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      Transcription Factor Positive Regulatory Domain 4 (PRDM4) Recruits Protein Arginine Methyltransferase 5 (PRMT5) to Mediate Histone Arginine Methylation and Control Neural Stem Cell Proliferation and Differentiation*

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          Background: Neural stem cells generate all the cell types of the central nervous system.

          Results: Transcription factor, PRDM4, recruits protein arginine methyltransferase 5 (PRMT5) to control the timing of neurogenesis.

          Conclusion: PRDM4- and PRMT5-mediated histone arginine methylation controls neural stem cell proliferation and differentiation.

          Significance: Histone arginine methylation is a novel epigenetic mechanism that regulates neural stem cell reprogramming.


          During development of the cerebral cortex, neural stem cells (NSCs) undergo a temporal switch from proliferative (symmetric) to neuron-generating (asymmetric) divisions. We investigated the role of Schwann cell factor 1 (SC1/PRDM4), a member of the PRDM family of transcription factors, in this critical transition. We discovered that SC1 recruits the chromatin modifier PRMT5, an arginine methyltransferase that catalyzes symmetric dimethylation of histone H4 arginine 3 (H4R3me2s) and that this modification is preferentially associated with undifferentiated cortical NSCs. Overexpressing SC1 in embryonic NSCs led to an increase in the number of Nestin-expressing precursors; mutational analysis of SC1 showed that this was dependent on recruitment of PRMT5. We found that SC1 protein levels are down-regulated at the onset of neurogenesis and that experimental knockdown of SC1 in primary NSCs triggers precocious neuronal differentiation. We propose that SC1 and PRMT5 are components of an epigenetic regulatory complex that maintains the “stem-like” cellular state of the NSC by preserving their proliferative capacity and modulating their cell cycle progression. Our findings provide evidence that histone arginine methylation regulates NSC differentiation.

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          Most cited references 44

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          The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells.

          In the developing cerebral cortex, neurons are born on a predictable schedule. Here we show in mice that the essential timing mechanism is programmed within individual progenitor cells, and its expression depends solely on cell-intrinsic and environmental factors generated within the clonal lineage. Multipotent progenitor cells undergo repeated asymmetric divisions, sequentially generating neurons in their normal in vivo order: first preplate cells, including Cajal-Retzius neurons, then deep and finally superficial cortical plate neurons. As each cortical layer arises, stem cells and neuroblasts become restricted from generating earlier-born neuron types. Growth as neurospheres or in co-culture with younger cells did not restore their plasticity. Using short-hairpin RNA (shRNA) to reduce Foxg1 expression reset the timing of mid- but not late-gestation progenitors, allowing them to remake preplate neurons and then cortical-plate neurons. Our data demonstrate that neural stem cells change neuropotency during development and have a window of plasticity when restrictions can be reversed.
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            Timing is everything: making neurons versus glia in the developing cortex.

            During development of the mammalian nervous system, neural stem cells generate neurons first and glia second, thereby allowing the initial establishment of neural circuitry, and subsequent matching of glial numbers and position to that circuitry. Here, we have reviewed work addressing the mechanisms underlying this timed cell genesis, with a particular focus on the developing cortex. These studies have defined an intriguing interplay between intrinsic epigenetic status, transcription factors, and environmental cues, all of which work together to establish this fascinating and complex biological timing mechanism.
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              PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing.

              Mammalian gene silencing is established through methylation of histones and DNA, although the order in which these modifications occur remains contentious. Using the human beta-globin locus as a model, we demonstrate that symmetric methylation of histone H4 arginine 3 (H4R3me2s) by the protein arginine methyltransferase PRMT5 is required for subsequent DNA methylation. H4R3me2s serves as a direct binding target for the DNA methyltransferase DNMT3A, which interacts through the ADD domain containing the PHD motif. Loss of the H4R3me2s mark through short hairpin RNA-mediated knockdown of PRMT5 leads to reduced DNMT3A binding, loss of DNA methylation and gene activation. In primary erythroid progenitors from adult bone marrow, H4R3me2s marks the inactive methylated globin genes coincident with localization of PRMT5. Our findings define DNMT3A as both a reader and a writer of repressive epigenetic marks, thereby directly linking histone and DNA methylation in gene silencing.

                Author and article information

                J Biol Chem
                J. Biol. Chem
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (9650 Rockville Pike, Bethesda, MD 20814, U.S.A. )
                14 December 2012
                9 October 2012
                9 October 2012
                : 287
                : 51
                : 42995-43006
                From the []Wolfson Institute for Biomedical Research and Research Department of Cell and Developmental Biology and
                the [§ ]Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, WC1E 6BT, United Kingdom
                Author notes
                [1 ] To whom correspondence should be addressed: Wolfson Institute for Biomedical Research and Research Dept. of Cell and Developmental Biology, University College London, Gower St., London WC1E 6BT, UK. Tel.: 44-207-679-6744; Fax: 44-207-209-0470; E-mail: a.chittka@ 123456ucl.ac.uk .
                © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

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