Hypermethylated in cancer 1 (HIC1) recruits polycomb repressive complex 2 (PRC2) to a subset of its target genes through interaction with human polycomb-like (hPCL) proteins.
HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene epigenetically silenced or deleted in many human cancers. HIC1 is involved in regulatory loops modulating p53- and E2F1-dependent cell survival, growth control, and stress responses. HIC1 is also essential for normal development because Hic1-deficient mice die perinatally and exhibit gross developmental defects throughout the second half of development. HIC1 encodes a transcriptional repressor with five C(2)H(2) zinc fingers mediating sequence-specific DNA binding and two repression domains: an N-terminal BTB/POZ domain and a central region recruiting CtBP and NuRD complexes. By yeast two-hybrid screening, we identified the Polycomb-like protein hPCL3 as a novel co-repressor for HIC1. Using multiple biochemical strategies, we demonstrated that HIC1 interacts with hPCL3 and its paralog PHF1 to form a stable complex with the PRC2 members EZH2, EED, and Suz12. Confirming the implication of HIC1 in Polycomb recruitment, we showed that HIC1 shares some of its target genes with PRC2, including ATOH1. Depletion of HIC1 by siRNA interference leads to a partial displacement of EZH2 from the ATOH1 promoter. Furthermore, in vivo, ATOH1 repression by HIC1 is associated with Polycomb activity during mouse cerebellar development. Thus, our results identify HIC1 as the first transcription factor in mammals able to recruit PRC2 to some target promoters through its interaction with Polycomb-like proteins.
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille Nord de France, Institut Pasteur de Lille, Lille 59021, France.
Gaylor
G
Boulay
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille Nord de France, Institut Pasteur de Lille, Lille 59021, France.
Marion
M
Dubuissez
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille Nord de France, Institut Pasteur de Lille, Lille 59021, France.
Capucine
C
Van Rechem
Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Orsay 91405, France, and.
Antoine
A
Forget
BRIC, University of Copenhagen, Ole Maaløes vej, 5, Dk-2200, Copenhagen, Denmark.
Kristian
K
Helin
Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Orsay 91405, France, and.
Olivier
O
Ayrault
CNRS UMR 8161, Institut de Biologie de Lille, Université Lille Nord de France, Institut Pasteur de Lille, Lille 59021, France,. Electronic address: dominique.leprince@ibl.fr.
Dominique
D
Leprince
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002531:Cerebellum / Q000196:embryology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016335:Zinc Fingers
D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C500942:ATOH1 protein, human; C500943:Atoh1 protein, mouse; C491488:EED protein, human; C107275:Eed protein, mouse; C499808:HIC1 protein, human; C096870:Hic1 protein, mouse; C497703:PHF19 protein, human; C430461:SUZ12 protein, human; C494163:Suz12 protein, mouse; C498409:EZH2 protein, human; C498410:Ezh2 protein, mouse