Differential regulation of HIC1 target genes by CtBP and NuRD, via an acetylation/SUMOylation switch, in quiescent versus proliferating cells.
The tumor suppressor gene HIC1 encodes a transcriptional repressor involved in regulatory loops modulating P53-dependent and E2F1-dependent cell survival, growth control, and stress responses. Despite its importance, few HIC1 corepressors and target genes have been characterized thus far. Using a yeast two-hybrid approach, we identify MTA1, a subunit of the NuRD complex, as a new HIC1 corepressor. This interaction is regulated by two competitive posttranslational modifications of HIC1 at lysine 314, promotion by SUMOylation, and inhibition by acetylation. Consistent with the role of HIC1 in growth control, we demonstrate that HIC1/MTA1 complexes bind on two new target genes, Cyclin D1 and p57KIP2 in quiescent but not in growing WI38 cells. In addition, HIC1/MTA1 and HIC1/CtBP complexes differentially bind on two mutually exclusive HIC1 binding sites (HiRE) on the SIRT1 promoter. SIRT1 transcriptional activation induced by short-term serum starvation coincides with loss of occupancy of the distal sites by HIC1/MTA1 and HIC1/CtBP. Upon longer starvation, both complexes are found but on a newly identified proximal HiRE that is evolutionarily conserved and specifically enriched with repressive histone marks. Our results decipher a mechanistic link between two competitive posttranslational modifications of HIC1 and corepressor recruitment to specific genes, leading to growth control.
Van Rechem
Capucine
C
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille Nord de France, Institut Pasteur de Lille, IFR 142, 1 Rue Calmette, 59017 Lille Cedex, France.
Boulay
Gaylor
G
Pinte
Sébastien
S
Stankovic-Valentin
Nicolas
N
Guérardel
Cateline
C
Leprince
Dominique
D
D000107:Acetylation; D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019940:Genes, bcl-1; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007399:Interphase; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D015534:Trans-Activators; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004268:DNA-Binding Proteins; C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; C089320:MTA1 protein, human; D011994:Recombinant Proteins; D012097:Repressor Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D015534:Trans-Activators; D004247:DNA; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex