Integrator governs NF-κB dwell time on chromatin to drive inflammatory transcription
NF-{kappa}B must remain bound to chromatin long enough to activate innate immune genes, but what stabilizes this transcriptionally productive state is unknown. Here, we identify the Integrator complex as an essential determinant of NF-{kappa}B chromatin residence in mouse and human cells. Integrator associated with NF-{kappa}B and co-occupied its genomic targets. Single-molecule tracking revealed…
NF-κB must remain bound to chromatin for sufficient time to activate genes related to the innate immune system. The Integrator complex has been identified as an essential factor determining how long NF-κB stays in the chromatin. Integrator is found bound to NF-κB and occupies its genomic targets together with it. Single-molecule tracking studies showed that Integrator prolongs the chromatin residence of RELA molecules in a low-mobility state.
When Catalytically inactive INTS11-E203Q is present, NF-κB-dependent transcription is fully restored, indicating that this chromatin-retention function is separate from RNA cleavage. Removing the Ints11 gene through conditional deletion prevented the activation of dendritic cells by TLR4 in adult mice and impaired the LPS-induced transcription in mouse embryonic fibroblasts.
In human cancer cells, losing Integrator also led to a decrease in TNF-induced inflammatory gene expression. These discoveries reveal a noncatalytic role for Integrator in stabilizing NF-κB at enhancers, which complements its established catalytic control over RNA polymerase II pause release. By linking signal recognition at enhancers to productive elongation, Integrator offers a molecular solution to a key challenge in multicellularity: transforming transient extracellular signals into coherent gene-expression programs in complex chromatin environments.
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