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Maintenance of gene expression homeostasis by systems-level feedback loops in response to changes in RNA polymerase II dosage [RNAPII_levels_DRB-TTseq]

ABSTRACT: Transcription is regulated by sequence-specific transcription factors and enzymes allowing access to genes in chromatin. However, recent data indicate that the abundance of RNA polymerase II (RNAPII) may itself under certain circumstances represent an additional, crucial determinant of transcription regulation. Here, we titrated the cellular dosage of human RPB1, the largest RNAPII subunit, using the dTAG system to more generally assess the importance of RNAPII levels. Unexpectedly, cells are extremely sensitive to RPB1 dosage, with a mere 30% reduction sufficient to perturb cell proliferation, cell cycle progression, and global transcription. Using a combination of sequencing and proteomic approaches, we uncover the existence of multiple feedback loops between transcriptional initiation, promotor-proximal pause release, transcript elongation, splicing, and mRNA half-life, which facilitate the maintenance of gene expression homeostasis. Together, our data suggests that gene expression is highly sensitive to RPB1 dosage and that the cellular levels of RNAPII must be tightly regulated.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307864 | GEO | 2025/11/19

REPOSITORIES: GEO

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Maintenance of gene expression homeostasis by systems-level feedback loops in response to changes in RNA polymerase II dosage [RNAPII_levels_mRNAseq]

Project description:Transcription is regulated by sequence-specific transcription factors and enzymes allowing access to genes in chromatin. However, recent data indicate that the abundance of RNA polymerase II (RNAPII) may itself under certain circumstances represent an additional, crucial determinant of transcription regulation. Here, we titrated the cellular dosage of human RPB1, the largest RNAPII subunit, using the dTAG system to more generally assess the importance of RNAPII levels. Unexpectedly, cells are extremely sensitive to RPB1 dosage, with a mere 30% reduction sufficient to perturb cell proliferation, cell cycle progression, and global transcription. Using a combination of sequencing and proteomic approaches, we uncover the existence of multiple feedback loops between transcriptional initiation, promotor-proximal pause release, transcript elongation, splicing, and mRNA half-life, which facilitate the maintenance of gene expression homeostasis. Together, our data suggests that gene expression is highly sensitive to RPB1 dosage and that the cellular levels of RNAPII must be tightly regulated.

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Maintenance of gene expression homeostasis by systems-level feedback loops in response to changes in RNA polymerase II dosage [RNAPII_levels_TTseq]

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Ubiquitin ligase WWP2 targets RNA polymerase II in a DNA-PK-dependent transcription shutoff circuitry for DNA repair

Project description:DNA double-strand breaks (DSBs) at RNA polymerase II (RNAPII)-transcribed genes lead to inhibition of transcription. DNA protein kinase (DNA-PK) complex plays a pivotal role in transcription inhibition at DSBs by stimulating proteasome-dependent eviction of RNAPII at these lesions. How DNA-PK triggers RNAPII eviction to inhibit transcription at DSBs remained unclear. Here we show that the HECT E3 ubiquitin ligase WWP2 associates with components of the DNA-PK and RNAPII complexes and is recruited to DSBs at RNAPII-transcribed genes. In response to DSBs, WWP2 targets the RNAPII subunit RPB1 for K48-linked ubiquitylation, thereby driving DNA-PK- and proteasome-dependent eviction of RNAPII. The lack of WWP2 or expression of non-ubiquitylatable RPB1 abrogates the loading of Non-Homologous End-Joining (NHEJ) factors, including DNA-PK and XRCC4/DNA ligase IV, and impairs DSB repair. These findings suggest that WWP2 operates in a DNA-PK-dependent shut-off circuitry for RNAPII clearance that promotes DSB repair by protecting the NHEJ machinery from collision with the transcription machinery.

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2014-12-04 | E-GEOD-55184 | biostudies-arrayexpress

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Project description:In this study we show that acute INTS6 depletion remodels the RNAPII interactome and enhances ARMC5 binding, the same as what we observed in Ints6 KO cells. To investigate how acute INTS6 depletion affects RNAPII function, we determined the RNAPII interactome in the the Ints6 degron cells. Chromatin fractions from DMSO and dTAG treated Ints6 degron cells (treated for 1 hour) were analyzed by RNAPII IP-mass spectrometry. There are 12 samples in this MS run, samples 6-dTAG repeats1-3 and 6-DMSO repeats 1-3 are involved in the paper.

2025-12-22 | PXD053351 | Pride

Precise modulation of mSWI/SNF identified dosage-sensitive chromatin regulation [CUT&Run]

Project description:ATP-dependent chromatin remodelers establish and arrange nucleosome distribution, modifying accessibility of DNA. Brg1 is exclusive ATPase subunit of mSWI/SNF complex. To understand the dosage dependent function of mSWI/SNF complex. We take an advantage of dTag system to precisely control abundancy of BRG1. We found overall Brg1-binding is sensitive to its abundance nevertheless OCT4-target or H3K27ac region, suggesting Brg1 genome-wide distribution rather than being actively recruited. We also reveal open chromatin dependency on BRG1. The chromatin accessibility of super enhancer shows buffered response on depletion of BRG1, whereas weak enhancer is sensitive. Finally, transcriptomic analysis identified that transcription shows buffered dependencies on BRG1 loss. Overall, our results highlight kinetics differences of BRG1-binding to transcriptome underline BRG1 dosage-sensitive mechanism.

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