CDYL bridges REST and histone methyltransferases for gene repression and suppression of cellular transformation.
The neuronal gene repressor REST/NRSF recruits corepressors, including CoREST, to modify histones and repress transcription. REST also functions as a tumor suppressor, but the mechanism remains unclear. We identified chromodomain on Y-like (CDYL) as a REST corepressor that physically bridges REST and the histone methylase G9a to repress transcription. Importantly, RNAi knockdown of REST, CDYL, and G9a, but not CoREST, induced oncogenic transformation of immortalized primary human cells and derepression of the proto-oncogene TrkC. Significantly, transgenic expression of TrkC also induced transformation. This implicates CDYL-G9a, but not CoREST, in REST suppression of transformation, possibly by oncogene repression. CDYL knockdown also augments transformation in a cell culture model of cervical cancer, where loss of heterozygosity of the CDYL locus occurs. These findings demonstrate molecular strategies by which REST carries out distinct biological functions via different corepressors and provide critical insights into the role of histone-modifying complexes in regulating cellular transformation.
Mulligan
Peter
P
Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Westbrook
Thomas F
TF
Ottinger
Matthias
M
Pavlova
Natalya
N
Chang
Bin
B
Macia
Eric
E
Shi
Yu-Jiang
YJ
Barretina
Jordi
J
Liu
Jinsong
J
Howley
Peter M
PM
Elledge
Stephen J
SJ
Shi
Yang
Y
D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism; D006367:HeLa Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D006836:Hydro-Lyases; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D046912:Multiprotein Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D050725:Papillomavirus E7 Proteins; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D034622:RNA Interference; D020812:Receptor, trkC / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D000099229:RE1-Silencing Transcription Factor
D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D006836:Hydro-Lyases; D008239:Lysine; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011496:Protein Methyltransferases; D011506:Proteins; D000090063:Proto-Oncogene Mas; D020812:Receptor, trkC; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C068651:E6 protein, Human papillomavirus type 16; C000715470:MAS1 protein, human; C121019:RCOR1 protein, human; C059731:oncogene protein E7, Human papillomavirus type 16; C118458:CDYL protein, human