Basis of gene-specific transcription regulation by the Integrator complex.

Autor:	Sabath K; Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland. Electronic address: kevin.sabath@imp.ac.at., Nabih A; Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland., Arnold C; European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117 Heidelberg, Germany., Moussa R; European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117 Heidelberg, Germany., Domjan D; Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland., Zaugg JB; European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117 Heidelberg, Germany., Jonas S; Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland. Electronic address: stefanie.jonas@mol.biol.ethz.ch.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 Jul 11; Vol. 84 (13), pp. 2525-2541.e12. Date of Electronic Publication: 2024 Jun 20.
DOI:	10.1016/j.molcel.2024.05.027
Abstrakt:	The Integrator complex attenuates gene expression via the premature termination of RNA polymerase II (RNAP2) at promoter-proximal pausing sites. It is required for stimulus response, cell differentiation, and neurodevelopment, but how gene-specific and adaptive regulation by Integrator is achieved remains unclear. Here, we identify two sites on human Integrator subunits 13/14 that serve as binding hubs for sequence-specific transcription factors (TFs) and other transcription effector complexes. When Integrator is attached to paused RNAP2, these hubs are positioned upstream of the transcription bubble, consistent with simultaneous TF-promoter tethering. The TFs co-localize with Integrator genome-wide, increase Integrator abundance on target genes, and co-regulate responsive transcriptional programs. For instance, sensory cilia formation induced by glucose starvation depends on Integrator-TF contacts. Our data suggest TF-mediated promoter recruitment of Integrator as a widespread mechanism for targeted transcription regulation. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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