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Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells

Abstract

Epigenetic mechanisms that maintain neurogenesis throughout adult life remain poorly understood1. Trithorax group (trxG) and Polycomb group (PcG) gene products are part of an evolutionarily conserved chromatin remodelling system that activate or silence gene expression, respectively2. Although PcG member Bmi1 has been shown to be required for postnatal neural stem cell self-renewal3,4, the role of trxG genes remains unknown. Here we show that the trxG member Mll1 (mixed-lineage leukaemia 1) is required for neurogenesis in the mouse postnatal brain. Mll1-deficient subventricular zone neural stem cells survive, proliferate and efficiently differentiate into glial lineages; however, neuronal differentiation is severely impaired. In Mll1-deficient cells, early proneural Mash1 (also known as Ascl1) and gliogenic Olig2 expression are preserved, but Dlx2, a key downstream regulator of subventricular zone neurogenesis, is not expressed. Overexpression of Dlx2 can rescue neurogenesis in Mll1-deficient cells. Chromatin immunoprecipitation demonstrates that Dlx2 is a direct target of MLL in subventricular zone cells. In differentiating wild-type subventricular zone cells, Mash1, Olig2 and Dlx2 loci have high levels of histone 3 trimethylated at lysine 4 (H3K4me3), consistent with their transcription. In contrast, in Mll1-deficient subventricular zone cells, chromatin at Dlx2 is bivalently marked by both H3K4me3 and histone 3 trimethylated at lysine 27 (H3K27me3), and the Dlx2 gene fails to properly activate. These data support a model in which Mll1 is required to resolve key silenced bivalent loci in postnatal neural precursors to the actively transcribed state for the induction of neurogenesis, but not for gliogenesis.

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Figure 1: Mll1 is required for normal SVZ-olfactory bulb neurogenesis.
Figure 2: Mll1 -deletion impairs postnatal SVZ-olfactory-bulb neurogenesis but not gliogenesis.
Figure 3: Mll1 -dependent DLX2 expression is required for postnatal SVZ neurogenesis.
Figure 4: Dlx2 is trimethylated at both H3K4 and H3K27 in Mll1 Δ/Δ cells.

References

  1. Hsieh, J. & Gage, F. H. Epigenetic control of neural stem cell fate. Curr. Opin. Genet. Dev. 14, 461–469 (2004)

    CAS  Article  Google Scholar 

  2. Schuettengruber, B., Chourrout, D., Vervoort, M., Leblanc, B. & Cavalli, G. Genome regulation by polycomb and trithorax proteins. Cell 128, 735–745 (2007)

    CAS  Article  Google Scholar 

  3. Molofsky, A. V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003)

    ADS  CAS  Article  Google Scholar 

  4. Fasano, C. A. et al. shRNA knockdown of Bmi-1 reveals a critical role for p21-Rb pathway in NSC self-renewal during development. Cell Stem Cell 1, 87–99 (2007)

    CAS  Article  Google Scholar 

  5. Lim, D. A. et al. In vivo transcriptional profile analysis reveals RNA splicing and chromatin remodeling as prominent processes for adult neurogenesis. Mol. Cell. Neurosci. 31, 131–148 (2006)

    CAS  Article  Google Scholar 

  6. Daser, A. & Rabbitts, T. H. Extending the repertoire of the mixed-lineage leukemia gene MLL in leukemogenesis. Genes Dev. 18, 965–974 (2004)

    CAS  Article  Google Scholar 

  7. Yu, B. D., Hess, J. L., Horning, S. E., Brown, G. A. & Korsmeyer, S. J. Altered Hox expression and segmental identity in Mll-mutant mice. Nature 378, 505–508 (1995)

    ADS  CAS  Article  Google Scholar 

  8. Jude, C. D. et al. Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. Cell Stem Cell 1, 324–337 (2007)

    CAS  Article  Google Scholar 

  9. Zhuo, L. et al. hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo . Genesis 31, 85–94 (2001)

    CAS  Article  Google Scholar 

  10. Han, Y. G. et al. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nature Neurosci. 11, 277–284 (2008)

    CAS  Article  Google Scholar 

  11. Luskin, M. B. Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron 11, 173–189 (1993)

    CAS  Article  Google Scholar 

  12. Lois, C. & Alvarez-Buylla, A. Long-distance neuronal migration in the adult mammalian brain. Science 264, 1145–1148 (1994)

    ADS  CAS  Article  Google Scholar 

  13. Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999)

    CAS  Article  Google Scholar 

  14. Wichterle, H., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Direct evidence for homotypic, glia-independent neuronal migration. Neuron 18, 779–791 (1997)

    CAS  Article  Google Scholar 

  15. Marshall, C. A., Suzuki, S. O. & Goldman, J. E. Gliogenic and neurogenic progenitors of the subventricular zone: who are they, where did they come from, and where are they going? Glia 43, 52–61 (2003)

    Article  Google Scholar 

  16. Picard-Riera, N. et al. Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc. Natl Acad. Sci. USA 99, 13211–13216 (2002)

    ADS  CAS  Article  Google Scholar 

  17. Menn, B. et al. Origin of oligodendrocytes in the subventricular zone of the adult brain. J. Neurosci. 26, 7907–7918 (2006)

    CAS  Article  Google Scholar 

  18. Spassky, N. et al. Adult ependymal cells are postmitotic and are derived from radial glial cells during embryogenesis. J. Neurosci. 25, 10–18 (2005)

    CAS  Article  Google Scholar 

  19. Lu, Q. R. et al. Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109, 75–86 (2002)

    CAS  Article  Google Scholar 

  20. Zhou, Q. & Anderson, D. J. The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109, 61–73 (2002)

    CAS  Article  Google Scholar 

  21. Scheffler, B. et al. Phenotypic and functional characterization of adult brain neuropoiesis. Proc. Natl Acad. Sci. USA 102, 9353–9358 (2005)

    ADS  CAS  Article  Google Scholar 

  22. Novak, A., Guo, C., Yang, W., Nagy, A. & Lobe, C. G. Z/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon Cre-mediated excision. Genesis 28, 147–155 (2000)

    CAS  Article  Google Scholar 

  23. Zappone, M. V. et al. Sox2 regulatory sequences direct expression of a β-geo transgene to telencephalic neural stem cells and precursors of the mouse embryo, revealing regionalization of gene expression in CNS stem cells. Development 127, 2367–2382 (2000)

    CAS  PubMed  Google Scholar 

  24. Parras, C. M. et al. Mash1 specifies neurons and oligodendrocytes in the postnatal brain. EMBO J. 23, 4495–4505 (2004)

    CAS  Article  Google Scholar 

  25. Long, J. E. et al. Dlx-dependent and -independent regulation of olfactory bulb interneuron differentiation. J. Neurosci. 27, 3230–3243 (2007)

    CAS  Article  Google Scholar 

  26. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006)

    CAS  Article  Google Scholar 

  27. Milne, T. A. et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol. Cell 10, 1107–1117 (2002)

    CAS  Article  Google Scholar 

  28. Lee, M. G. et al. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318, 447–450 (2007)

    ADS  CAS  Article  Google Scholar 

  29. Swigut, T. & Wysocka, J. H3K27 demethylases, at long last. Cell 131, 29–32 (2007)

    CAS  Article  Google Scholar 

  30. Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007)

    ADS  CAS  Article  Google Scholar 

  31. Wysocka, J. et al. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell 121, 859–872 (2005)

    CAS  Article  Google Scholar 

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Acknowledgements

We thank J. Rubenstein for anti-DLX2 antibodies and the pCAG-Dlx2 plasmid, D. Rowitch for anti-OLIG2 antibodies, and Y. Dou and R. Roeder for anti-MLL1 antibodies. This work was supported by the Neurosurgery Research and Education Foundation/American Association of Neurological Surgeons, Sandler Family Foundation, Northern California Institute for Research and Education, and the Clinical and Translational Research Institute at the University of California, San Francisco (D.A.L.), California Institute for Regenerative Medicine New Faculty Award and The Chicago Community Trust Searle Scholar Award (J.W.), and the Goldhirsch Foundation, J.G. Bowes Research Fund, and National Institutes of Health (NIH) 5R37-NS028478 (A.A.-B.).

Author Contributions D.A.L. conceived the project, designed and performed experiments, coordinated collaborations, and wrote the manuscript. Y.-C.H. worked on most experiments, quantified all in vivo data, and helped prepare the figures. T.S. and J.W. performed ChIP experiments, helped analyse data and contributed ideas. A.L.M and P.A.E. provided the Mll1F/F mouse, helped perform preliminary experiments in Mll1+/- mice and contributed ideas. J.M.G.V. provided electron microscopy data and histological interpretation. A.A.-B. contributed ideas, interpreted results and helped write the manuscript. All authors discussed the results and edited the manuscript.

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Correspondence to Daniel A. Lim or Arturo Alvarez-Buylla.

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Lim, D., Huang, YC., Swigut, T. et al. Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells. Nature 458, 529–533 (2009). https://doi.org/10.1038/nature07726

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