7425 (2002)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004)

    CAS  Article  Google Scholar 

  3. 3

    Hakimi, M. A., Dong, Y., Lane, W. S., Speicher, D. W. & Shiekhattar, R. A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J. Biol. Chem. 278, 7234–7239 (2003)

    CAS  Article  Google Scholar 

  4. 4

    Binda, C. et al. A 30-angstrom-long U-shaped catalytic tunnel in the crystal structure of polyamine oxidase. Struct. Fold. Des. 7, 265–276 (1999)

    CAS  Article  Google Scholar 

  5. 5

    Binda, C. et al. Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures. Proc. Natl Acad. Sci. USA 100, 9750–9755 (2003)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Andres, M. E. et al. CoREST: a functional corepressor required for regulation of neural-specific gene expression. Proc. Natl Acad. Sci. USA 96, 9873–9878 (1999)

    ADS  CAS  Article  Google Scholar 

  7. 7

    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)

    CAS  Article  Google Scholar 

  8. 8

    Battaglioli, E. et al. REST repression of neuronal genes requires components of the hSWI.SNF complex. J. Biol. Chem. 277, 41038–41045 (2002)

    CAS  Article  Google Scholar 

  9. 9

    Ballas, N. et al. Regulation of neuronal traits by a novel transcriptional complex. Neuron 31, 353–365 (2001)

    CAS  Article  Google Scholar 

  10. 10

    Grimes, J. A. et al. The co-repressor mSin3A is a functional component of the REST-CoREST repressor complex. J. Biol. Chem. 275, 9461–9467 (2000)

    CAS  Article  Google Scholar 

  11. 11

    Yamagoe, S. et al. Interaction of histone acetylases and deacetylases in vivo. Mol. Cell. Biol. 23, 1025–1033 (2003)

    CAS  Article  Google Scholar 

  12. 12

    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)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Lunyak, V. V. et al. Corepressor-dependent silencing of chromosomal regions encoding neuronal genes. Science 298, 1747–1752 (2002)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Dallman, J. E., Allopenna, J., Bassett, A., Travers, A. & Mandel, G. A conserved role but different partners for the transcriptional corepressor CoREST in fly and mammalian nervous system formation. J. Neurosci. 24, 7186–7193 (2004)

    CAS  Article  Google Scholar 

  15. 15

    Yu, J., Li, Y., Ishizuka, T., Guenther, M. G. & Lazar, M. A. A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation. EMBO J. 22, 3403–3410 (2003)

    CAS  Article  Google Scholar 

  16. 16

    Boyer, L. A. et al. Essential role for the SANT domain in the functioning of multiple chromatin remodeling enzymes. Mol. Cell 10, 935–942 (2002)

    CAS  Article  Google Scholar 

  17. 17

    Aasland, R., Stewart, A. F. & Gibson, T. The SANT domain: a putative DNA-binding domain in the SWI-SNF and ADA complexes, the transcriptional co-repressor N-CoR and TFIIIB. Trends Biochem. Sci. 21, 87–88 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Guenther, M. G., Barak, O. & Lazar, M. A. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol. Cell. Biol. 21, 6091–6101 (2001)

    CAS  Article  Google Scholar 

  19. 19

    Ding, Z., Gillespie, L. L. & Paterno, G. D. Human MI-ER1 alpha and beta function as transcriptional repressors by recruitment of histone deacetylase 1 to their conserved ELM2 domain. Mol. Cell. Biol. 23, 250–258 (2003)

    CAS  Article  Google Scholar 

  20. 20

    Sterner, D. E., Wang, X., Bloom, M. H., Simon, G. M. & Berger, S. L. The SANT domain of Ada2 is required for normal acetylation of histones by the yeast SAGA complex. J. Biol. Chem. 277, 8178–8186 (2002)

    CAS  Article  Google Scholar 

  21. 21

    Barak, O. et al. Isolation of human NURF: a regulator of Engrailed gene expression. EMBO J. 22, 6089–6100 (2003)

    CAS  Article  Google Scholar 

  22. 22

    Dong, Y. et al. Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol. Cell 12, 1087–1099 (2003)

    CAS  Article  Google Scholar 

  23. 23

    Gregory, R. I. et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004)

    ADS  CAS  Article  Google Scholar 

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Acknowledgements

We would like to thank D. Bochar and M. A. Hakimi for generating baculoviruses encoding BHC subunits. We are grateful to R. Gregory for comments on the manuscript. R.S. was supported by a grant from the American Cancer Society (ACS).

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Correspondence to Ramin Shiekhattar.

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Supplementary Figures

Supplementary Figures S1-S3. Supplementary Figure S1, CoREST enhances histone demethylation. Supplementary Figure S2, both SANT domains are involved in nucleosomal demethylation. Supplementary Figure S3 BHC110 depletion increases mRNA levels of Synapsin and muscarinic Acetylcholine receptor 4. (PDF 1058 kb)

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Lee, M., Wynder, C., Cooch, N. et al. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437, 432–435 (2005). https://doi.org/10.1038/nature04021

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