Rapid, Transcription-Independent Loss of Nucleosomes over a Large Chromatin Domain at Hsp70 Loci

Petesch, Steven J.; Lis, John T.

doi:10.1016/j.cell.2008.05.029

Cited by 299 publications

(373 citation statements)

References 68 publications

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“…But nucleosomes can also be removed from gene bodies independently of transcription. Previous studies of the Hsp70 locus in Drosophila have shown that heat-shock induces rapid and transcription-independent loss of gene-body nucleosomes (Petesch and Lis 2008). Finally, it is possible that the 14°C temperature increase itself perturbs nucleosomes.…”

Section: Nucleosome Fragility Increases Throughout Heat-shock Genes Umentioning

confidence: 99%

Nucleosome fragility is associated with future transcriptional response to developmental cues and stress inC. elegans

Jeffers

Lieb

2016

Genome Res.

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Nucleosomes have structural and regulatory functions in all eukaryotic DNA-templated processes. The position of nucleosomes on DNA and the stability of the underlying histone-DNA interactions affect the access of regulatory proteins to DNA. Both stability and position are regulated through DNA sequence, histone post-translational modifications, histone variants, chromatin remodelers, and transcription factors. Here, we explored the functional implications of nucleosome properties on gene expression and development in Caenorhabditis elegans embryos. We performed a time-course of micrococcal nuclease (MNase) digestion and measured the relative sensitivity or resistance of nucleosomes throughout the genome. Fragile nucleosomes were defined by nucleosomal DNA fragments that were recovered preferentially in early MNase-digestion time points. Nucleosome fragility was strongly and positively correlated with the AT content of the underlying DNA sequence. There was no correlation between promoter nucleosome fragility and the levels of histone modifications or histone variants. Genes with fragile nucleosomes in their promoters tended to be lowly expressed and expressed in a contextspecific way, operating in neuronal response, the immune system, and stress response. In addition to DNA-encoded nucleosome fragility, we also found fragile nucleosomes at locations where we expected to find destabilized nucleosomes, for example, at transcription factor binding sites where nucleosomes compete with DNA-binding factors. Our data suggest that in C. elegans promoters, nucleosome fragility is in large part DNA-encoded and that it poises genes for future context-specific activation in response to environmental stress and developmental cues.[Supplemental material is available for this article.]The fundamental unit of eukaryotic chromatin is the nucleosome, which consists of 147 bp of DNA wrapped around an octamer of histone proteins (Luger et al. 1997). Nucleosomes have important structural and regulatory functions in organizing the genome and restricting access of regulatory factors to the DNA sequence (Henikoff 2008). As such, the interactions between nucleosomes and DNA strongly influence the regulation of gene expression by determining DNA accessibility for transcription factors (TFs) and RNA polymerase. In addition to regulated nucleosome assembly and disassembly through the action of histone chaperones and chromatin remodelers, nucleosome stability is influenced by histone modifications, histone variants, DNA features encoded in cis, and competition with DNA-binding factors in trans . A complete picture of the mechanisms governing nucleosome stability is fundamental to understanding how gene expression is dynamically regulated.Nucleosome stability has been studied in vitro using sensitivity to enzymatic digestion or salt concentration (Bloom and Anderson 1978;Burton et al. 1978;Li et al. 1993;Polach and Widom 1995;Wu and Travers 2004;Jin and Felsenfeld 2007). Genome-wide adaptations of these methods have been used to identify nuc...

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Section: Nucleosome Fragility Increases Throughout Heat-shock Genes Umentioning

confidence: 99%

Nucleosome fragility is associated with future transcriptional response to developmental cues and stress inC. elegans

Jeffers

Lieb

2016

Genome Res.

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“…While some ARTDs modify substrates by transferring iteratively multiple ADP-ribose units resulting in poly-ADP-ribosylation (PARylation), most ARTDs mono-ADP-ribosylate (MARylate) their substrates (Kleine et al, 2008). ARTDs function in DNA damage repair (Malanga and Althaus, 2005;Nicolae et al, 2014Nicolae et al, , 2015, the unfolded protein response (Jwa and Chang, 2012), apoptosis Koh et al, 2005), heat shock (Petesch and Lis, 2008), cellular signaling (Feijs et al, 2013a;, cell division (Chang et al, 2004(Chang et al, , 2005(Chang et al, , 2009Ha et al, 2012), as well as transcription and chromatin regulation Schreiber et al, 2006). PARylating ARTDs (pARTDs; ARTD1-6), most prominently ARTD1, have been the focus of cancer related research during the past two decades.…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage

Venkannagari

Verheugd

Koivunen

et al. 2016

Cell Chemical Biology

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SUMMARYMembers of the human diphtheria toxin-likeADP-ribosyltransferase (ARTD or PARP) family play important roles in regulating biological activities by mediating either a mono-ADP-ribosylation MARylation) of a substrate or a poly-ADP-ribosylation (PARylation). ARTD10/PARP10 belongs to the MARylating ARTDs (mARTDs) subfamily, and plays important roles in biological processes that range from cellular signaling, DNA repair, and cell proliferation to immune response. Despite their biological and disease relevance, no selective inhibitors for mARTDs are available. Here we describe a small-molecule ARTD10 inhibitor, OUL35, a selective and potent inhibitor for this enzyme. We characterize its selectivity profile, model its binding, and demonstrate activity in HeLa cells where OUL35 rescued cells from ARTD10 induced cell death. Using OUL35 as a cell biology tool we show that ARTD10 inhibition sensitizes the cells to the hydroxyurea-induced genotoxic stress. Our study supports the proposed role of ARTD10 in DNA-damage repair and provides a tool compound for selective inhibition of ARTD10-mediated MARylation.3

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“…PARP1-ECFP (red) and PARP Δ300 -EYFP (green) protein localization was detected by autofluorescence of ECFP and EYFP. binding of PARP and its enzymatic activation were shown to be critical for Pol2 polymerase-dependent transcription within the Hsp70 gene (7,27). Here, we compared distribution of PARP1-ECFP and PARP Δ300 -EYFP proteins along the hsp70 locus in parp C03256 mutants.…”

Section: Parp δ300 Protein Is Enriched In Regions Of Euchromatin and Ismentioning

confidence: 99%

“…PARP1 enzymatic activity has also been shown to be required for normal assembly of higher order chromatin structures and for transcriptional activation (6). Moreover, it has been shown that PARP1 regulates the transcription of these genes by inducing chromatin loosening at targeted genetic loci (6,7). Finally, PARP1 establishes silent chromatin domains and represses retrotransposable elements (8).…”

mentioning

confidence: 99%

Uncoupling of the transactivation and transrepression functions of PARP1 protein

Kotova

Jarnik

Tulin

2010

Proc. Natl. Acad. Sci. U.S.A.

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Poly(ADP ribose) polymerase 1 (PARP1) is a nuclear protein that regulates chromatin remodeling and transcription as well as DNA repair and genome stability pathways. Recent studies have revealed a paradoxical dual role of PARP1 protein in transcription. Specifically, although PARP1 controls transcriptional activation of a subset of genes that are heat shock-or hormone-dependent, it also directly inactivates transcription, establishes heterochromatin domains, and silences retrotransposable elements. However, the domains required for these disparate functions are currently unknown. In this paper, we report the discovery of a previously undescribed mutation in the Drosophila Parp locus. We show that the mutants express a deletion mutant of PARP1 protein with an altered DNA binding domain that carries only the second Znfinger. We demonstrate that this alteration specifically excludes PARP1 protein from heterochromatin and makes PARP1 unable to maintain repression of retrotransposable elements. By characterizing the biological activity of this unique PARP1 mutant protein isoform, we have uncoupled the transactivation and transrepression functions of this protein.chromatin | poly(ADP ribose) polymerase | transcription P oly(ADP ribose) polymerase 1 (PARP1) protein has been known for decades as a nuclear protein that recognizes and binds nicks and ends of DNA and catalyses poly(ADP ribose) (pADPr) synthesis (1). The basic enzymatic reactions catalyzed by PARP1 involve transferring ADPr from nicotinamide-adenine dinucleotide to either a protein acceptor or an existing pADPr chain, the average length of which is 80 or more residues (2). PARP1 protein can modify numerous chromatin proteins in vivo and in vitro (3). A key role of PARP1 was shown in DNA repair and apoptosis (3), where PARP works as a trigger between the DNA repair (4) and apoptotic pathways (5). PARP1 enzymatic activity has also been shown to be required for normal assembly of higher order chromatin structures and for transcriptional activation (6). Moreover, it has been shown that PARP1 regulates the transcription of these genes by inducing chromatin loosening at targeted genetic loci (6, 7). Finally, PARP1 establishes silent chromatin domains and represses retrotransposable elements (8).The characterization of deletion mutants of PARP that distinguish among the varied functions of this protein is essential to establish a more complete understanding of PARP1 protein biology. At present, however, we have identified neither the mechanism of PARP protein targeting to specific chromatin domains nor the mechanism of local PARP activation. Closing these gaps in our current knowledge is complicated because the presence of 18 paralogous PARP proteins (9) in mammals most likely results in corresponding functional redundancies. The Drosophila genome (8, 10, 11) encodes only a single nuclear PARP (PARP1), making this animal an invaluable model system for the study of PARP functions.The PARP1 protein has three functionally defined domains conserved from human to Droso...

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Rapid, Transcription-Independent Loss of Nucleosomes over a Large Chromatin Domain at Hsp70 Loci

Cited by 299 publications

References 68 publications

Nucleosome fragility is associated with future transcriptional response to developmental cues and stress inC. elegans

Nucleosome fragility is associated with future transcriptional response to developmental cues and stress inC. elegans

Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage

Uncoupling of the transactivation and transrepression functions of PARP1 protein

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