Integrator governs NF-κB dwell time on chromatin to drive inflammatory transcription
- 1Department of Human Genetics, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, 1501 NW 10th Avenue, Miami, FL 33136, USA
Abstract
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 that Integrator markedly prolonged the chromatin residence of RELA molecules in a low-mobility state. Catalytically inactive INTS11-E203Q fully restored NF-{kappa}B-dependent transcription, separating this chromatin-retention function from RNA cleavage. Conditional Ints11 deletion abolished TLR4-dependent dendritic-cell activation in adult mice and impaired LPS-induced transcription in mouse embryonic fibroblasts. Loss of Integrator in human cancer cells similarly suppressed TNF-induced inflammatory gene expression. These findings uncover a noncatalytic function for Integrator that stabilizes NF-{kappa}B at enhancers, complementing its established catalytic control of RNA polymerase II pause release. By coupling signal recognition at enhancers to productive elongation, Integrator provides a molecular solution to a central challenge of multicellularity: converting transient extracellular cues into coherent gene-expression programs across complex chromatin landscapes.
Related
- Integrator complex removes lesion-stalled RNA polymerase II after transcription-coupled repair to facilitate transcription restart
- Tunable kinetic destabilization governs RNA polymerase passage through a DNA-bound transcription factor
- Transcription factor Fra-1 reprograms androgen receptor chromatin binding and super-enhancers in osteoblast differentiation
- Dose-dependent sensitivity of human three-dimensional chromatin to a heart disease–linked transcription factor
- Chromatin and transcription factor profiling in rare stem cell populations using CUT&Tag
BibTeX
@misc{shiekhattar2026integrator,
title = {{Integrator governs NF-κB dwell time on chromatin to drive inflammatory transcription}},
author = {R. Shiekhattar and P. K. R. Cingaram and J. Yue and F. Liu and H. Gomes Dos Santos and G. S. Gaidosh and S. Sidoli and B. A. Garcia and F. Lai and M. Xu and O. Lopez and G. M. Lavezzo and F. Beckedorff and S. D. Nimer},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754463},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754463v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Integrator governs NF-κB dwell time on chromatin to drive inflammatory transcription
AU - R. Shiekhattar
AU - P. K. R. Cingaram
AU - J. Yue
AU - F. Liu
AU - H. Gomes Dos Santos
AU - G. S. Gaidosh
AU - S. Sidoli
AU - B. A. Garcia
AU - F. Lai
AU - M. Xu
AU - O. Lopez
AU - G. M. Lavezzo
AU - F. Beckedorff
AU - S. D. Nimer
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754463
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754463v1
AB - 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 that Integrator markedly prolonged the chromatin residence of RELA molecules in a low-mobility state. Catalytically inactive INTS11-E203Q fully restored NF-{kappa}B-dependent transcription, separating this chromatin-retention function from RNA cleavage. Conditional Ints11 deletion abolished TLR4-dependent dendritic-cell activation in adult mice and impaired LPS-induced transcription in mouse embryonic fibroblasts. Loss of Integrator in human cancer cells similarly suppressed TNF-induced inflammatory gene expression. These findings uncover a noncatalytic function for Integrator that stabilizes NF-{kappa}B at enhancers, complementing its established catalytic control of RNA polymerase II pause release. By coupling signal recognition at enhancers to productive elongation, Integrator provides a molecular solution to a central challenge of multicellularity: converting transient extracellular cues into coherent gene-expression programs across complex chromatin landscapes.
ER -