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Splicing Inhibition Reveals Novel Roles for SF3B1 in Transcription Dynamics and R-Loop Metabolism

ABSTRACT: Efficient co-transcriptional splicing has been proposed to suppress the formation of genome-destabilizing R-loops upon interaction between nascent RNA and the DNA template. To test this, we inhibited the SF3B splicing complex using Pladienolide B (PladB) in human K562 cells and mapped R-loop genomic distributions. PladB caused widespread intron retention, as expected, and nearly 2,000 instances of R-loops gains. However, only minimal overlap existed between these two events, arguing that unspliced introns do not cause excessive R-loops. Instead, R-loop gains were driven by a loss of transcription termination over a specific subset of stress-response genes, defining a new class of “downstream of genes” (DoG) aberrant R-loops. Unexpectedly, the predominant response to splicing inhibition was a global R-loop loss over thousands of genes, resulting from a profound loss of transcription elongation. Thus, acute splicing inhibition triggered profound and contrasting alterations in transcriptional dynamics, which were reflected in the global R-loop landscape.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148768 | GEO | 2020/06/10

REPOSITORIES: GEO

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