A p53 enhancer region regulates target genes through chromatin conformations in <i>cis</i> and in <i>trans</i>

Link, Nichole; Kurtz, Paula; O'Neal, Melissa; Garcia-Hughes, Gianella; Abrams, John

doi:10.1101/gad.225565.113

Cited by 35 publications

(53 citation statements)

References 34 publications

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“…Thus, the inhibition of Tip60/NuA4 results in the upregulation of .100 genes associated with a DNA damage response. These include the known direct targets of p53 such as reaper, eiger, and Xrp1 (Brodsky et al 2000;Akdemir et al 2007;Link et al 2013), as well as several p53-independent targets such as Gadd45, Snap25, and Traf4 (van Bergeijk et al 2012). Figure 4Q shows a subset of targets, their regulation by p53 and DREAM, as well as whether they overlap with known locations of Tip60 binding.…”

Section: The Transcriptional Response To Tip60 Inhibitionmentioning

confidence: 99%

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Roles for the Histone Modifying and Exchange Complex NuA4 in Cell Cycle Progression in Drosophila melanogaster

Flegel¹,

Grushko²,

Bolin³

et al. 2016

Genetics

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Robust and synchronous repression of E2F-dependent gene expression is critical to the proper timing of cell cycle exit when cells transition to a postmitotic state. Previously NuA4 was suggested to act as a barrier to proliferation in Drosophila by repressing E2F-dependent gene expression. Here we show that NuA4 activity is required for proper cell cycle exit and the repression of cell cycle genes during the transition to a postmitotic state in vivo. However, the delay of cell cycle exit caused by compromising NuA4 is not due to additional proliferation or effects on E2F activity. Instead NuA4 inhibition results in slowed cell cycle progression through late S and G2 phases due to aberrant activation of an intrinsic p53-independent DNA damage response. A reduction in NuA4 function ultimately produces a paradoxical cell cycle gene expression program, where certain cell cycle genes become derepressed in cells that are delayed during the G2 phase of the final cell cycle. Bypassing the G2 delay when NuA4 is inhibited leads to abnormal mitoses and results in severe tissue defects. NuA4 physically and genetically interacts with components of the E2F complex termed Drosophila, Rbf, E2F and Myb/Multi-vulva class B (DREAM/MMB), and modulates a DREAM/MMB-dependent ectopic neuron phenotype in the posterior wing margin. However, this effect is also likely due to the cell cycle delay, as simply reducing Cdk1 is sufficient to generate a similar phenotype. Our work reveals that the major requirement for NuA4 in the cell cycle in vivo is to suppress an endogenous DNA damage response, which is required to coordinate proper S and G2 cell cycle progression with differentiation and cell cycle gene expression.KEYWORDS DNA damage; proliferation; H2Av; cell cycle checkpoint; cell cycle exit A conserved eukaryotic transcriptional oscillator controls cell cycle gene expression in proliferating cells and underlies the well-studied Cyclin/Cdk cell cycle protein oscillator (Orlando et al. 2008;Oikonomou and Cross 2010). In metazoans, this oscillator depends upon transcriptional activation of several hundred cell cycle genes, initiated by E2F transcription factor complexes followed by E2F inhibition (or degradation) (Shibutani et al. 2008;Zielke et al. 2011;Sadasivam and Decaprio 2013). This generates an oscillation of chromatin opening and closing at cell cycle genes that is thought to properly coordinate G1/S and G2/M gene expression as well as the transition to a noncycling state (Litovchick et al. 2007(Litovchick et al. , 2011Forristal et al. 2014). Disruption of this coordination can affect cell cycle progression by causing inappropriate gene expression (Reis and Edgar 2004;Wen et al. 2008;Forristal et al. 2014). While the oscillation of E2F activity is required for robust cell cycle gene expression Korenjak et al. 2012), E2F complexes are not absolutely essential for cell cycle progression or timely cell cycle exit in Drosophila (Frolov et al. 2001(Frolov et al. , 2005. In the absence of E2F activity there must be E2F-independ...

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Section: The Transcriptional Response To Tip60 Inhibitionmentioning

confidence: 99%

mentioning

confidence: 99%

Roles for the Histone Modifying and Exchange Complex NuA4 in Cell Cycle Progression in Drosophila melanogaster

Flegel¹,

Grushko²,

Bolin³

et al. 2016

Genetics

View full text Add to dashboard Cite

show abstract

“…Droplet digital RT-PCR reactions (Figs. 1B, 4) were previously described (Link et al 2013). Primers and fluorescent probes specific for the TAHRE , and a p53-null c-Myc-expressing (E,F) mouse depicting elevated expression of mouse IAP gag (red staining; left panels) (Dewannieux et al 2004) and mouse L1 ORF1p (red staining; right panels) (Soper et al 2008) in tumors (C-F ).…”

Section: Rt-pcrmentioning

confidence: 99%

p53 genes function to restrain mobile elements

et al. 2015

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Throughout the animal kingdom, p53 genes govern stress response networks by specifying adaptive transcriptional responses. The human member of this gene family is mutated in most cancers, but precisely how p53 functions to mediate tumor suppression is not well understood. Using Drosophila and zebrafish models, we show that p53 restricts retrotransposon activity and genetically interacts with components of the piRNA (piwi-interacting RNA) pathway. Furthermore, transposon eruptions occurring in the p53 − germline were incited by meiotic recombination, and transcripts produced from these mobile elements accumulated in the germ plasm. In gene complementation studies, normal human p53 alleles suppressed transposons, but mutant p53 alleles from cancer patients could not. Consistent with these observations, we also found patterns of unrestrained retrotransposons in p53-driven mouse and human cancers. Furthermore, p53 status correlated with repressive chromatin marks in the 5 ′ sequence of a synthetic LINE-1 element. Together, these observations indicate that ancestral functions of p53 operate through conserved mechanisms to contain retrotransposons. Since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates oncogenic disease in part by restricting transposon mobility.

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“…Chromatin loops are restricted to one TAD, and current work focuses on determining organizational mechanisms defining these territories. Long-range intrachromosomal chromatin structures of hundreds of kilobases or interchromosomal interactions involving p53 have been reported in Drosophila (Link et al 2013). In humans, with the exception of the wellknown HS40 enhancer and a-globin gene (Zhou et al 2006;Vernimmen et al 2007;Bau et al 2011) forming a 500-kb interaction domain on chromosome 16, precise DNA Ó 2014 Robin et al This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml).…”

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confidence: 99%

Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances

et al. 2014

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While global chromatin conformation studies are emerging, very little is known about the chromatin conformation of human telomeres. Most studies have focused on the role of telomeres as a tumor suppressor mechanism. Here we describe how telomere length regulates gene expression long before telomeres become short enough to produce a DNA damage response (senescence). We directly mapped the interactions adjacent to specific telomere ends using a Hi-C (chromosome capture followed by high-throughput sequencing) technique modified to enrich for specific genomic regions. We demonstrate that chromosome looping brings the telomere close to genes up to 10 Mb away from the telomere when telomeres are long and that the same loci become separated when telomeres are short. Furthermore, expression array analysis reveals that many loci, including noncoding RNAs, may be regulated by telomere length. We report three genes (ISG15 [interferon-stimulated gene 15 kd], DSP [Desmoplakin], and C1S [complement component 1s subcomplement]) located at three different subtelomeric ends (1p, 6p, and 12p) whose expressions are altered with telomere length. Additionally, we confirmed by in situ analysis (3D-FISH [three-dimensional fluorescence in situ hybridization]) that chromosomal looping occurs between the loci of those genes and their respective telomere ends. We term this process TPE-OLD for ''telomere position effect over long distances.'' Our results suggest a potential novel mechanism for how telomere shortening could contribute to aging and disease initiation/progression in human cells long before the induction of a critical DNA damage response.

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A p53 enhancer region regulates target genes through chromatin conformations in cis and in trans

Cited by 35 publications

References 34 publications

Roles for the Histone Modifying and Exchange Complex NuA4 in Cell Cycle Progression in Drosophila melanogaster

Roles for the Histone Modifying and Exchange Complex NuA4 in Cell Cycle Progression in Drosophila melanogaster

p53 genes function to restrain mobile elements

Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances

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