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NDF/GLYR1 Promotes RNA Polymerase II Processivity via Pol II Binding and Nucleosome Destabilization

ABSTRACT: The Nucleosome Destabilizing Factor (NDF) facilitates transcription through chromatin, but its precise mechanism remains incompletely understood. Here, we identify a critical region (amino acids 140-160) within NDF that specifically interacts with phosphorylated RPB1, the largest subu-nit of elongating RNA Polymerase II (Pol II). Mutations in this region disrupt Pol II interaction and impair Pol II elongation both in vitro and in cells, yet do not affect NDF's ability to destabilize nu-cleosomes, establishing a functional separation between these two activities. Cellular studies re-veal that NDF knockout cells display faster Pol II elongation rates but produce fewer nascent tran-scripts, demonstrating NDF's primary role in maintaining transcriptional processivity through-out gene bodies. Our findings demonstrate that NDF uses distinct mechanisms to ensure productive transcription elongation rather than simply enhancing elongation speed, offering new insights in-to how transcription efficiency is maintained in chromatin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294087 | GEO | 2025/05/28

REPOSITORIES: GEO

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NDF/GLYR1 Promotes RNA Polymerase II Processivity via Pol II Binding and Nucleosome Destabilization

Project description:The Nucleosome Destabilizing Factor (NDF) facilitates transcription through chromatin, but its precise mechanism remains incompletely understood. Here, we identify a critical region (amino acids 140-160) within NDF that specifically interacts with phosphorylated RPB1, the largest subu-nit of elongating RNA Polymerase II (Pol II). Mutations in this region disrupt Pol II interaction and impair Pol II elongation both in vitro and in cells, yet do not affect NDF's ability to destabilize nu-cleosomes, establishing a functional separation between these two activities. Cellular studies re-veal that NDF knockout cells display faster Pol II elongation rates but produce fewer nascent tran-scripts, demonstrating NDF's primary role in maintaining transcriptional processivity through-out gene bodies. Our findings demonstrate that NDF uses distinct mechanisms to ensure productive transcription elongation rather than simply enhancing elongation speed, offering new insights in-to how transcription efficiency is maintained in chromatin.

2025-05-28 | GSE294088 | GEO

NDF Is a Transcription Factor that Stimulates Elongation by RNA Polymerase II

Project description:RNA polymerase II (Pol II) elongation is a critical step in gene expression. Here we find that NDF, which was identified as a bilaterian nucleosome-destabilizing factor, is also a Pol II transcription factor that stimulates elongation with plain DNA templates in the absence of nucleosomes. NDF binds directly to Pol II and enhances elongation by a different mechanism than does transcription factor TFIIS. Moreover, yeast Pdp3, which is related to NDF, binds to Pol II and stimulates elongation. Thus, NDF is a Pol II-binding transcription elongation factor that is localized over gene bodies and is conserved from yeast to humans.

2022-03-10 | GSE185464 | GEO

NDF/GLYR1 Promotes RNA Polymerase II Processivity via Pol II Binding and Nucleosome Destabilization

Project description:NDF/GLYR1 Promotes RNA Polymerase II Processivity via Pol II Binding and Nucleosome Destabilization

| PRJNA1248046 | ENA

NDF/GLYR1 Promotes RNA Polymerase II Processivity via Pol II Binding and Nucleosome Destabilization

Project description:NDF/GLYR1 Promotes RNA Polymerase II Processivity via Pol II Binding and Nucleosome Destabilization

| PRJNA1248047 | ENA

Regulation of RNA polymerase II processivity by Spt5 is restricted to a narrow window in elongation

Project description:Spt5 is a highly conserved RNA polymerase II (Pol II)-associated pausing and elongation factor. However, its impact on global elongation and Pol II processivity in mammalian cells has not been clarified. Here, we show that depleting Spt5 in mouse embryonic fibroblasts (MEFs) does not cause global elongation defects or decreased elongation rates. Instead, in the absence of Spt5, a fraction of Pol II molecules are dislodged during elongation thus decreasing the number of Pol II complexes that complete the transcription cycle. Most strikingly, this decrease is restricted to a narrow window between 15-20 kb from the promoter, a distance which coincides with the stage where accelerating Pol II attains maximum elongation speed and processivity. Consequently, long genes show a greater dependency on Spt5 for optimal elongation efficiency and overall gene expression than short genes. We propose that an important role of Spt5 in mammalian elongation is to promote the processivity of those Pol II complexes that are transitioning towards maximum elongation speed 15-20 kb from the promoter.

2018-03-06 | GSE106313 | GEO

A Nucleosome Destabilizing Factor that Facilitates Transcription in Chromatin

Project description:Our understanding of transcription by RNA polymerase II (Pol II) is limited by our knowledge of the factors that mediate this critically important process. Here we describe the identification of NDF, a nucleosome destabilizing factor that facilitates Pol II transcription in chromatin. NDF has a PWWP motif, interacts with nucleosomes near the dyad, partially disassembles nucleosomes in an ATP-independent manner, and enhances transcription by Pol II through nucleosomes in vitro and in cell nuclei. NDF affects gene expression and co-localizes with H3K36me3 over transcribed regions of a subset of active genes with a preference for longer genes relative to shorter genes. Moreover, induction of transcription leads to the recruitment of NDF over gene bodies. In humans, NDF is present in all tested tissue types, is essential in stem cells, and is frequently overexpressed in breast cancer. Thus, NDF is a factor of primary importance for Pol II transcription in chromatin.

2019-01-25 | E-MTAB-6466 | biostudies-arrayexpress

A Nucleosome Destabilizing Factor that Facilitates Transcription in Chromatin

Project description:Our understanding of transcription by RNA polymerase II (Pol II) is limited by our knowledge of the factors that mediate this critically important process. Here we describe the identification of NDF, a nucleosome destabilizing factor that facilitates Pol II transcription in chromatin. NDF has a PWWP motif, interacts with nucleosomes near the dyad, destabilizes nucleosomes in an ATP-independent manner, and facilitates transcription by Pol II through nucleosomes in a purified and defined transcription system as well as in cell nuclei. Upon transcriptional induction, NDF is recruited to the transcribed regions of thousands of genes and co-localizes with a subset of H3K36me3-enriched regions. Notably, the recruitment of NDF to gene bodies is accompanied by an increase in the transcript levels of many of the NDF-enriched genes. In addition, the global loss of NDF results in a decrease in the RNA levels of many genes. In humans, NDF is present at high levels in all tested tissue types, is essential in stem cells, and is frequently overexpressed in breast cancer. These findings indicate that NDF is a nucleosome destabilizing factor that is recruited to gene bodies during transcriptional activation and facilitates Pol II transcription through nucleosomes.

2018-04-16 | GSE109690 | GEO

Structure of transcribing RNA polymerase II-Elongin complex

Project description:Elongin is a hetero-trimeric elongation factor for RNA polymerase (Pol) II transcription that is conserved among metazoa. We solved three structures of human Elongin bound to transcribing Pol II using cryo-EM assisted by crosslinking mass spectrometry. The structures show that Elongin subunit ELOA binds the RPB2 side of Pol II and anchors the ELOB-8 ELOC subunit heterodimer. ELOA contains an N-terminal ‘latch’ that binds between the end of the RPB1 bridge helix and the funnel helices, thereby inducing a conformational change near the Pol II active center. The latch is strictly required for the elongation-stimulatory activity of Elongin, but not for its binding to Pol II, indicating that Elongin functions by allosterically influencing the conformational mobility of the active center. Structural comparisons show that Elongin binding to Pol II is incompatible with association of super elongation complex, the PAF1 complex, and RTF1, which also contains a latch element that stimulates Pol II.

2023-10-11 | PXD045446 | Pride

CDK7 kinase activity promotes RNA polymerase II promoter escape by facilitating initiation factor release

Project description:Cyclin-dependent kinase 7 (CDK7), part of the general transcription factor TFIIH, promotes gene transcription by phosphorylating the C-terminal domain of RNA polymerase II (RNA Pol II). Here, we combine rapid CDK7 kinase inhibition with multi-omics analysis to unravel the direct functions of CDK7 in human cells. CDK7 inhibition causes RNA Pol II retention at promoters, leading to decreased RNA Pol II initiation and immediate global downregulation of transcript synthesis. Elongation, termination, and recruitment of co-transcriptional factors are not directly affected. Although RNA Pol II, initiation factors, and Mediator accumulate at promoters, RNA Pol II complexes can also proceed into gene bodies without promoter-proximal pausing while retaining initiation factors and Mediator. Further downstream, RNA Pol II phosphorylation increases and initiation factors and Mediator are released, allowing recruitment of elongation factors and an increase in RNA Pol II elongation velocity. Collectively, CDK7 kinase activity promotes the release of initiation factors and Mediator from RNA Pol II, facilitating RNA Pol II escape from the promoter.

2024-05-31 | PXD037842 | Pride

RNA Polymerase II-associated factor 1 regulates the release and phosphorylation of paused RNA Polymerase II

Project description:Release of promoter-proximal paused RNA polymerase II (Pol II) during early elongation is a critical step in transcriptional regulation in metazoan cells. Paused Pol II release is thought to require the kinase activity of cyclin-dependent kinase 9 (CDK9) for the phosphorylation of DRB sensitivity-inducing factor, negative elongation factor, and C-terminal domain (CTD) serine-2 of Pol II. We found that Pol II-associated factor 1 (PAF1) is a critical regulator of paused Pol II release, that positive transcription elongation factor b (P-TEFb) directly regulates the initial recruitment of PAF1 complex (PAF1C) to genes, and that the subsequent recruitment of CDK12 is dependent on PAF1C. These findings reveal cooperativity among P-TEFb, PAF1C, and CDK12 in pausing release and Pol II CTD phosphorylation. Comparison of the chromatin occupancy of [1] PAF1, CDC73, LEO1, CTR9, total Pol II, and CTD serine 2-phosphorylated Pol II by ChIP-seq in THP1 cells; [2] PAF1, Pol II, Pol II (ser-5p), CDK12, and CDK9 by ChIP-seq in control and PAF1 knockdown cells; [3] LEO1 and Pol II by ChIP-seq in control and flavopiridol treated THP1 cells.

2015-12-11 | E-GEOD-62171 | biostudies-arrayexpress

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