title: An RB-EZH2 Complex Mediates Silencing of Repetitive DNA Sequences.
abstract: Repetitive genomic regions include tandem sequence repeats and interspersed repeats, such as endogenous retroviruses and LINE-1 elements. Repressive heterochromatin domains silence expression of these sequences through mechanisms that remain poorly understood. Here, we present evidence that the retinoblastoma protein (pRB) utilizes a cell-cycle-independent interaction with E2F1 to recruit enhancer of zeste homolog 2 (EZH2) to diverse repeat sequences. These include simple repeats, satellites, LINEs, and endogenous retroviruses as well as transposon fragments. We generated a mutant mouse strain carrying an F832A mutation in Rb1 that is defective for recruitment to repetitive sequences. Loss of pRB-EZH2 complexes from repeats disperses H3K27me3 from these genomic locations and permits repeat expression. Consistent with maintenance of H3K27me3 at the Hox clusters, these mice are developmentally normal. However, susceptibility to lymphoma suggests that pRB-EZH2 recruitment to repetitive elements may be cancer relevant.
authors.affiliation: London Regional Cancer Program, London, ON N6A 4L6, Canada; Department of Biochemistry, Western University, London, ON N6A 3K7, Canada.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Ishak
authors.affiliation: London Regional Cancer Program, London, ON N6A 4L6, Canada; Department of Biochemistry, Western University, London, ON N6A 3K7, Canada.
authors.forename: Aren E
authors.initials: AE
authors.lastname: Marshall
authors.affiliation: London Regional Cancer Program, London, ON N6A 4L6, Canada; Department of Biochemistry, Western University, London, ON N6A 3K7, Canada.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Passos
authors.affiliation: Children's Health Research Institute, London, ON N6A 4L6, Canada; Department of Biochemistry, Western University, London, ON N6A 3K7, Canada.
authors.forename: Carlee R
authors.initials: CR
authors.lastname: White
authors.affiliation: London Regional Cancer Program, London, ON N6A 4L6, Canada; Department of Biochemistry, Western University, London, ON N6A 3K7, Canada.
authors.forename: Seung J
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: London Regional Cancer Program, London, ON N6A 4L6, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cecchini
authors.affiliation: London Regional Cancer Program, London, ON N6A 4L6, Canada; Department of Biochemistry, Western University, London, ON N6A 3K7, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Ferwati
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, PA 15213, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: MacDonald
authors.affiliation: Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Howlett
authors.affiliation: Animal Care Services, University of British Columbia, Vancouver, BC V6T1Z4, Canada.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Welch
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Rubin
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, PA 15213, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Mellissa R W
authors.initials: MRW
authors.lastname: Mann
authors.affiliation: London Regional Cancer Program, London, ON N6A 4L6, Canada; Children's Health Research Institute, London, ON N6A 4L6, Canada; Department of Biochemistry, Western University, London, ON N6A 3K7, Canada. Electronic address: fdick@uwo.ca.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Dick
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008643:Mesentery / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D061251:Primary Cell Culture; D011485:Protein Binding; D012091:Repetitive Sequences, Nucleic Acid; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D013160:Splenic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D006657:Histones; D016160:Retinoblastoma Protein; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse
keywords: H3K27me3; Polycomb; cancer; epigenetics; heterochromatin; repetitive DNA; retinoblastoma protein