Publications by authors named "Jane Mellor"

50 Publications

Cold-induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm.

EMBO J 2020 Nov 9;39(22):e105604. Epub 2020 Oct 9.

Department of Biochemistry, University of Oxford, Oxford, UK.

Cooling patients to sub-physiological temperatures is an integral part of modern medicine. We show that cold exposure induces temperature-specific changes to the higher-order chromatin and gene expression profiles of human cells. These changes are particularly dramatic at 18°C, a temperature synonymous with that experienced by patients undergoing controlled deep hypothermia during surgery. Cells exposed to 18°C exhibit largely nuclear-restricted transcriptome changes. These include the nuclear accumulation of mRNAs encoding components of the negative limbs of the core circadian clock, most notably REV-ERBα. This response is accompanied by compaction of higher-order chromatin and hindrance of mRNPs from engaging nuclear pores. Rewarming reverses chromatin compaction and releases the transcripts into the cytoplasm, triggering a pulse of negative limb gene proteins that reset the circadian clock. We show that cold-induced upregulation of REV-ERBα is sufficient to trigger this reset. Our findings uncover principles of the cellular cold response that must be considered for current and future applications involving therapeutic deep hypothermia.
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http://dx.doi.org/10.15252/embj.2020105604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667876PMC
November 2020

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.

Lancet Oncol 2020 03 31;21(3):398-411. Epub 2020 Jan 31.

Department of Surgery, University of Southampton, Southampton, UK. Electronic address:

Background: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival.

Methods: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m administered intravenously over 2 h and oral capecitabine 1000 mg/m twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m every 2 weeks with regimen one and three or a loading dose of 400 mg/m followed by a weekly infusion of 250 mg/m with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367.

Findings: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0-77·5). Median progression-free survival was 22·2 months (95% CI 18·3-26·8) in the chemotherapy alone group and 15·5 months (13·8-19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87-1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5-71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02-2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3-4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]).

Interpretation: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting.

Funding: Cancer Research UK.
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http://dx.doi.org/10.1016/S1470-2045(19)30798-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052737PMC
March 2020

Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence.

Mol Cell 2019 10 29;76(1):110-125.e9. Epub 2019 Aug 29.

The Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, OX3 7FY, UK. Electronic address:

Failure to make adaptive immune responses is a hallmark of aging. Reduced B cell function leads to poor vaccination efficacy and a high prevalence of infections in the elderly. Here we show that reduced autophagy is a central molecular mechanism underlying immune senescence. Autophagy levels are specifically reduced in mature lymphocytes, leading to compromised memory B cell responses in old individuals. Spermidine, an endogenous polyamine metabolite, induces autophagy in vivo and rejuvenates memory B cell responses. Mechanistically, spermidine post-translationally modifies the translation factor eIF5A, which is essential for the synthesis of the autophagy transcription factor TFEB. Spermidine is depleted in the elderly, leading to reduced TFEB expression and autophagy. Spermidine supplementation restored this pathway and improved the responses of old human B cells. Taken together, our results reveal an unexpected autophagy regulatory mechanism mediated by eIF5A at the translational level, which can be harnessed to reverse immune senescence in humans.
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http://dx.doi.org/10.1016/j.molcel.2019.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863385PMC
October 2019

Elucidating the Role of Chromatin State and Transcription Factors on the Regulation of the Yeast Metabolic Cycle: A Multi-Omic Integrative Approach.

Front Genet 2018 30;9:578. Epub 2018 Nov 30.

Genomics of Gene Expression Laboratory Centro de Investigación Príncipe Felipe, Valencia, Spain.

The Yeast Metabolic Cycle (YMC) is a model system in which levels of around 60% of the yeast transcripts cycle over time. The spatial and temporal resolution provided by the YMC has revealed that changes in the yeast metabolic landscape and chromatin status can be related to cycling gene expression. However, the interplay between histone modifications and transcription factor activity during the YMC is still poorly understood. Here we apply an innovative statistical approach to integrate chromatin state (ChIP-seq) and gene expression (RNA-seq) data to investigate the transcriptional control during the YMC. By using the multivariate regression models N-PLS (Partial Least Squares) and MORE (Multi-Omics REgulation) methodologies, we assessed the contribution of histone marks and transcription factors to the regulation of gene expression in the YMC. We found that H3K18ac and H3K9ac were the most important histone modifications, whereas Sfp1, Hfi1, Pip2, Mig2, and Yhp1 emerged as the most relevant transcription factors. A significant association in the co-regulation of gene expression was found between H3K18ac and the transcription factors Pip2 (involved in fatty acids metabolism), Xbp1 (cyclin implicated in the regulation of carbohydrate and amino acid metabolism), and Hfi1 (involved in the formation of the SAGA complex). These results evidence the crucial role of histone lysine acetylation levels in the regulation of gene expression in the YMC through the coordinated action of transcription factors and lysine acetyltransferases.
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http://dx.doi.org/10.3389/fgene.2018.00578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284056PMC
November 2018

: Linking Metabolism and Epigenetics.

Front Genet 2018 23;9:493. Epub 2018 Oct 23.

Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

Mutations in genes encoding enzymes of the tricarboxylic acid cycle often contribute to cancer development and progression by disrupting cell metabolism and altering the epigenetic landscape. This is exemplified by the isoforms of isocitrate dehydrogenase (IDH1/2), which metabolize isocitrate to α-Ketoglutarate (α-KG). Gain of function mutations in or result in reduced levels of α-KG as a result of increased formation of D-2-Hydroxyglutarate (2-HG). α-KG is an essential co-factor for certain histone and DNA demethylases, while 2-HG is a competitive inhibitor. These mutations are thought to result in hypermethylated histones and DNA which in turn alters gene expression and drives cancer progression. While this model seems to be generally accepted in the field, the exact molecular mechanisms still remain elusive. How much of this model has been rigorously demonstrated and what is just being assumed? Are the effects genome-wide or focused on specific loci? This aims at elucidating the key questions that remain to be addressed, the experimental techniques that could be used to gain further insight into the molecular mechanisms involved and the additional consequences of these mutations beyond DNA and protein methylation.
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http://dx.doi.org/10.3389/fgene.2018.00493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206167PMC
October 2018

Antisense transcription-dependent chromatin signature modulates sense transcript dynamics.

Mol Syst Biol 2018 02 12;14(2):e8007. Epub 2018 Feb 12.

Department of Biochemistry, University of Oxford, Oxford, UK

Antisense transcription is widespread in genomes. Despite large differences in gene size and architecture, we find that yeast and human genes share a unique, antisense transcription-associated chromatin signature. We asked whether this signature is related to a biological function for antisense transcription. Using quantitative RNA-FISH, we observed changes in sense transcript distributions in nuclei and cytoplasm as antisense transcript levels were altered. To determine the mechanistic differences underlying these distributions, we developed a mathematical framework describing transcription from initiation to transcript degradation. At , high levels of antisense transcription alter sense transcription dynamics, reducing rates of transcript production and processing, while increasing transcript stability. This relationship with transcript stability is also observed as a genome-wide association. Establishing the antisense transcription-associated chromatin signature through disruption of the Set3C histone deacetylase activity is sufficient to similarly change these rates even in the absence of antisense transcription. Thus, antisense transcription alters sense transcription dynamics in a chromatin-dependent manner.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810148PMC
http://dx.doi.org/10.15252/msb.20178007DOI Listing
February 2018

CRISPRi is not strand-specific at all loci and redefines the transcriptional landscape.

Elife 2017 10 23;6. Epub 2017 Oct 23.

Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

CRISPRi, an adapted CRISPR-Cas9 system, is proposed to act as a strand-specific roadblock to repress transcription in eukaryotic cells using guide RNAs (sgRNAs) to target catalytically inactive Cas9 (dCas9) and offers an alternative to genetic interventions for studying pervasive antisense transcription. Here, we successfully use click chemistry to construct DNA templates for sgRNA expression and show, rather than acting simply as a roadblock, sgRNA/dCas9 binding creates an environment that is permissive for transcription initiation/termination, thus generating novel sense and antisense transcripts. At in , sgRNA/dCas9 targeting to the non-template strand for antisense transcription results in antisense transcription termination, premature termination of a proportion of sense transcripts and initiation of a novel antisense transcript downstream of the sgRNA/dCas9-binding site. This redefinition of the transcriptional landscape by CRISPRi demonstrates that it is not strand-specific and highlights the controls and locus understanding required to properly interpret results from CRISPRi interventions.
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http://dx.doi.org/10.7554/eLife.29878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665645PMC
October 2017

Longevity effect of a polysaccharide from Chlorophytum borivilianum on Caenorhabditis elegans and Saccharomyces cerevisiae.

PLoS One 2017 20;12(7):e0179813. Epub 2017 Jul 20.

L'Oréal Research and Innovation, Aulnay-sous-Bois, France.

The traditional Indian medicine, Ayurveda, provides insights and practical solutions towards a healthy life style. Rasayana is a branch of Ayurveda known for preserving and promoting health, enhancing the quality of life and delaying the aging process. In the traditional knowledge, the Rasayana herb, Chlorophytum borivilianum (C. borivilanum) is regarded as a general health promoting tonic that delays aging and increases lifespan, cognitive function and physical strength. Aging is a complex and multifactorial physiological phenomenon that manifests itself over a wide range of biological systems, tissues, and functions. Longevity is an obvious marker of physiological aging. Simple model systems such as the single-cell budding yeast Saccharomyces cerevisiae (S. cerevisiae) and the nematode, Caenorhabditis elegans (C. elegans) are widely used to study the aging process and longevity. Here, we show that a polysaccharide fraction obtained from C. borivilianum increases the lifespan of S. cerevisiae and C. elegans, using an automated screening platform (ChronoscreenTM). Chemical analysis of this extract revealed a low molecular weight polysaccharide of 1000 Da, predominantly comprising Glu1→6Glu linkage. This polysaccharide showed significant dose-dependent extension of the median lifespan of S. cerevisiae by up to 41% and of the median lifespan of C. elegans by up to 10%. Taking cue from these results and the traditionally described benefits of Rasayanas on skin rejuvenation, we tested in vitro the polysaccharide for potential skin benefits. In a keratinocyte culture, we observed that this polysaccharide increased cell proliferation significantly, and induced synthesis of hyaluronic acid (HA), a well-known extracellular matrix component. Furthermore, when added to culture medium of human reconstructed epidermis, we observed an enhanced production of epidermal markers, e.g. CD44 and HA that are otherwise diminished in aged skin. Together, these results suggest that in addition to life-span extension of S. cerevisiae and C. elegans, a polysaccharide from the Rasayana herb, C. borivilianum may have beneficial effects on skin aging parameters.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179813PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519035PMC
September 2017

A randomised controlled trial to assess the cost-effectiveness of intensive versus no scheduled follow-up in patients who have undergone resection for colorectal cancer with curative intent.

Health Technol Assess 2017 05;21(32):1-86

University Surgery, University of Southampton, Southampton, UK.

Background: Intensive follow-up after surgery for colorectal cancer is common practice but lacks a firm evidence base.

Objective: To assess whether or not augmenting symptomatic follow-up in primary care with two intensive methods of follow-up [monitoring of blood carcinoembryonic antigen (CEA) levels and scheduled imaging] is effective and cost-effective in detecting the recurrence of colorectal cancer treatable surgically with curative intent.

Design: Randomised controlled open-label trial. Participants were randomly assigned to one of four groups: (1) minimum follow-up ( = 301), (2) CEA testing only ( = 300), (3) computerised tomography (CT) only ( = 299) or (4) CEA testing and CT ( = 302). Blood CEA was measured every 3 months for 2 years and then every 6 months for 3 years; CT scans of the chest, abdomen and pelvis were performed every 6 months for 2 years and then annually for 3 years. Those in the minimum and CEA testing-only arms had a single CT scan at 12-18 months. The groups were minimised on adjuvant chemotherapy, gender and age group (three strata).

Setting: Thirty-nine NHS hospitals in England with access to high-volume services offering surgical treatment of metastatic recurrence.

Participants: A total of 1202 participants who had undergone curative treatment for Dukes' stage A to C colorectal cancer with no residual disease. Adjuvant treatment was completed if indicated. There was no evidence of metastatic disease on axial imaging and the post-operative blood CEA level was ≤ 10 µg/l.

Main Outcome Measures:  Surgical treatment of recurrence with curative intent.  Time to detection of recurrence, survival after treatment of recurrence, overall survival and quality-adjusted life-years (QALYs) gained.

Results:  During 5 years of scheduled follow-up, cancer recurrence was detected in 203 (16.9%) participants. The proportion of participants with recurrence surgically treated with curative intent was 6.3% (76/1202), with little difference according to Dukes' staging (stage A, 5.1%; stage B, 7.4%; stage C, 5.6%;  = 0.56). The proportion was two to three times higher in each of the three more intensive arms (7.5% overall) than in the minimum follow-up arm (2.7%) (difference 4.8%;  = 0.003). Surgical treatment of recurrence with curative intent was 2.7% (8/301) in the minimum follow-up group, 6.3% (19/300) in the CEA testing group, 9.4% (28/299) in the CT group and 7.0% (21/302) in the CEA testing and CT group. Surgical treatment of recurrence with curative intent was two to three times higher in each of the three more intensive follow-up groups than in the minimum follow-up group; adjusted odds ratios (ORs) compared with minimum follow-up were as follows: CEA testing group, OR 2.40, 95% confidence interval (CI) 1.02 to 5.65; CT group, OR 3.69, 95% CI 1.63 to 8.38; and CEA testing and CT group, OR 2.78, 95% CI 1.19 to 6.49. A Kaplan-Meier survival analysis confirmed no significant difference between arms (log-rank  = 0.45). The baseline-adjusted Cox proportional hazards ratio comparing the minimum and intensive arms was 0.87 (95% CI 0.67 to 1.15). These CIs suggest a maximum survival benefit from intensive follow-up of 3.8%.  The incremental cost per patient treated surgically with curative intent compared with minimum follow-up was £40,131 with CEA testing, £43,392 with CT and £85,151 with CEA testing and CT. The lack of differential impact on survival resulted in little difference in QALYs saved between arms. The additional cost per QALY gained of moving from minimum follow-up to CEA testing was £25,951 and for CT was £246,107. When compared with minimum follow-up, combined CEA testing and CT was more costly and generated fewer QALYs, resulting in a negative incremental cost-effectiveness ratio (-£208,347) and a dominated policy.

Limitations: Although this is the largest trial undertaken at the time of writing, it has insufficient power to assess whether or not the improvement in detecting treatable recurrence achieved by intensive follow-up leads to a reduction in overall mortality.

Conclusions: Rigorous staging to detect residual disease is important before embarking on follow-up. The benefit of intensive follow-up in detecting surgically treatable recurrence is independent of stage. The survival benefit from intensive follow-up is unlikely to exceed 4% in absolute terms and harm cannot be absolutely excluded. A longer time horizon is required to ascertain whether or not intensive follow-up is an efficient use of scarce health-care resources. Translational analyses are under way, utilising tumour tissue collected from Follow-up After Colorectal Surgery trial participants, with the aim of identifying potentially prognostic biomarkers that may guide follow-up in the future.

Trial Registration: Current Controlled Trials ISRCTN41458548.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 21, No. 32. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta21320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494506PMC
May 2017

Paf1 Has Distinct Roles in Transcription Elongation and Differential Transcript Fate.

Mol Cell 2017 Feb 9;65(4):685-698.e8. Epub 2017 Feb 9.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address:

RNA polymerase II (Pol2) movement through chromatin and the co-transcriptional processing and fate of nascent transcripts is coordinated by transcription elongation factors (TEFs) such as polymerase-associated factor 1 (Paf1), but it is not known whether TEFs have gene-specific functions. Using strand-specific nucleotide resolution techniques, we show that levels of Paf1 on Pol2 vary between genes, are controlled dynamically by environmental factors via promoters, and reflect levels of processing and export factors on the encoded transcript. High levels of Paf1 on Pol2 promote transcript nuclear export, whereas low levels reflect nuclear retention. Strains lacking Paf1 show marked elongation defects, although low levels of Paf1 on Pol2 are sufficient for transcription elongation. Our findings support distinct Paf1 functions: a core general function in transcription elongation, satisfied by the lowest Paf1 levels, and a regulatory function in determining differential transcript fate by varying the level of Paf1 on Pol2.
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http://dx.doi.org/10.1016/j.molcel.2017.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316414PMC
February 2017

Is H3K4me3 instructive for transcription activation?

Bioessays 2017 01 7;39(1):1-12. Epub 2016 Nov 7.

Department of Biochemistry, University of Oxford, Oxford, UK.

Tri-methylation of lysine 4 on histone H3 (H3K4me3) is a near-universal chromatin modification at the transcription start site of active genes in eukaryotes from yeast to man and its levels reflect the amount of transcription. Because of this association, H3K4me3 is often described as an 'activating' histone modification and assumed to have an instructive role in the transcription of genes, but the field is lacking a conserved mechanism to support this view. The overwhelming finding from genome-wide studies is that actually very little transcription changes upon removal of most H3K4me3 under steady-state or dynamically changing conditions, including at mammalian CpG island promoters. Instead, rather than a major role in instructing transcription, time-resolved experiments provide more evidence supporting the deposition of H3K4me3 into chromatin as a result of transcription, influencing processes such as memory of previous states, transcriptional consistency between cells in a population and transcription termination.
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http://dx.doi.org/10.1002/bies.201600095DOI Listing
January 2017

The molecular basis of metabolic cycles and their relationship to circadian rhythms.

Authors:
Jane Mellor

Nat Struct Mol Biol 2016 Dec;23(12):1035-1044

Department of Biochemistry, University of Oxford, Oxford, UK.

Metabolic cycles result from the partitioning of oxidative and reductive metabolism into rhythmic phases of gene expression and oscillating post-translational protein modifications. Relatively little is known about how these switches in gene expression are controlled, although recent studies have suggested that transcription itself may play a central role. This review explores the molecular basis of the metabolic and gene-expression oscillations in the yeast Saccharomyces cerevisiae, as well as how they relate to other biological time-keeping mechanisms, such as circadian rhythms.
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http://dx.doi.org/10.1038/nsmb.3311DOI Listing
December 2016

The Chromatin Remodeler ISW1 Is a Quality Control Factor that Surveys Nuclear mRNP Biogenesis.

Cell 2016 11;167(5):1201-1214.e15

Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR944, CNRS UMR7212, Hôpital St. Louis 1, Avenue Claude Vellefaux, 75475 Paris Cedex, France.

Chromatin dynamics play an essential role in regulating DNA transaction processes, but it is unclear whether transcription-associated chromatin modifications control the mRNA ribonucleoparticles (mRNPs) pipeline from synthesis to nuclear exit. Here, we identify the yeast ISW1 chromatin remodeling complex as an unanticipated mRNP nuclear export surveillance factor that retains export-incompetent transcripts near their transcription site. This tethering activity of ISW1 requires chromatin binding and is independent of nucleosome sliding activity or changes in RNA polymerase II processivity. Combination of in vivo UV-crosslinking and genome-wide RNA immunoprecipitation assays show that Isw1 and its cofactors interact directly with premature mRNPs. Our results highlight that the concerted action of Isw1 and the nuclear exosome ensures accurate surveillance mechanism that proofreads the efficiency of mRNA biogenesis.
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http://dx.doi.org/10.1016/j.cell.2016.10.048DOI Listing
November 2016

Using both strands: The fundamental nature of antisense transcription.

Bioarchitecture 2016 ;6(1):12-21

a Department of Biochemistry ; University of Oxford ; Oxford , UK.

Non-coding transcription across the antisense strands of genes is an abundant, pervasive process in eukaryotes from yeast to humans, however its biological function remains elusive. Here, we provide commentary on a recent study of ours, which demonstrates a genome-wide role for antisense transcription: establishing a unique, dynamic chromatin architecture over genes. Antisense transcription increases the level of nucleosome occupancy and histone acetylation at the promoter and body of genes, without necessarily modulating the level of protein-coding sense transcription. It is also associated with high levels of histone turnover. By allowing genes to sample a wider range of chromatin configurations, antisense transcription could serve to make genes more sensitive to changing signals, priming them for responses to developmental programs or stressful cellular environments. Given the abundance of antisense transcription and the breadth of these chromatin changes, we propose that antisense transcription represents a fundamental, canonical feature of eukaryotic genes.
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http://dx.doi.org/10.1080/19490992.2015.1130779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914025PMC
July 2016

The clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a 2 × 2 factorial randomised controlled trial.

Health Technol Assess 2015 Dec;19(102):1-104

Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.

Background: Alcoholic hepatitis (AH) is a distinct presentation of alcoholic liver disease arising in patients who have been drinking to excess for prolonged periods, which is characterised by jaundice and liver failure. Severe disease is associated with high short-term mortality. Prednisolone and pentoxifylline (PTX) are recommended in guidelines for treatment of severe AH, but trials supporting their use have given heterogeneous results and controversy persists about their benefit.

Objectives: The aim of the clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis trial was to resolve the clinical dilemma on the use of prednisolone or PTX.

Design: The trial was a randomised, double-blind, 2 × 2 factorial, multicentre design.

Setting: Sixty-five gastroenterology and hepatology inpatient units across the UK.

Participants: Patients with a clinical diagnosis of AH who had a Maddrey's discriminant function value of ≥ 32 were randomised into four arms: A, placebo/placebo; B, placebo/prednisolone; C, PTX/placebo; and D, PTX/prednisolone. Of the 5234 patients screened for the trial, 1103 were randomised and after withdrawals, 1053 were available for primary end-point analysis.

Interventions: Those allocated to prednisolone were given 40 mg daily for 28 days and those allocated to PTX were given 400 mg three times per day for 28 days.

Outcomes: The primary outcome measure was mortality at 28 days. Secondary outcome measures included mortality or liver transplant at 90 days and at 1 year. Rates of recidivism among survivors and the impact of recidivism on mortality were assessed.

Results: At 28 days, in arm A, 45 of 269 (16.7%) patients died; in arm B, 38 of 266 (14.3%) died; in arm C, 50 of 258 (19.4%) died; and in arm D, 35 of 260 (13.5%) died. For PTX, the odds ratio for 28-day mortality was 1.07 [95% confidence interval (CI) 0.77 to 1.40; p = 0.686)] and for prednisolone the odds ratio was 0.72 (95% CI 0.52 to 1.01; p = 0.056). In the logistic regression analysis, accounting for indices of disease severity and prognosis, the odds ratio for 28-day mortality in the prednisolone-treated group was 0.61 (95% CI 0.41 to 0.91; p = 0.015). At 90 days and 1 year there were no significant differences in mortality rates between the treatment groups. Serious infections occurred in 13% of patients treated with prednisolone compared with 7% of controls (p = 0.002). At the 90-day follow-up, 45% of patients reported being completely abstinent, 9% reported drinking within safety limits and 33% had an unknown level of alcohol consumption. At 1 year, 37% of patients reported being completely abstinent, 10% reported drinking within safety limits and 39% had an unknown level of alcohol consumption. Only 22% of patients had attended alcohol rehabilitation treatment at 90 days and 1 year.

Conclusions: We conclude that prednisolone reduces the risk of mortality at 28 days, but this benefit is not sustained beyond 28 days. PTX had no impact on survival. Future research should focus on interventions to promote abstinence and on treatments that suppress the hepatic inflammation without increasing susceptibility to infection.

Trial Registration: This trial is registered as EudraCT 2009-013897-42 and Current Controlled Trials ISRCTN88782125.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 102. See the NIHR Journals Library website for further project information. The NIHR Clinical Research Network provided research nurse support and the Imperial College Biomedical Research Centre also provided funding.
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http://dx.doi.org/10.3310/hta191020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4781103PMC
December 2015

The Interleaved Genome.

Trends Genet 2016 Jan 21;32(1):57-71. Epub 2015 Nov 21.

Department of Biochemistry, South Parks Road, Oxford, OX1 3QU, UK.

Eukaryotic genomes are pervasively transcribed but until recently this noncoding transcription was considered to be simply noise. Noncoding transcription units overlap with genes and genes overlap other genes, meaning genomes are extensively interleaved. Experimental interventions reveal high degrees of interdependency between these transcription units, which have been co-opted as gene regulatory mechanisms. The precise outcome depends on the relative orientation of the transcription units and whether two overlapping transcription events are contemporaneous or not, but generally involves chromatin-based changes. Thus transcription itself regulates transcription initiation or repression at many regions of the genome.
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http://dx.doi.org/10.1016/j.tig.2015.10.006DOI Listing
January 2016

Site and Stage of Colorectal Cancer Influence the Likelihood and Distribution of Disease Recurrence and Postrecurrence Survival: Data From the FACS Randomized Controlled Trial.

Ann Surg 2016 Jun;263(6):1143-7

*University Surgery, University of Southampton, Southampton, United Kingdom†Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom‡Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom.

Objectives: To describe patterns of recurrence and postrecurrence survival in a large cohort of accurately staged patients with Dukes' A-C colorectal cancer.

Background: Recurrence remains a frequent cause of mortality after the treatment of colorectal cancer with curative intent. Understanding the likelihood and site of recurrence informs adjuvant treatment and follow-up.

Methods: Retrospective cohort analysis of data from the FACS (follow-up after colorectal cancer surgery) trial after a median 4.4 years of follow-up; postrecurrence survival was calculated using the Kaplan-Meier method.

Results: Complete data were available for 94% of patients; 189 (17%) patients had experienced recurrence. Incidence of recurrence varied according to the site of the primary (right colon: 51/379, 14%; left colon: 68/421, 16%; rectum: 70/332, 21%; P = 0.023) and initial stage (Dukes' A: 26/249, 10%; Dukes' B: 81/537, 15%; Dukes' C: 82/346, 24%; P < 0.0001). Pulmonary recurrence was most frequently associated with rectal tumors, and multisite/other recurrence with right-sided colonic tumors. Recurrences from lower-stage tumors were more likely to be treatable with curative intent (Dukes' A: 13/26, 50%; Dukes' B: 32/81, 40%; Dukes' C: 20/82, 24%; P = 0.03). Those with rectal tumors benefited most from follow-up (proportion with treatable recurrence: rectum 30/332, 9%; left colon 23/421, 6%; right colon 12/379, 3%; P = 0.003). Both initial stage (log rank P = 0.005) and site of primary (log rank P = 0.01) influenced postrecurrence survival.

Conclusions: The likelihood and site of recurrence, and survival, are influenced by the site and stage of the primary tumor. Those with rectal cancers benefited most from follow-up.ISRCTN 41458548.
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http://dx.doi.org/10.1097/SLA.0000000000001351DOI Listing
June 2016

Sense and antisense transcription are associated with distinct chromatin architectures across genes.

Nucleic Acids Res 2015 Sep 29;43(16):7823-37. Epub 2015 Jun 29.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK

Genes from yeast to mammals are frequently subject to non-coding transcription of their antisense strand; however the genome-wide role for antisense transcription remains elusive. As transcription influences chromatin structure, we took a genome-wide approach to assess which chromatin features are associated with nascent antisense transcription, and contrast these with features associated with nascent sense transcription. We describe a distinct chromatin architecture at the promoter and gene body specifically associated with antisense transcription, marked by reduced H2B ubiquitination, H3K36 and H3K79 trimethylation and increased levels of H3 acetylation, chromatin remodelling enzymes, histone chaperones and histone turnover. The difference in sense transcription between genes with high or low levels of antisense transcription is slight; thus the antisense transcription-associated chromatin state is not simply analogous to a repressed state. Using mutants in which the level of antisense transcription is reduced at GAL1, or altered genome-wide, we show that non-coding transcription is associated with high H3 acetylation and H3 levels across the gene, while reducing H3K36me3. Set1 is required for these antisense transcription-associated chromatin changes in the gene body. We propose that nascent antisense and sense transcription have fundamentally distinct relationships with chromatin, and that both should be considered canonical features of eukaryotic genes.
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http://dx.doi.org/10.1093/nar/gkv666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4652749PMC
September 2015

Prednisolone or pentoxifylline for alcoholic hepatitis.

N Engl J Med 2015 Apr;372(17):1619-28

From Imperial College (M.R.T., N.V.), King's College Hospital (J.O.), and the Royal Free Hospital (D.P.), London, Royal Liverpool Hospital (P. Richardson) and Aintree Hospital (S.H.), Liverpool, Addenbrookes Hospital, Cambridge (M.A.), Derby Royal Hospital, Derby (A.A.), Southampton Clinical Trials Unit, University of Southampton (M.B., N.D., J.M., I.R., P. Roderick, L.S.), and University Hospital Southampton NHS Foundation Trust (M.W.), Southampton, Faculty of Medical Sciences, Newcastle University (C.P.D.), and Newcastle upon Tyne Hospitals NHS Foundation Trust (S.M.), Newcastle upon Tyne, Sheffield Teaching Hospitals Foundation Trust, Sheffield (D.G.), Edinburgh Royal Infirmary, Edinburgh (A. MacGilchrist), Leicester Royal Infirmary, Leicester (A.G.), Bristol Royal Infirmary, Bristol (A. McCune), Nottingham University Hospitals NHS Trust and National Institute for Health Research Biomedical Research Unit, Queens Medical Centre, Nottingham (S.R.), and the Glasgow Royal Infirmary, Glasgow (E.H.F.) - all in the United Kingdom.

Background: Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists.

Methods: We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline.

Results: A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002).

Conclusions: Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).
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http://dx.doi.org/10.1056/NEJMoa1412278DOI Listing
April 2015

Transcription mediated insulation and interference direct gene cluster expression switches.

Elife 2014 Nov 19;3:e03635. Epub 2014 Nov 19.

Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

In yeast, many tandemly arranged genes show peak expression in different phases of the metabolic cycle (YMC) or in different carbon sources, indicative of regulation by a bi-modal switch, but it is not clear how these switches are controlled. Using native elongating transcript analysis (NET-seq), we show that transcription itself is a component of bi-modal switches, facilitating reciprocal expression in gene clusters. HMS2, encoding a growth-regulated transcription factor, switches between sense- or antisense-dominant states that also coordinate up- and down-regulation of transcription at neighbouring genes. Engineering HMS2 reveals alternative mono-, di- or tri-cistronic and antisense transcription units (TUs), using different promoter and terminator combinations, that underlie state-switching. Promoters or terminators are excluded from functional TUs by read-through transcriptional interference, while antisense TUs insulate downstream genes from interference. We propose that the balance of transcriptional insulation and interference at gene clusters facilitates gene expression switches during intracellular and extracellular environmental change.
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http://dx.doi.org/10.7554/eLife.03635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275577PMC
November 2014

Lysine acetylation controls local protein conformation by influencing proline isomerization.

Mol Cell 2014 Sep 7;55(5):733-44. Epub 2014 Aug 7.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address:

Gene transcription responds to stress and metabolic signals to optimize growth and survival. Histone H3 (H3) lysine 4 trimethylation (K4me3) facilitates state changes, but how levels are coordinated with the environment is unclear. Here, we show that isomerization of H3 at the alanine 15-proline 16 (A15-P16) peptide bond is influenced by lysine 14 (K14) and controls gene-specific K4me3 by balancing the actions of Jhd2, the K4me3 demethylase, and Spp1, a subunit of the Set1 K4 methyltransferase complex. Acetylation at K14 favors the A15-P16trans conformation and reduces K4me3. Environmental stress-induced genes are most sensitive to the changes at K14 influencing H3 tail conformation and K4me3. By contrast, ribosomal protein genes maintain K4me3, required for their repression during stress, independently of Spp1, K14, and P16. Thus, the plasticity in control of K4me3, via signaling to K14 and isomerization at P16, informs distinct gene regulatory mechanisms and processes involving K4me3.
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http://dx.doi.org/10.1016/j.molcel.2014.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157579PMC
September 2014

Proline isomerization is influenced by local lysine acetylation-deacetylation.

Microb Cell 2014 Jan 23;1(11):390-392. Epub 2014 Jan 23.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.

Acetylation of lysine residues has several characterised functions in chromatin. These include neutralization of the lysine's positive charge to directly influence histone tail-DNA/internucleosomal interactions or indirect effects via bromodomain-containing effector proteins. Recently, we described a novel function of lysine acetylation to influence proline isomerization and thus local protein conformation. We found that acetylation of lysine 14 in the histone H3 N-terminal tail (H3K14ac), an intrinsically disordered domain, increased the proportion of neighbouring proline 16 (H3P16) in the conformation. This conformation of the tail was associated with reduced tri-methylation on histone H3 lysine 4 (H3K4me3) due to both decreased methylation by the Set1 methyltransferase (with the me3-specific subunit Spp1) and increased demethylation by the demethylase Jhd2. Interestingly, H3K4me3 on individual genes was differentially affected by substitution of H3K14 or H3P16, with ribosomal protein genes losing the least H3K4me3 and environmental stress-induced genes losing the most.
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http://dx.doi.org/10.15698/mic2014.11.176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349129PMC
January 2014

Steroids or pentoxifylline for alcoholic hepatitis (STOPAH): study protocol for a randomised controlled trial.

Trials 2013 Aug 19;14:262. Epub 2013 Aug 19.

Hepatology Section, Imperial College, Norfolk Place, London, Paddington W2 1NY, UK.

Background: Alcoholic hepatitis is the most florid presentation of alcohol-related liver disease. In its severe form, defined by a Maddrey's discriminant function (DF) ≥32, the 28-day mortality rate is approximately 35%. A number of potential treatments have been subjected to clinical trials, of which two, corticosteroids and pentoxifylline, may have therapeutic benefit. The role of corticosteroids is controversial as trial results have been inconsistent, whereas the role of pentoxifylline requires confirmation as only one previous placebo-controlled trial has been published.

Methods/design: STOPAH is a multicentre, double-blind, factorial (2 × 2) trial in which patients are randomised to one of four groups:1. Group A: placebo / placebo2. Group B: placebo / prednisolone3. Group C: pentoxifylline / placebo4. Group D: pentoxifylline / prednisoloneThe trial aims to randomise 1,200 patients with severe alcoholic hepatitis, in order to provide sufficient power to determine whether either of the two interventions is effective. The primary endpoint of the study is mortality at 28 days, with secondary endpoints being mortality at 90 days and 1 year.

Discussion: STOPAH aims to be a definitive study to resolve controversy around the existing treatments for alcoholic hepatitis. Eligibility criteria are based on clinical parameters rather than liver biopsy, which are aligned with standard clinical practice in most hospitals. The use of a factorial design will allow two treatments to be evaluated in parallel, with efficient use of patient numbers to achieve high statistical power.

Trial Registration: EudraCT reference number: 2009-013897-42 ISRCTN reference number: ISRCTN88782125.
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http://dx.doi.org/10.1186/1745-6215-14-262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766225PMC
August 2013

Analysis of C. elegans intestinal gene expression and polyadenylation by fluorescence-activated nuclei sorting and 3'-end-seq.

Nucleic Acids Res 2012 Jul 29;40(13):6304-18. Epub 2012 Mar 29.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.

Despite the many advantages of Caenorhabditis elegans, biochemical approaches to study tissue-specific gene expression in post-embryonic stages are challenging. Here, we report a novel experimental approach for efficient determination of tissue-specific transcriptomes involving the rapid release and purification of nuclei from major tissues of post-embryonic animals by fluorescence-activated nuclei sorting (FANS), followed by deep sequencing of linearly amplified 3'-end regions of transcripts (3'-end-seq). We employed these approaches to compile the transcriptome of the developed C. elegans intestine and used this to analyse tissue-specific cleavage and polyadenylation. In agreement with intestinal-specific gene expression, highly expressed genes have enriched GATA-elements in their promoter regions and their functional properties are associated with processes that are characteristic for the intestine. We systematically mapped pre-mRNA cleavage and polyadenylation sites, or polyA sites, including more than 3000 sites that have previously not been identified. The detailed analysis of the 3'-ends of the nuclear mRNA revealed widespread alternative polyA site use (APA) in intestinally expressed genes. Importantly, we found that intestinal polyA sites that undergo APA tend to have U-rich and/or A-rich upstream auxiliary elements that may contribute to the regulation of 3'-end formation in the intestine.
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http://dx.doi.org/10.1093/nar/gks282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401467PMC
July 2012

A pre-initiation complex at the 3'-end of genes drives antisense transcription independent of divergent sense transcription.

Nucleic Acids Res 2012 Mar 28;40(6):2432-44. Epub 2011 Nov 28.

Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.

The precise nature of antisense transcripts in eukaryotes such as Saccharomyces cerevisiae remains elusive. Here we show that the 3' regions of genes possess a promoter architecture, including a pre-initiation complex (PIC), which mirrors that at the 5' region and which is much more pronounced at genes with a defined antisense transcript. Remarkably, for genes with an antisense transcript, average levels of PIC components at the 3' region are ∼60% of those at the 5' region. Moreover, at these genes, average levels of nascent antisense transcription are ∼45% of sense transcription. We find that this 3' promoter architecture persists for highly transcribed antisense transcripts where there are only low levels of transcription in the divergent sense direction, suggesting that the 3' regions of genes can drive antisense transcription independent of divergent sense transcription. To validate this, we insert short 3' regions into the middle of other genes and find that they are capable of both initiating antisense transcripts and terminating sense transcripts. Our results suggest that antisense transcription can be regulated independently of divergent sense transcription in a PIC-dependent manner and we propose that regulated production of antisense transcripts represents a fundamental and widespread component of gene regulation.
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http://dx.doi.org/10.1093/nar/gkr1121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315312PMC
March 2012

A role for Snf2-related nucleosome-spacing enzymes in genome-wide nucleosome organization.

Science 2011 Sep;333(6050):1758-60

Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.

The positioning of nucleosomes within the coding regions of eukaryotic genes is aligned with respect to transcriptional start sites. This organization is likely to influence many genetic processes, requiring access to the underlying DNA. Here, we show that the combined action of Isw1 and Chd1 nucleosome-spacing enzymes is required to maintain this organization. In the absence of these enzymes, regular positioning of the majority of nucleosomes is lost. Exceptions include the region upstream of the promoter, the +1 nucleosome, and a subset of locations distributed throughout coding regions where other factors are likely to be involved. These observations indicate that adenosine triphosphate-dependent remodeling enzymes are responsible for directing the positioning of the majority of nucleosomes within the Saccharomyces cerevisiae genome.
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http://dx.doi.org/10.1126/science.1206097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428865PMC
September 2011

Transcription: from regulatory ncRNA to incongruent redundancy.

Authors:
Jane Mellor

Genes Dev 2010 Jul;24(14):1449-55

Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

Transcription is such a fundamental process and has been studied by so many for so long that skeptics might ask what more there is to learn. Those who attended the meeting summarized here on the dynamics of eukaryotic transcription during development were not disappointed. Studying the transcription of genes in stem cells during early development and in model organisms has illuminated mechanisms for transcriptional control that would have been hard to accept even 5 years ago, and consistently challenges the textbook view of transcriptional regulation.
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http://dx.doi.org/10.1101/gad.1950310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904934PMC
July 2010

Repressive and non-repressive chromatin at native telomeres in Saccharomyces cerevisiae.

Epigenetics Chromatin 2009 Dec 2;2(1):18. Epub 2009 Dec 2.

1Department of Oncology, University of Western Ontario, Ontario, Canada.

Background: In Saccharomyces cerevisiae genes that are located close to a telomere can become transcriptionally repressed by an epigenetic process known as telomere position effect. There is large variation in the level of the telomere position effect among telomeres, with many native ends exhibiting little repression.

Results: Chromatin analysis, using microccocal nuclease and indirect end labelling, reveals distinct patterns for ends with different silencing states. Differences were observed in the promoter accessibility of a subtelomeric reporter gene and a characteristic array of phased nucleosomes was observed on the centromere proximal side of core X at a repressive end. The silent information regulator proteins 2 - 4, the yKu heterodimer and the subtelomeric core X element are all required for the maintenance of the chromatin structure of repressive ends. However, gene deletions of particular histone modification proteins can eliminate the silencing without the disruption of this chromatin structure.

Conclusion: Our data identifies chromatin features that correlate with the silencing state and indicate that an array of phased nucleosomes is not sufficient for full repression.
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http://dx.doi.org/10.1186/1756-8935-2-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225887PMC
December 2009

Linking the cell cycle to histone modifications: Dot1, G1/S, and cycling K79me2.

Authors:
Jane Mellor

Mol Cell 2009 Sep;35(6):729-30

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.

In a recent issue of Molecular Cell, Schulze et al. (2009) described distinct distributions and regulation of Dot1-dependent methylation states at lysine 79 on histone H3 and showed cell-cycle regulation of K79 dimethylation on genes expressed during the G1/S phase.
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http://dx.doi.org/10.1016/j.molcel.2009.09.010DOI Listing
September 2009