Polycomb Repressive Complex 2 Methylates Elongin A to Regulate Transcription

Polycomb repressive complex 2 (PRC2-EZH2) methylates histone H3 at lysine 27 (H3K27) and is required to maintain gene repression during development. Misregulation of PRC2 is linked to a range of neoplastic malignancies, which is believed to involve methylation of H3K27. However, the full spectrum of non-histone substrates of PRC2 that might also contribute to PRC2 function is not known. We characterized the target recognition specificity of the PRC2 active site and used the resultant data to screen for uncharacterized potential targets. The RNA polymerase II (Pol II) transcription elongation factor, Elongin A (EloA), is methylated by PRC2 in vivo. Mutation of the methylated EloA residue decreased repression of a subset of PRC2 target genes as measured by both steady-state and nascent RNA levels and perturbed embryonic stem cell differentiation. We propose that PRC2 modulates transcription of a subset of low expression target genes in part via methylation of EloA. [Display omitted] •Characterization of PRC2 substrate preference identified potential methylation targets•The transcription elongation factor Elongin A is methylated by PRC2 in vivo•Methylation of Elongin A tunes transcription of low expression PRC2 target genes•Loss of Elongin A methylation interferes with differentiation potential in mES cells We show that the transcription elongation factor, Elongin A, is methylated by PRC2 in vivo. Inability to methylate EloA results in upregulation of a subset of PRC2 target genes and interferes with differentiation potential of mES cells. PRC2 modulates expression of target genes in part via methylation of EloA.