title: An epigenetic switch induced by Shh signalling regulates gene activation during development and medulloblastoma growth.
abstract: The Sonic hedgehog (Shh) signalling pathway plays important roles during development and in cancer. Here we report a Shh-induced epigenetic switch that cooperates with Gli to control transcription outcomes. Before induction, poised Shh target genes are marked by a bivalent chromatin domain containing a repressive histone H3K27me3 mark and an active H3K4me3 mark. Shh activation induces a local switch of epigenetic cofactors from the H3K27 methyltransferase polycomb repressive complex 2 (PRC2) to an H3K27me3 demethylase Jmjd3/Kdm6b-centred coactivator complex. We also find that non-enzymatic activities of Jmjd3 are important and that Jmjd3 recruits the Set1/MLL H3K4 methyltransferase complexes in a Shh-dependent manner to resolve the bivalent domain. In vivo, changes of the bivalent domain accompanied Shh-activated cerebellar progenitor proliferation. Overall, our results reveal a regulatory mechanism that underlies the activation of Shh target genes and provides insight into the causes of various diseases and cancers exhibiting altered Shh signalling.
authors.affiliation: Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Xuanming
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Zilai
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Mou
authors.initials: M
authors.lastname: Cao
authors.affiliation: Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center and Department of Host Defense, RIMD, Osaka University, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center and Department of Host Defense, RIMD, Osaka University, Osaka, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Shpargel
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Magnuson
authors.affiliation: Center for Inflammation and Epigenetics, The Methodist Hospital Research Institute, Houston, Texas 77030, USA.
authors.forename: Qingtian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Center for Inflammation and Epigenetics, The Methodist Hospital Research Institute, Houston, Texas 77030, USA.
authors.forename: Rongfu
authors.initials: R
authors.lastname: Wang
authors.affiliation: NIDDK, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Chaochen
authors.initials: C
authors.lastname: Wang
authors.affiliation: NIDDK, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
authors.affiliation: Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000254:growth & development; D044127:Epigenesis, Genetic; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011247:Pregnancy; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C465570:Shh protein, mouse; D000071676:Zinc Finger Protein GLI1; D051788:Myeloid-Lymphoid Leukemia Protein; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D063151:Polycomb Repressive Complex 2