Fig. 6. SET1 complexes counteract premature transcription termination by ZC3H4.

a A schematic illustrating the ZC3H4-dTAG line (top panel) and a genomic snapshot showing cTT-seq signal at a SET1-dependent gene (Rft1) before (UNT, dark red) and after (light red) 2 h treatment with dTAG13 (bottom panels). b Metaplot analysis of transcription (cTT-seq) in the ZC3H4-dTAG line in cells that are either untreated (UNT) or treated with dTAG13 for 2 h at all transcribed SET1-dependent genes (n = 2633). c, d As per a and b but for the dTAG-SET1A/B line. e, f As per a and b but for the dTAG-SET1A/B/ZC3H4 line. g A box plot showing the log2 fold change in transcription at transcribed SET1-independent (n = 9151) and SET1-dependent (n = 2633) genes in the dTAG-SET1A/B, ZC3H4-dTAG, and dTAG-SET1A/B/ZC3H4 lines after treatment with dTAG13 for 2 h. The boxes show interquartile range, centre line represents median, whiskers extend by 1.5× IQR or the most extreme point (whichever is closer to the median), while notches extend by 1.58× IQR/sqrt(n), giving a roughly 95% confidence interval for comparing medians. h A cartoon illustrating a model whereby WDR82-containing SET1 complexes bind to CpG-dense regions in CGIs downstream of TSSs to enable genic transcription by counteracting premature transcription termination by WDR82-containing ZC3H4 complexes. The defined mechanism through which SET1 complexes counteract the function of ZC3H4 complexes remains to be determined, but this likely involves both SET1 and ZC3H4 complexes interacting with the CTD of RNA Pol II and the integration of their distinct activities determining the effect on transcription. In contrast, extragenic transcription that emanates from regions lacking SET1 complex occupancy is subject to termination by WDR82-containing ZC3H4 complexes. In this model, CGIs and SET1 complex occupancy would distinguish genic from extragenic transcription, and protect genic transcription from premature transcription termination to enable gene expression.