Proximal termination generates a transcriptional state that determines the rate of establishment of Polycomb silencing

The mechanisms and timescales controlling de novo establishment of chromatin-mediated transcriptional silencing by Polycomb repressive complex 2 (PRC2) are unclear. Here, we investigate PRC2 silencing at Arabidopsis FLOWERING LOCUS C (FLC), known to involve co-transcriptional RNA processing, histone demethylation activity, and PRC2 function, but so far not mechanistically connected. We develop and test a computational model describing proximal polyadenylation/termination mediated by the RNA-binding protein FCA that induces H3K4me1 removal by the histone demethylase FLD. H3K4me1 removal feeds back to reduce RNA polymerase II (RNA Pol II) processivity and thus enhance early termination, thereby repressing productive transcription. The model predicts that this transcription-coupled repression controls the level of transcriptional antagonism to PRC2 action. Thus, the effectiveness of this repression dictates the timescale for establishment of PRC2/H3K27me3 silencing. We experimentally validate these mechanistic model predictions, revealing that co-transcriptional processing sets the level of productive transcription at the locus, which then determines the rate of the ON-to-OFF switch to PRC2 silencing. [Display omitted] •Transcription, co-transcriptional processing, and chromatin state are tightly linked•Transcription-coupled repression links H3K4me1 removal to proximal polyadenylation•Mathematical modeling reveals how this mechanistically links to silencing by PRC2•More effective transcription-coupled repression enables faster epigenetic silencing Mechanistic links between transcription, co-transcriptional processing, chromatin state, and epigenetic silencing remain poorly understood. Menon et al. used mathematical modeling and experiments to reveal a transcription-coupled repression mechanism involving feedback between chromatin state and proximal polyadenylation, which controls transcriptional antagonism to PRC2, thereby determining the establishment rate of PRC2 silencing at a locus.