RB–E2F1 recruits EZH2 to repetitive sequences, promoting repression via H3K27me3 deposition.

  • Major finding: RB–E2F1 recruits EZH2 to repetitive sequences, promoting repression via H3K27me3 deposition.

  • Concept: A mutation in Rb1 that prevents its recruitment to repeats induces spontaneous lymphoma in mice.

  • Impact: Derepression of repetitive sequences via RB–EZH2 loss of function may increase cancer susceptibility.

Approximately half of the human genome is composed of repetitive genomic elements, which can be silenced by repressive heterochromatic domains. Derepression of repetitive elements has been linked to cancer, but the mechanisms underlying the silencing of repetitive sequences are not well understood. Ishak and colleagues found that the retinoblastoma protein (RB) bound to diverse repetitive genomic sequences, including short interspersed nuclear elements, long interspersed nuclear elements, long terminal repeat–containing endogenous retroviruses, and simple repeat sequences. A cell cycle–independent interaction between RB and the transcription factor E2F1 enhanced the interaction with repetitive elements, and, in Rb1F832A mice that are homozygous for a substitution that disrupts the RB–E2F1 interaction, RB occupancy of repetitive sequences was reduced. RNA sequencing of mouse embryonic fibroblasts (MEF) revealed that RB–E2F1 was required for silencing of repetitive elements, as Rb1F832A MEFs displayed greater expression of a variety of repeats including transposable elements, satellites, and simple repeats. Mechanistically, RB–E2F1 recruited the histone methyltransferase EZH2 to repetitive sequences, promoting H3K27me3 deposition that led to heterochromatin spreading and silencing at repetitive elements. Notably, Rb1F832A mice had an increased susceptibility to cancer, most commonly lymphoma, and the tumors expressed diverse repetitive sequences. Expression of repetitive sequences can stimulate an immune response, and interferon α and β were upregulated in splenocytes, suggesting that the immune response may clear cells with aberrant repeat expression, which may explain why normal splenocytes from Rb1F832A mice did not consistently show expression of repetitive elements. Collectively, these findings provide a mechanism by which RB promotes silencing of repetitive elements through EZH2 recruitment, and show that misexpression of repetitive elements may increase susceptibility to cancer.

Ishak CA, Marshall AE, Passos DT, White CR, Kim SJ, Cecchini MJ, et al. An RB-EZH2 complex mediates silencing of repetitive DNA sequences. Mol Cell 2016;64:1074–87.

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