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

Nature volume 458, pages 529–533 (2009)Cite this article

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.

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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.

Author information

Author notes

  1. Yin-Cheng Huang

    Present address: Present address: Department of Neurosurgery, Graduate Institute of Clinical Medical Science, ChangGung Univerisity, Kwei-Shan, Tao-yuan, Taiwan.,

  2. Daniel A. Lim and Yin-Cheng Huang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurological Surgery,,

    Daniel A. Lim, Yin-Cheng Huang & Arturo Alvarez-Buylla

  2. Institute for Regeneration Medicine, and,,

    Daniel A. Lim, Yin-Cheng Huang & Arturo Alvarez-Buylla

  3. Veteran’s Affairs Medical Center, University of California, San Francisco, 505 Parnassus Street M779, San Francisco, California 94143, USA ,

    Daniel A. Lim

  4. Department of Chemical and Systems Biology, Department of Developmental Biology Stanford University School of Medicine, Stanford, California 94305, USA,

    Tomek Swigut & Joanna Wysocka

  5. Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire 03755, USA,

    Anika L. Mirick & Patricia Ernst

  6. Laboratorio de Neurobiologia Comparada, Instituto Cavanilles, Universidad de Valencia, Valencia 46012, Spain

    Jose Manuel Garcia-Verdugo

  7. Laboratorio de Morfologia Celular, Centro de Investigación Príncipe Felipe, CIBERNED, Valencia 46012, Spain ,

    Jose Manuel Garcia-Verdugo

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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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