Abstract 1298 Control of gene outputs by the Integrator complex and premature transcription termination events

The metazoan-specific Integrator complex catalyzes 3' end processing of small nuclear RNAs (snRNAs) as well as premature transcription termination events that attenuate expression of many protein-coding genes, in some cases by more than 100 fold. The Integrator complex has RNA endonuclease and protein phosphatase activities, but how Integrator activity can be toggled on/off at a given gene locus depending on cellular transcriptional needs remains poorly understood. We recently showed that the Integrator phosphatase module is critical at only a subset of Drosophila protein-coding genes and that PP2A recruitment is a tunable step that modulates transcription termination efficiency at these loci. By profiling the transcriptome after individual depletion of each Integrator subunit, we now further find that gene loci can have highly distinct dependencies on Integrator subunits. For example, some protein-coding loci are controlled by only one Integrator subunit, while others require most of the subunits. We will present ongoing work that is exploring the underlying regulatory mechanisms that enable gene-specific control by Integrator, as well as how disease-associated mutations in Integrator subunits can lead to dysregulation of only a subset of Integrator regulated genes. This work was supported by grants from NIGMS, CPRIT, and the National Natural Science Foundation of China. J.E.W. is a CPRIT Scholar in Cancer Research.