Dicer promotes genome stability via the bromodomain transcriptional co-activator BRD4

RNA interference is required for post-transcriptional silencing, but also has additional roles in transcriptional silencing of centromeres and genome stability. However, these roles have been difficult to detect in mammals. Strikingly, we found that Dicer-deficient embryonic stem cells have strong proliferation and chromosome segregation defects as well as increased transcription of centromeric satellite repeats, which triggers the interferon response. We conducted a CRISPR-Cas9 genetic screen to restore viability and identified transcriptional activators, histone H3K9 methyltransferases, and chromosome segregation factors as suppressors, resembling Dicer suppressors identified in independent screens in fission yeast. The strongest suppressors were mutations in the transcriptional co-activator Brd4, which reversed the strand-specific transcription of major satellite repeats suppressing the interferon response, and in the histone acetyltransferase Elp3. We show that identical mutations in the second bromodomain of Brd4 rescue Dicer-dependent silencing and chromosome segregation defects in both mammalian cells and fission yeast. This remarkable conservation demonstrates that RNA interference has an ancient role in transcriptional silencing of satellite repeats, which is essential for cell cycle progression and proper chromosome segregation. Our results have pharmacological implications for cancer and autoimmune diseases characterized by unregulated transcription of satellite repeats. RNA-seq of Dicer1 mutant mouse embryonic stem cell (mESC) clones and induced populations at day 8, Brd4 mutant mESCs, Elp3 mutant mESCs, double mutant Dicer1/Brd4 mutant clones and induced populations, double mutant Dicer1/Elp3 mutant clones; small RNA sequencing of wild type mESCs, Dicer1 induced population, Dicer1 mutant clones, and Dgcr8 knockout mESCs; BRD4 ChIP-seq of wild type mESCs, Dicer1 induced mutant population, and Dicer1 mutant clones; H3K9 me2 and me3 ChIP-seq of wild type mESCs, Dicer1 induced populations of mESCs, and Dicer1 mutant mESC clones with input and H3 control