title: Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes.
abstract: The HMG-box transcription factor Sox2 plays a role throughout neurogenesis and also acts at other stages of development, as illustrated by the multiple organs affected in the anophthalmia syndrome caused by SOX2 mutations. Here we combined proteomic and genomic approaches to characterize gene regulation by Sox2 in neural stem cells. Chd7, a chromatin remodeling ATPase associated with CHARGE syndrome, was identified as a Sox2 transcriptional cofactor. Sox2 and Chd7 physically interact, have overlapping genome-wide binding sites and regulate a set of common target genes including Jag1, Gli3 and Mycn, genes mutated in Alagille, Pallister-Hall and Feingold syndromes, which show malformations also associated with SOX2 anophthalmia syndrome or CHARGE syndrome. Regulation of disease-associated genes by a Sox2-Chd7 complex provides a plausible explanation for several malformations associated with SOX2 anophthalmia syndrome or CHARGE syndrome. Indeed, we found that Chd7-haploinsufficient embryos showed severely reduced expression of Jag1 in the developing inner ear.
authors.affiliation: Department of Cell Biology, Erasmus Medical Center (MC), Rotterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Engelen
authors.forename: Umut
authors.initials: U
authors.lastname: Akinci
authors.forename: Jan Christian
authors.initials: JC
authors.lastname: Bryne
authors.forename: Jun
authors.initials: J
authors.lastname: Hou
authors.forename: Cristina
authors.initials: C
authors.lastname: Gontan
authors.forename: Maaike
authors.initials: M
authors.lastname: Moen
authors.forename: Dorota
authors.initials: D
authors.lastname: Szumska
authors.forename: Christel
authors.initials: C
authors.lastname: Kockx
authors.forename: Wilfred
authors.initials: W
authors.lastname: van Ijcken
authors.forename: Dick H W
authors.initials: DH
authors.lastname: Dekkers
authors.forename: Jeroen
authors.initials: J
authors.lastname: Demmers
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Rijkers
authors.forename: Shoumo
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Sjaak
authors.initials: S
authors.lastname: Philipsen
authors.forename: Larysa H
authors.initials: LH
authors.lastname: Pevny
authors.forename: Frank G
authors.initials: FG
authors.lastname: Grosveld
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: Rottier
authors.forename: Boris
authors.initials: B
authors.lastname: Lenhard
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Poot
mesh_terms: D000818:Animals; D000853:Anophthalmos / Q000235:genetics; D058747:CHARGE Syndrome / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D007758:Ear, Inner / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins
chemical_list: D002135:Calcium-Binding Proteins; C507367:Chd7 protein, mouse; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D055748:SOXB1 Transcription Factors; D000072099:Serrate-Jagged Proteins; C527783:Sox2 protein, mouse