title: Coordinated histone modifications mediated by a CtBP co-repressor complex.
abstract: The transcriptional co-repressor CtBP (C-terminal binding protein) is implicated in tumorigenesis because it is targeted by the adenovirus E1A protein during oncogenic transformation. Genetic studies have also identified a crucial function for CtBP in animal development. CtBP is recruited to DNA by transcription factors that contain a PXDLS motif, but the detailed molecular events after the recruitment of CtBP to DNA and the mechanism of CtBP function in tumorigenesis are largely unknown. Here we report the identification of a CtBP complex that contains the essential components for both gene targeting and coordinated histone modifications, allowing for the effective repression of genes targeted by CtBP. Inhibiting the expression of CtBP and its associated histone-modifying activities by RNA-mediated interference resulted in alterations of histone modifications at the promoter of the tumour invasion suppressor gene E-cadherin and increased promoter activity in a reporter assay. These findings identify a molecular mechanism by which CtBP mediates transcriptional repression and provide insight into CtBP participation in oncogenesis.
authors.affiliation: Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA. yang_shi@hms.harvard.edu
authors.forename: Yujiang
authors.initials: Y
authors.lastname: Shi
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: El Bachir
authors.initials: el B
authors.lastname: Affar
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Whetstine
authors.forename: Fei
authors.initials: F
authors.lastname: Lan
authors.forename: Hidesato
authors.initials: H
authors.lastname: Ogawa
authors.forename: Margaret Po-Shan
authors.initials: MP
authors.lastname: Luke
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakatani
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000429:Alcohol Oxidoreductases; D015820:Cadherins / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism*; D006801:Humans; D046911:Macromolecular Substances; D008780:Methyltransferases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011496:Protein Methyltransferases; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D046911:Macromolecular Substances; D010750:Phosphoproteins; D012097:Repressor Proteins; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006655:Histone Deacetylases