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KAP1 targets actively transcribed genomic loci to exert pleomorphic effects on RNA Polymerase II- and III-mediated expression

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE106976 | GEO | 2018/11/16

REPOSITORIES: GEO

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KAP1 targets actively transcribed genomic loci to exert pleomorphic effects on RNA polymerase II activity.

Project description:KAP1 (KRAB-associated protein 1) is best known as a co-repressor responsible for inducing heterochromatin formation, notably at transposable elements. However, it has also been observed to bind the transcription start site of actively expressed genes. To address this paradox, we characterized the protein interactome of KAP1 in the human K562 erythro-leukaemia cell line. We found that the regulator can associate with a wide range of nucleic acid binding proteins, nucleosome remodellers, chromatin modifiers and other transcription modulators. We further determined that KAP1 is recruited at actively transcribed polymerase II promoters, where its depletion resulted in pleomorphic effects, whether expression of these genes was normally constitutive or inducible, consistent with the breadth of possible KAP1 interactors. This article is part of a discussion meeting issue 'Crossroads between transposons and gene regulation'.

| S-EPMC7061982 | biostudies-literature

KAP1 targets actively transcribed genomic loci to exert pleomorphic effects on RNA Polymerase II- and III-mediated expression [ChIP-Seq]

Project description:KAP1 (KRAB-associated protein 1) is best known as a co-repressor responsible for inducing heterochromatin formation notably at transposable elements. However, it has also been observed to bind the transcription start site of actively expressed genes. To address this paradox, we characterized the protein interactome of KAP1 in human embryonic stem cells and in the K562 erythro-leukemia cell line. We found that the regulator can associate with a wide range of nucleic acid binding proteins, nucleosome remodelers, chromatin modifiers and other transcription modulators. We further determined that KAP1 is recruited not only at actively transcribed polymerase II promoters, but also at genetic units driven by polymerase III, for instance tRNA genes. While KAP1 depletion induced a mild downregulation of these genes, at PolII-transcribed units it resulted in pleomorphic effects, whether expression of these genes was normally constitutive or inducible, consistent with the breadth of possible KAP1 interactors

2018-11-16 | GSE106974 | GEO

KAP1 targets actively transcribed genomic loci to exert pleomorphic effects on RNA Polymerase II- and III-mediated expression [RNA-Seq, small RNA-Seq]

2018-11-16 | GSE106975 | GEO

KAP1 targets actively transcribed genomic loci to exert pleomorphic effects on RNA Polymerase II- and III-mediated expression

Project description:KAP1 targets actively transcribed genomic loci to exert pleomorphic effects on RNA Polymerase II- and III-mediated expression

| PRJNA418703 | ENA

KAP1 targets actively transcribed genomic loci to exert pleomorphic effects on RNA Polymerase II- and III-mediated expression [ChIP-Seq]

Project description:KAP1 targets actively transcribed genomic loci to exert pleomorphic effects on RNA Polymerase II- and III-mediated expression [ChIP-Seq]

| PRJNA418708 | ENA

KAP1 targets actively transcribed genomic loci to exert pleomorphic effects on RNA Polymerase II- and III-mediated expression [RNA-Seq, small RNA-Seq]

Project description:KAP1 targets actively transcribed genomic loci to exert pleomorphic effects on RNA Polymerase II- and III-mediated expression [RNA-Seq, small RNA-Seq]

| PRJNA418707 | ENA

DSIF and RNA polymerase II CTD phosphorylation coordinate the recruitment of Rpd3S to actively transcribed genes.

Project description:Histone deacetylase Rpd3 is part of two distinct complexes: the large (Rpd3L) and small (Rpd3S) complexes. While Rpd3L targets specific promoters for gene repression, Rpd3S is recruited to ORFs to deacetylate histones in the wake of RNA polymerase II, to prevent cryptic initiation within genes. Methylation of histone H3 at lysine 36 by the Set2 methyltransferase is thought to mediate the recruitment of Rpd3S. Here, we confirm by ChIP-Chip that Rpd3S binds active ORFs. Surprisingly, however, Rpd3S is not recruited to all active genes, and its recruitment is Set2-independent. However, Rpd3S complexes recruited in the absence of H3K36 methylation appear to be inactive. Finally, we present evidence implicating the yeast DSIF complex (Spt4/5) and RNA polymerase II phosphorylation by Kin28 and Ctk1 in the recruitment of Rpd3S to active genes. Taken together, our data support a model where Set2-dependent histone H3 methylation is required for the activation of Rpd3S following its recruitment to the RNA polymerase II C-terminal domain.

| S-EPMC2965751 | biostudies-literature

Pausing sites of RNA polymerase II on actively transcribed genes are enriched in DNA double-stranded breaks.

Project description:DNA double-stranded breaks (DSBs) are strongly associated with active transcription, and promoter-proximal pausing of RNA polymerase II (Pol II) is a critical step in transcriptional regulation. Mapping the distribution of DSBs along actively expressed genes and identifying the location of DSBs relative to pausing sites can provide mechanistic insights into transcriptional regulation. Using genome-wide DNA break mapping/sequencing techniques at single-nucleotide resolution in human cells, we found that DSBs are preferentially located around transcription start sites of highly transcribed and paused genes and that Pol II promoter-proximal pausing sites are enriched in DSBs. We observed that DSB frequency at pausing sites increases as the strength of pausing increases, regardless of whether the pausing sites are near or far from annotated transcription start sites. Inhibition of topoisomerase I and II by camptothecin and etoposide treatment, respectively, increased DSBs at the pausing sites as the concentrations of drugs increased, demonstrating the involvement of topoisomerases in DSB generation at the pausing sites. DNA breaks generated by topoisomerases are short-lived because of the religation activity of these enzymes, which these drugs inhibit; therefore, the observation of increased DSBs with increasing drug doses at pausing sites indicated active recruitment of topoisomerases to these sites. Furthermore, the enrichment and locations of DSBs at pausing sites were shared among different cell types, suggesting that Pol II promoter-proximal pausing is a common regulatory mechanism. Our findings support a model in which topoisomerases participate in Pol II promoter-proximal pausing and indicated that DSBs at pausing sites contribute to transcriptional activation.

| S-EPMC7086017 | biostudies-literature

Integrator endonuclease drives promoter-proximal termination at all RNA polymerase II-transcribed loci.

Project description:RNA polymerase II (RNAPII) pausing in early elongation is critical for gene regulation. Paused RNAPII can be released into productive elongation by the kinase P-TEFb or targeted for premature termination by the Integrator complex. Integrator comprises endonuclease and phosphatase activities, driving termination by cleavage of nascent RNA and removal of stimulatory phosphorylation. We generated a degron system for rapid Integrator endonuclease (INTS11) depletion to probe the direct consequences of Integrator-mediated RNA cleavage. Degradation of INTS11 elicits nearly universal increases in active early elongation complexes. However, these RNAPII complexes fail to achieve optimal elongation rates and exhibit persistent Integrator phosphatase activity. Thus, only short transcripts are significantly upregulated following INTS11 loss, including transcription factors, signaling regulators, and non-coding RNAs. We propose a uniform molecular function for INTS11 across all RNAPII-transcribed loci, with differential effects on particular genes, pathways, or RNA biotypes reflective of transcript lengths rather than specificity of Integrator activity.

| S-EPMC9680917 | biostudies-literature

The nuclear RNA polymerase II surveillance system targets polymerase III transcripts.

Project description:A key question in nuclear RNA surveillance is how target RNAs are recognized. To address this, we identified in vivo binding sites for nuclear RNA surveillance factors, Nrd1, Nab3 and the Trf4/5–Air1/2–Mtr4 polyadenylation (TRAMP) complex poly(A) polymerase Trf4, by UV crosslinking. Hit clusters were reproducibly found over known binding sites on small nucleolar RNAs (snoRNAs), pre-mRNAs and cryptic, unstable non-protein-coding RNAs (ncRNAs) ('CUTs'), along with ~642 predicted long anti-sense ncRNAs (asRNAs), ~178 intergenic ncRNAs and, surprisingly, ~1384 mRNAs. Five putative asRNAs tested were confirmed to exist and were stabilized by loss of Nrd1, Nab3 or Trf4. Mapping of micro-deletions and substitutions allowed clear definition of preferred, in vivo Nab3 and Nrd1 binding sites. Nrd1 and Nab3 were believed to be Pol II specific but, unexpectedly, bound many oligoadenylated Pol III transcripts, predominately pre-tRNAs. Depletion of Nrd1 or Nab3 stabilized tested Pol III transcripts and their oligoadenylation was dependent on Nrd1–Nab3 and TRAMP. Surveillance targets were enriched for non-encoded A-rich tails. These were generally very short (1–5 nt), potentially explaining why adenylation destabilizes these RNAs while stabilizing mRNAs with long poly(A) tails.

| S-EPMC3102002 | biostudies-literature

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