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  • 1
    Publication Date: 2009-02-13
    Description: Epigenetic mechanisms that maintain neurogenesis throughout adult life remain poorly understood. Trithorax group (trxG) and Polycomb group (PcG) gene products are part of an evolutionarily conserved chromatin remodelling system that activate or silence gene expression, respectively. Although PcG member Bmi1 has been shown to be required for postnatal neural stem cell self-renewal, 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800116/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800116/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lim, Daniel A -- Huang, Yin-Cheng -- Swigut, Tomek -- Mirick, Anika L -- Garcia-Verdugo, Jose Manuel -- Wysocka, Joanna -- Ernst, Patricia -- Alvarez-Buylla, Arturo -- 5R37-NS028478/NS/NINDS NIH HHS/ -- R37 NS028478/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Mar 26;458(7237):529-33. doi: 10.1038/nature07726. Epub 2009 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Street M779, San Francisco, California 94143, USA. limd@neurosurg.ucsf.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19212323" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cell Differentiation ; Cell Lineage ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; Chromatin/*metabolism ; *Chromatin Assembly and Disassembly ; Chromatin Immunoprecipitation ; Histone-Lysine N-Methyltransferase ; Histones/metabolism ; Homeodomain Proteins/chemistry/genetics/metabolism ; Methylation ; Mice ; Myeloid-Lymphoid Leukemia Protein/deficiency/genetics/*metabolism ; Nerve Tissue Proteins/metabolism ; *Neurogenesis ; Neuroglia/cytology/metabolism ; Neurons/*cytology/metabolism ; Olfactory Bulb/cytology/metabolism ; Stem Cells/*cytology/metabolism ; Transcription Factors/chemistry/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-03-23
    Description: The genome is extensively transcribed into long intergenic noncoding RNAs (lincRNAs), many of which are implicated in gene silencing. Potential roles of lincRNAs in gene activation are much less understood. Development and homeostasis require coordinate regulation of neighbouring genes through a process termed locus control. Some locus control elements and enhancers transcribe lincRNAs, hinting at possible roles in long-range control. In vertebrates, 39 Hox genes, encoding homeodomain transcription factors critical for positional identity, are clustered in four chromosomal loci; the Hox genes are expressed in nested anterior-posterior and proximal-distal patterns colinear with their genomic position from 3' to 5'of the cluster. Here we identify HOTTIP, a lincRNA transcribed from the 5' tip of the HOXA locus that coordinates the activation of several 5' HOXA genes in vivo. Chromosomal looping brings HOTTIP into close proximity to its target genes. HOTTIP RNA binds the adaptor protein WDR5 directly and targets WDR5/MLL complexes across HOXA, driving histone H3 lysine 4 trimethylation and gene transcription. Induced proximity is necessary and sufficient for HOTTIP RNA activation of its target genes. Thus, by serving as key intermediates that transmit information from higher order chromosomal looping into chromatin modifications, lincRNAs may organize chromatin domains to coordinate long-range gene activation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670758/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670758/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Kevin C -- Yang, Yul W -- Liu, Bo -- Sanyal, Amartya -- Corces-Zimmerman, Ryan -- Chen, Yong -- Lajoie, Bryan R -- Protacio, Angeline -- Flynn, Ryan A -- Gupta, Rajnish A -- Wysocka, Joanna -- Lei, Ming -- Dekker, Job -- Helms, Jill A -- Chang, Howard Y -- HG003143/HG/NHGRI NIH HHS/ -- R01 HG003143/HG/NHGRI NIH HHS/ -- R01 HG003143-06/HG/NHGRI NIH HHS/ -- R01 HG003143-06S1/HG/NHGRI NIH HHS/ -- R01 HG003143-06S2/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Apr 7;472(7341):120-4. doi: 10.1038/nature09819. Epub 2011 Mar 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21423168" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cells, Cultured ; Chromatin/*genetics/metabolism ; DNA, Intergenic/genetics ; Embryo, Mammalian/metabolism ; Fibroblasts/metabolism ; Gene Expression Regulation, Developmental/*genetics ; Gene Knockdown Techniques ; Genes, Homeobox/*genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/chemistry/metabolism ; Humans ; Lysine/metabolism ; Methylation ; Mice ; Molecular Sequence Data ; Multigene Family/genetics ; Organ Specificity ; RNA, Untranslated/*genetics ; Transcription, Genetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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