title: FBXL10 protects Polycomb-bound genes from hypermethylation.
abstract: Nearly all CpG-dense promoters are occupied by the multidomain chromosomal protein FBXL10. We show here that complete inactivation of the Fbxl10 gene leads to dense de novo methylation only of promoters that are co-occupied by both FBXL10 and Polycomb repressive complexes; this methylation results in pervasive defects in embryonic development and the death of homozygous Fbxl10-mutant embryos at midgestation. Deletion of key components of Polycomb repressive complexes 1 and 2 did not lead to ectopic genomic methylation. These results indicate that FBXL10 protects Polycomb-occupied promoters against ectopic de novo methylation. To our knowledge, FBXL10 is the first reported factor whose loss leads to a gain in genomic DNA methylation.
authors.affiliation: Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boulard
authors.affiliation: Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Edwards
authors.affiliation: Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Bestor
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018899:CpG Islands; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000502:physiology; D044127:Epigenesis, Genetic; D044783:F-Box Proteins / Q000502:physiology*; D063990:Gene Ontology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D044783:F-Box Proteins; D063146:Polycomb-Group Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C524747:Kdm2b protein, mouse; D063150:Polycomb Repressive Complex 1; C489842:Rnf2 protein, mouse; D044767:Ubiquitin-Protein Ligases