Coordinated histone modifications mediated by a CtBP co-repressor complex.
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.
Shi
Yujiang
Y
Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA. yang_shi@hms.harvard.edu
Sawada
Jun-ichi
J
Sui
Guangchao
G
Affar
El Bachir
el B
Whetstine
Johnathan R
JR
Lan
Fei
F
Ogawa
Hidesato
H
Luke
Margaret Po-Shan
MP
Nakatani
Yoshihiro
Y
Shi
Yang
Y
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*
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