ZFP-1(AF10)/DOT-1 Complex Opposes H2B Ubiquitination to Reduce Pol II Transcription

Inhibition of transcriptional elongation plays an important role in gene regulation in metazoans, including C. elegans, which lacks Negative Elongation Factor homologs. Here we combine genomic and biochemical approaches to dissect a novel role of C. elegans AF10 homolog, ZFP-1, in transcriptional control. We show that ZFP-1 and its interacting partner DOT-1.1 have a global role in negatively modulating the level of Pol II transcription on essential widely expressed genes. Moreover,the ZFP-1/DOT-1.1 complex contributes to progressive Pol II stalling on essential genes during development and to rapid Pol II stalling during stress response. The slowing down of Pol II transcription by ZFP-1/DOT-1.1 is associated with an increase in H3K79 methylation and a decrease in H2B monoubiquitination, which promotes transcription. We propose a model where recruitment of ZFP-1/DOT-1.1 and deposition of H3K79 methylation at highly expressed genes initiates a negative feedback mechanism for modulation of their expression. GRO-seq (Global Run-On sequening) for nascent transcript detectiong on WT and zfp-1(ok554) mutant nematode (C. elegans) larvae in L3 stage, performed in duplicate per condition (4 samples total).