KAP1 negatively regulates RNA polymerase II elongation kinetics to activate signal-induced transcription

Usman Hyder, Ashwini Challa, Micah Thornton, Tulip Nandu, W. Lee Kraus and Iván D’Orso ()
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Usman Hyder: The University of Texas Southwestern Medical Center
Ashwini Challa: The University of Texas Southwestern Medical Center
Micah Thornton: The University of Texas Southwestern Medical Center
Tulip Nandu: The University of Texas Southwestern Medical Center
W. Lee Kraus: The University of Texas Southwestern Medical Center
Iván D’Orso: The University of Texas Southwestern Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Signal-induced transcriptional programs regulate critical biological processes through the precise spatiotemporal activation of Immediate Early Genes (IEGs); however, the mechanisms of transcription induction remain poorly understood. By combining an acute depletion system with several genomics approaches to interrogate synchronized, temporal transcription, we reveal that KAP1/TRIM28 is a first responder that fulfills the temporal and heightened transcriptional demand of IEGs. Acute KAP1 loss triggers an increase in RNA polymerase II elongation kinetics during early stimulation time points. This elongation defect derails the normal progression through the transcriptional cycle during late stimulation time points, ultimately leading to decreased recruitment of the transcription apparatus for re-initiation thereby dampening IEGs transcriptional output. Collectively, KAP1 plays a counterintuitive role by negatively regulating transcription elongation to support full activation across multiple transcription cycles of genes critical for cell physiology and organismal functions.

Date: 2024
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DOI: 10.1038/s41467-024-49905-7

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