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 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. Access through your institution Buy or subscribe This is a preview of subscription

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CONTROL EMBRYONIC BRAIN DEVELOPMENT Article Open access 13 August 2020 ZFP462 SAFEGUARDS NEURAL LINEAGE SPECIFICATION BY TARGETING G9A/GLP-MEDIATED HETEROCHROMATIN TO SILENCE ENHANCERS

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  Download references 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

_Mll1__F/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 * Yin-Cheng Huang Present

address: Present address: Department of Neurosurgery, Graduate Institute of Clinical Medical Science, ChangGung Univerisity, Kwei-Shan, Tao-yuan, Taiwan., * Daniel A. Lim and Yin-Cheng

Huang: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Department of Neurological Surgery,, Daniel A. Lim, Yin-Cheng Huang & Arturo Alvarez-Buylla * Institute

for Regeneration Medicine, and,, Daniel A. Lim, Yin-Cheng Huang & Arturo Alvarez-Buylla * Veteran’s Affairs Medical Center, University of California, San Francisco, 505 Parnassus Street

M779, San Francisco, California 94143, USA , Daniel A. Lim * Department of Chemical and Systems Biology, Department of Developmental Biology Stanford University School of Medicine, Stanford,

California 94305, USA, Tomek Swigut & Joanna Wysocka * Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire 03755, USA, Anika L. Mirick & Patricia Ernst *

Laboratorio de Neurobiologia Comparada, Instituto Cavanilles, Universidad de Valencia, Valencia 46012, Spain Jose Manuel Garcia-Verdugo * Laboratorio de Morfologia Celular, Centro de

Investigación Príncipe Felipe, CIBERNED, Valencia 46012, Spain , Jose Manuel Garcia-Verdugo Authors * Daniel A. Lim View author publications You can also search for this author inPubMed 

Google Scholar * Yin-Cheng Huang View author publications You can also search for this author inPubMed Google Scholar * Tomek Swigut View author publications You can also search for this

author inPubMed Google Scholar * Anika L. Mirick View author publications You can also search for this author inPubMed Google Scholar * Jose Manuel Garcia-Verdugo View author publications

You can also search for this author inPubMed Google Scholar * Joanna Wysocka View author publications You can also search for this author inPubMed Google Scholar * Patricia Ernst View author

publications You can also search for this author inPubMed Google Scholar * Arturo Alvarez-Buylla View author publications You can also search for this author inPubMed Google Scholar

CORRESPONDING AUTHORS Correspondence to Daniel A. Lim or Arturo Alvarez-Buylla. SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURES This file contains Supplementary Figures 1-9 with Legends (PDF

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ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 23 July 2007 * Accepted: 15 December 2008 * Published: 11 February 2009 * Issue Date: 26 March 2009 *

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