PT  - JOURNAL ARTICLE
AU  - Sabath, Kevin
AU  - Nabih, Amena
AU  - Arnold, Christian
AU  - Moussa, Rim
AU  - Domjan, David
AU  - Zaugg, Judith B.
AU  - Jonas, Stefanie
TI  - Mechanistic basis of gene-specific transcription regulation by the Integrator complex
AID  - 10.1101/2024.01.24.576984
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.01.24.576984
4099  - http://biorxiv.org/content/early/2024/01/25/2024.01.24.576984.short
4100  - http://biorxiv.org/content/early/2024/01/25/2024.01.24.576984.full
AB  - The Integrator complex (INT) regulates gene expression via premature transcription termination of RNA polymerase II (RNAP2) at promoter-proximal pausing sites. This attenuation of transcription is required for cellular response to external stimuli, cell differentiation and neurodevelopment. How gene-specific regulation is achieved by INT in an inducible manner remains unclear. Here, we identify two sites on INT subunits 13/14 that serve as direct binding hubs for diverse sets of sequence-specific transcription factors (TFs) and other transcription effector complexes. The TFs co-localize with INT genome-wide, increase INT abundance on target genes and co-regulate inducible transcriptional programs. Consistently, disruption of INT-TF contacts impairs sensory cilia formation in response to glucose starvation. Structural analysis places INT’s TF binding hubs upstream of the transcription bubble when attached to paused RNAP2, consistent with simultaneous TF-promoter association. Our data establish TF-mediated recruitment of INT to promoters as a widespread mechanism for targeted and inducible transcription attenuation.Competing Interest StatementThe authors have declared no competing interest.