title: CDYL bridges REST and histone methyltransferases for gene repression and suppression of cellular transformation.
abstract: 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.
authors.affiliation: Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Mulligan
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Westbrook
authors.forename: Matthias
authors.initials: M
authors.lastname: Ottinger
authors.forename: Natalya
authors.initials: N
authors.lastname: Pavlova
authors.forename: Bin
authors.initials: B
authors.lastname: Chang
authors.forename: Eric
authors.initials: E
authors.lastname: Macia
authors.forename: Yu-Jiang
authors.initials: YJ
authors.lastname: Shi
authors.forename: Jordi
authors.initials: J
authors.lastname: Barretina
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Peter M
authors.initials: PM
authors.lastname: Howley
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
mesh_terms: 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
chemical_list: 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