title: Activation of neuronal gene expression by the JMJD3 demethylase is required for postnatal and adult brain neurogenesis.
abstract: The epigenetic mechanisms that enable lifelong neurogenesis from neural stem cells (NSCs) in the adult mammalian brain are poorly understood. Here, we show that JMJD3, a histone H3 lysine 27 (H3K27) demethylase, acts as a critical activator of neurogenesis from adult subventricular zone (SVZ) NSCs. JMJD3 is upregulated in neuroblasts, and Jmjd3 deletion targeted to SVZ NSCs in both developing and adult mice impairs neuronal differentiation. JMJD3 regulates neurogenic gene expression via interaction at not only promoter regions but also neurogenic enhancer elements. JMJD3 localizes at neural enhancers genome-wide in embryonic brain, and in SVZ NSCs, JMJD3 regulates the I12b enhancer of Dlx2. In Jmjd3-deleted SVZ cells, I12b remains enriched with H3K27me3 and Dlx2-dependent neurogenesis fails. These findings support a model in which JMJD3 and the poised state of key transcriptional regulatory elements comprise an epigenetic mechanism that enables the activation of neurogenic gene expression in adult NSCs throughout life.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Dae Hwi
authors.initials: DH
authors.lastname: Park
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Sung Jun
authors.initials: SJ
authors.lastname: Hong
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Salinas
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Siyuan John
authors.initials: SJ
authors.lastname: Liu
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Shawn W
authors.initials: SW
authors.lastname: Sun
authors.affiliation: European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Sgualdino
authors.affiliation: European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Testa
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Matzuk
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Iwamori
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: limd@neurosurg.ucsf.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lim
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse