An RB-EZH2 Complex Mediates Silencing of Repetitive DNA Sequences

Authors

Charles A. Ishak, London Regional Cancer Program
Aren E. Marshall, London Regional Cancer Program
Daniel T. Passos, London Regional Cancer Program
Carlee R. White, Children's Health Research Institute, London, ON
Seung J. Kim, London Regional Cancer Program
Matthew J. Cecchini, London Regional Cancer Program
Sara Ferwati, London Regional Cancer Program
William A. MacDonald, Magee-Womens Research Institute
Christopher J. Howlett, Western University
Ian D. Welch, The University of British Columbia
Seth M. Rubin, University of California, Santa Cruz
Mellissa R.W. Mann, Magee-Womens Research Institute
Frederick A. Dick, London Regional Cancer ProgramFollow

Document Type

Article

Publication Date

12-15-2016

Journal

Molecular Cell

Volume

64

Issue

6

First Page

1074

Last Page

1087

URL with Digital Object Identifier

10.1016/j.molcel.2016.10.021

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.