title: Role of Tet1/3 Genes and Chromatin Remodeling Genes in Cerebellar Circuit Formation.
abstract: Although mechanisms underlying early steps in cerebellar development are known, evidence is lacking on genetic and epigenetic changes during the establishment of the synaptic circuitry. Using metagene analysis, we report pivotal changes in multiple reactomes of epigenetic pathway genes in cerebellar granule cells (GCs) during circuit formation. During this stage, Tet genes are upregulated and vitamin C activation of Tet enzymes increases the levels of 5-hydroxymethylcytosine (5hmC) at exon start sites of upregulated genes, notably axon guidance genes and ion channel genes. Knockdown of Tet1 and Tet3 by RNAi in ex vivo cerebellar slice cultures inhibits dendritic arborization of developing GCs, a critical step in circuit formation. These findings demonstrate a role for Tet genes and chromatin remodeling genes in the formation of cerebellar circuitry.
authors.affiliation: Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: David
authors.initials: D
authors.lastname: Girardo
authors.affiliation: Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Eve-Ellen
authors.initials: EE
authors.lastname: Govek
authors.affiliation: Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Keisha
authors.initials: K
authors.lastname: John
authors.affiliation: Laboratory of Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Marian
authors.initials: M
authors.lastname: Mellén
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Jill P
authors.initials: JP
authors.lastname: Mesirov
authors.affiliation: Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10065, USA. Electronic address: hatten@rockefeller.edu.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Hatten
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; D049308:Dioxygenases; C551915:Tet3 protein, mouse