Publications
32 results found
Periyasamy M, Singh A, Gemma C, et al., 2020, Induction of APOBEC3B expression by chemotherapy drugs is mediated by DNA-PK directed activation of NF-κB, Oncogene, Vol: 15 December 2020, Pages: 1077-1090, ISSN: 0950-9232
The mutagenic APOBEC3B (A3B) cytosine deaminase is frequently over-expressed in cancer and promotes tumour heterogeneity and therapy resistance. Hence, understanding the mechanisms that underlie A3B over-expression is important, especially for developing therapeutic approaches to reducing A3B levels, and consequently limiting cancer mutagenesis. We previously demonstrated that A3B is repressed by p53 and p53 mutation increases A3B expression. Here, we investigate A3B expression upon treatment with chemotherapeutic drugs that activate p53, including 5-fluorouracil, etoposide and cisplatin. Contrary to expectation, these drugs induced A3B expression and concomitant cellular cytosine deaminase activity. A3B induction was p53-independent, as chemotherapy drugs stimulated A3B expression in p53 mutant cells. These drugs commonly activate ATM, ATR and DNA-PKcs. Using specific inhibitors and gene knockdowns, we show that activation of DNA-PKcs and ATM by chemotherapeutic drugs promotes NF-kB activity, with consequent recruitment of NF-kB to the A3B gene promoter to drive A3B expression. Further, we find that A3B knockdown re-sensitises resistant cells to cisplatin, and A3B knockout enhances sensitivity to chemotherapy drugs. Our data highlight a role for A3B in resistance to chemotherapy and indicate that stimulation of A3B expression by activation of DNA repair and NF-kB pathways could promote cancer mutations and expedite chemoresistance.
Palinkas HL, Bekesi A, Rona G, et al., 2020, Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments, eLife, Vol: 9, Pages: 1-37, ISSN: 2050-084X
Numerous anti-cancer drugs perturb thymidylate biosynthesis and lead to genomic uracil incorporation contributing to their antiproliferative effect. Still, it is not yet characterized if uracil incorporations have any positional preference. Here, we aimed to uncover genome-wide alterations in uracil pattern upon drug treatments in human cancer cell line models derived from HCT116. We developed a straightforward U-DNA sequencing method (U-DNA-Seq) that was combined with in situ super-resolution imaging. Using a novel robust analysis pipeline, we found broad regions with elevated probability of uracil occurrence both in treated and non-treated cells. Correlation with chromatin markers and other genomic features shows that non-treated cells possess uracil in the late replicating constitutive heterochromatic regions, while drug treatment induced a shift of incorporated uracil towards segments that are normally more active/functional. Data were corroborated by colocalization studies via dSTORM microscopy. This approach can be applied to study the dynamic spatio-temporal nature of genomic uracil.
Pálinkás HL, Békési A, Róna G, et al., 2020, Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments, Publisher: eLife Sciences Publications Ltd
<jats:title>ABSTRACT</jats:title><jats:p>Numerous anti-cancer drugs perturb thymidylate biosynthesis and lead to genomic uracil incorporation contributing to their antiproliferative effect. Still, it is not yet characterized if uracil incorporations have any positional preference. Here, we aimed to uncover genome-wide alterations in uracil pattern upon drug-treatment in human cancer cell-line HCT116. We developed a straightforward U-DNA sequencing method (U-DNA-Seq) that was combined with <jats:italic>in situ</jats:italic> super-resolution imaging. Using a novel robust analysis pipeline, we found broad regions with elevated probability of uracil occurrence both in treated and non-treated cells. Correlation with chromatin markers and other genomic features shows that non-treated cells possess uracil in the late replicating constitutive heterochromatic regions, while drug treatment induced a shift of incorporated uracil towards more active/functional segments. Data were corroborated by colocalization studies via dSTORM microscopy. This approach can also be applied to study the dynamic <jats:italic>spatio-temporal</jats:italic> nature of genomic uracil.</jats:p>
Ricci B, Millner TO, Pomella N, et al., 2020, Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma, ONCOGENE, Vol: 39, Pages: 2523-2538, ISSN: 0950-9232
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- Citations: 12
Janes J, Dong Y, Schoof M, et al., 2018, Chromatin accessibility dynamics across <i>C-elegans</i> development and ageing, ELIFE, Vol: 7, ISSN: 2050-084X
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- Citations: 35
Periyasamy M, Singh A, Gemma C, et al., 2017, p53 controls expression of the DNA deaminase APOBEC3B to limit its potential mutagenic activity in cancer cells, Nucleic Acids Research, Vol: 45, Pages: 11056-11069, ISSN: 1362-4962
Cancer genome sequencing has implicated the cytosine deaminase activity of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) genes as an important source of mutations in diverse cancers, with APOBEC3B (A3B) expression especially correlated with such cancer mutations. To better understand the processes directing A3B over-expression in cancer, and possible therapeutic avenues for targeting A3B, we have investigated the regulation of A3B gene expression. Here, we show that A3B expression is inversely related to p53 status in different cancer types and demonstrate that this is due to a direct and pivotal role for p53 in repressing A3B expression. This occurs through the induction of p21 (CDKN1A) and the recruitment of the repressive DREAM complex to the A3B gene promoter, such that loss of p53 through mutation, or human papilloma virus-mediated inhibition, prevents recruitment of the complex, thereby causing elevated A3B expression and cytosine deaminase activity in cancer cells. As p53 is frequently mutated in cancer, our findings provide a mechanism by which p53 loss can promote cancer mutagenesis.
Holland ML, Lowe R, Caton PW, et al., 2016, Early-life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice, Science, Vol: 353, ISSN: 1095-9203
A suboptimal early-life environment, due to poor nutrition or stress during pregnancy, can influence lifelong phenotypes in the progeny. Epigenetic factors are thought to be key mediators of these effects. We show that protein restriction in mice from conception until weaning induces a linear correlation between growth restriction and DNA methylation at ribosomal DNA (rDNA). This epigenetic response remains into adulthood and is restricted to rDNA copies associated with a specific genetic variant within the promoter. Related effects are also found in models of maternal high-fat or obesogenic diets. Our work identifies environmentally induced epigenetic dynamics that are dependent on underlying genetic variation and establishes rDNA as a genomic target of nutritional insults.
Patel H, Abduljabbar R, Lai CF, et al., 2016, CDK7, cyclin H and MAT1 is elevated in breast cancer and is prognostic in estrogen receptor- positive breast cancer, Clinical Cancer Research, Vol: 22, Pages: 5929-5938, ISSN: 1557-3265
PURPOSE: CDK-activation kinase (CAK) is required for the regulation of the cell-cycle and is a trimeric complex consisting of Cyclin Dependent Kinase 7 (CDK7), Cyclin H and the accessory protein, MAT1. CDK7 also plays a critical role in regulating transcription, primarily by phosphorylating RNA polymerase II, as well as transcription factors such as estrogen receptor-alpha(ERalpha).). Deregulation of cell cycle and transcriptional control is aare general featurefeatures of cancertumor cells, highlighting the potential for the use of CDK7 inhibitors as novel cancer therapeutics in cancer. EXPERIMENTAL DESIGN: mRNA and protein expression of CDK7 and its essential co-factors cyclinH and MAT1, were evaluated in breast cancer samples to determine if their levels are altered in cancer. Immunohistochemical staining of >900 breast cancers was used to determine the association with clinicopathological features and patient outcome. RESULTS: We show that expression of CDK7, cyclinH and MAT1 are all closely linked at the mRNA and protein level and their expression is elevated in breast cancer compared with the normal breast tissue. Intriguingly, CDK7 expression was inversely proportional to tumour grade and size and outcome analysis showed an association between CAK levels and better outcome. Moreover, CDK7 expression was positively associated with ERalpha expression and in particular with phosphorylation of ERalpha at serine 118, a site important for ERalpha transcriptional activity. CONCLUSIONS: Expression of components of the CAK complex, CDK7, MAT1 and Cyclin H are elevated in breast cancer and correlates with ERalpha.. Like ERalpha, CDK7 expression is inversely proportional to poor prognostic factors and survival.
Lowe R, Gemma C, Rakyan VK, et al., 2015, Sexually dimorphic gene expression emerges with embryonic genome activation and is dynamic throughout development, BMC Genomics, Vol: 16, ISSN: 1471-2164
BACKGROUND: As sex determines mammalian development, understanding the nature and developmental dynamics of the sexually dimorphic transcriptome is important. To explore this, we generated 76 genome-wide RNA-seq profiles from mouse eight-cell embryos, late gestation and adult livers, together with 4 ground-state pluripotent embryonic (ES) cell lines from which we generated both RNA-seq and multiple ChIP-seq profiles. We complemented this with previously published data to yield 5 snap-shots of pre-implantation development, late-gestation placenta and somatic tissue and multiple adult tissues for integrative analysis. RESULTS: We define a high-confidence sex-dimorphic signature of 69 genes in eight-cell embryos. Sex-chromosome-linked components of this signature are largely conserved throughout pre-implantation development and in ES cells, whilst the autosomal component is more dynamic. Sex-biased gene expression is reflected by enrichment for activating and repressive histone modifications. The eight-cell signature is largely non-overlapping with that defined from fetal liver, neither was it correlated with adult liver or other tissues analysed. The number of sex-dimorphic genes increases throughout development. We identified many more dimorphic genes in adult compared to fetal liver. However, approximately two thirds of the dimorphic genes identified in fetal liver were also dimorphic in adult liver. Sex-biased expression differences unique to adult liver were enriched for growth hormone-responsiveness. Sexually dimorphic gene expression in pre-implantation development is driven by sex-chromosome based transcription, whilst later development is characterised by sex dimorphic autosomal transcription. CONCLUSION: This systematic study identifies three distinct phases of sex dimorphism throughout mouse development, and has significant implications for understanding the developmental origins of sex-specific phenotypes and disease in mammals.
Gemma C, Ramagopalan SV, Down TA, et al., 2013, Inactive or moderately active human promoters are enriched for inter-individual epialleles, Genome Biology, Vol: 14, ISSN: 1474-760X
BACKGROUND: Inter-individual epigenetic variation, due to genetic, environmental or random influences, is observed in many eukaryotic species. In mammals, however, the molecular nature of epiallelic variation has been poorly defined, partly due to the restricted focus on DNA methylation. Here we report the first genome-scale investigation of mammalian epialleles that integrates genomic, methylomic, transcriptomic and histone state information. RESULTS: First, in a small sample set, we demonstrate that non-genetically determined inter-individual differentially methylated regions (iiDMRs) can be temporally stable over at least 2 years. Then, we show that iiDMRs are associated with changes in chromatin state as measured by inter-individual differences in histone variant H2A.Z levels. However, the correlation of promoter iiDMRs with gene expression is negligible and not improved by integrating H2A.Z information. We find that most promoter epialleles, whether genetically or non-genetically determined, are associated with low levels of transcriptional activity, depleted for housekeeping genes, and either depleted for H3K4me3/enriched for H3K27me3 or lacking both these marks in human embryonic stem cells. The preferential enrichment of iiDMRs at regions of relative transcriptional inactivity validates in a larger independent cohort, and is reminiscent of observations previously made for promoters that undergo hypermethylation in various cancers, in vitro cell culture and ageing. CONCLUSIONS: Our work identifies potential key features of epiallelic variation in humans, including temporal stability of non-genetically determined epialleles, and concomitant perturbations of chromatin state. Furthermore, our work suggests a novel mechanistic link among inter-individual epialleles observed in the context of normal variation, cancer and ageing.
Lowe R, Gemma C, Beyan H, et al., 2013, Buccals are likely to be a more informative surrogate tissue than blood for epigenome-wide association studies, EPIGENETICS, Vol: 8, Pages: 445-454, ISSN: 1559-2294
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- Citations: 112
Beyan H, Down TA, Ramagopalan SV, et al., 2012, Guthrie card methylomics identifies temporally stable epialleles that are present at birth in humans, Genome Research, Vol: 22, Pages: 2138-2145, ISSN: 1549-5469
A major concern in common disease epigenomics is distinguishing causal from consequential epigenetic variation. One means of addressing this issue is to identify the temporal origins of epigenetic variants via longitudinal analyses. However, prospective birth-cohort studies are expensive and time consuming. Here, we report DNA methylomics of archived Guthrie cards for the retrospective longitudinal analyses of in-utero-derived DNA methylation variation. We first validate two methodologies for generating comprehensive DNA methylomes from Guthrie cards. Then, using an integrated epigenomic/genomic analysis of Guthrie cards and follow-up samplings, we identify interindividual DNA methylation variation that is present both at birth and 3 yr later. These findings suggest that disease-relevant epigenetic variation could be detected at birth, i.e., before overt clinical disease. Guthrie card methylomics offers a potentially powerful and cost-effective strategy for studying the dynamics of interindividual epigenomic variation in a range of common human diseases.
Fernandez Gianotti T, Castano G, Gemma C, et al., 2011, Mitochondrial DNA copy number is modulated by genetic variation in the signal transducer and activator of transcription 3 (<i>STAT3</i>), METABOLISM-CLINICAL AND EXPERIMENTAL, Vol: 60, Pages: 1142-1149, ISSN: 0026-0495
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- Citations: 11
Sookoian S, Soledad Rosselli M, Gemma C, et al., 2010, Epigenetic Regulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease: Impact of Liver Methylation of the Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Promoter, HEPATOLOGY, Vol: 52, Pages: 1992-2000, ISSN: 0270-9139
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- Citations: 220
Burgueno A, Gemma C, Fernandez Gianotti T, et al., 2010, Increased levels of resistin in rotating shift workers: A potential mediator of cardiovascular risk associated with circadian misalignment, ATHEROSCLEROSIS, Vol: 210, Pages: 625-629, ISSN: 0021-9150
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- Citations: 29
Sookoian S, Fernandez Gianotti T, Gemma C, et al., 2010, Role of genetic variation in insulin-like growth factor 1 receptor on insulin resistance and arterial hypertension, JOURNAL OF HYPERTENSION, Vol: 28, Pages: 1194-1202, ISSN: 0263-6352
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- Citations: 12
Gemma C, Sookoian S, Dieuzeide G, et al., 2010, Methylation of <i>TFAM</i> gene promoter in peripheral white blood cells is associated with insulin resistance in adolescents, MOLECULAR GENETICS AND METABOLISM, Vol: 100, Pages: 83-87, ISSN: 1096-7192
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- Citations: 41
Sookoian S, Gemma C, Pirola CJ, 2010, Influence of hepatocyte nuclear factor 4α (<i>HNF4</i>α) gene variants on the risk of type 2 diabetes: A meta-analysis in 49,577 individuals, MOLECULAR GENETICS AND METABOLISM, Vol: 99, Pages: 80-89, ISSN: 1096-7192
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- Citations: 17
Burgueno AL, Sookoian S, Gianotti TF, et al., 2009, Genetic Variation in the <i>FAAH</i> Gene and Metabolic Syndrome-related Phenotypes, OBESITY, Vol: 17, Pages: 1979-1980, ISSN: 1930-7381
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- Citations: 2
Sookoian S, Castano G, Fernandez Gianotti T, et al., 2009, Polymorphisms of MRP2 (<i>ABCC2</i>) are associated with susceptibility to nonalcoholic fatty liver disease, JOURNAL OF NUTRITIONAL BIOCHEMISTRY, Vol: 20, Pages: 765-770, ISSN: 0955-2863
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- Citations: 44
Gemma C, Sookoian S, Alvarinas J, et al., 2009, Maternal Pregestational BMI Is Associated With Methylation of the <i>PPARGC1A</i> Promoter in Newborns, OBESITY, Vol: 17, Pages: 1032-1039, ISSN: 1930-7381
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- Citations: 120
Sookoian S, Castano G, Fernandez Gianotti T, et al., 2008, Genetic variants in <i>STAT3</i> are associated with nonalcoholic fatty liver disease, CYTOKINE, Vol: 44, Pages: 201-206, ISSN: 1043-4666
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- Citations: 50
Gianotti TF, Sookoian S, Dieuzeide G, et al., 2008, A decreased mitochondrial DNA content is related to insulin resistance in adolescents, OBESITY, Vol: 16, Pages: 1591-1595, ISSN: 1930-7381
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- Citations: 59
Gianotti TF, Sookoian S, Gemma C, et al., 2008, Study of genetic variation in the <i>STAT3</i> on obesity and insulin resistance in male adults, OBESITY, Vol: 16, Pages: 1702-1707, ISSN: 1930-7381
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- Citations: 9
Sookoian S, Genuna C, Gianotti TF, et al., 2008, Genetic variants of <i>Clock</i> transcription factor are associated with individual susceptibility to obesity, AMERICAN JOURNAL OF CLINICAL NUTRITION, Vol: 87, Pages: 1606-1615, ISSN: 0002-9165
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- Citations: 192
Sookoian S, Gianotti TF, Gemma C, et al., 2008, Contribution of the functional 5-HTTLPR variant of the <i>SLC6A4</i> gene to obesity risk in male adults, OBESITY, Vol: 16, Pages: 488-491, ISSN: 1930-7381
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- Citations: 48
Sookoian S, Castano G, Gemma C, et al., 2007, Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease, WORLD JOURNAL OF GASTROENTEROLOGY, Vol: 13, Pages: 4242-4248, ISSN: 1007-9327
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- Citations: 84
Sookoian S, Gemma C, Gianotti TF, et al., 2007, Serotonin and serotonin transporter gene variant in rotating shift workers, SLEEP, Vol: 30, Pages: 1049-1053, ISSN: 0161-8105
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- Citations: 20
Landa MS, Garcia SI, Schuman ML, et al., 2007, Knocking down the diencephalic thyrotropin-releasing hormone precursor gene normalizes obesity-induced hypertension in the rat, AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, Vol: 292, Pages: E1388-E1394, ISSN: 0193-1849
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- Citations: 20
Sookoian S, Gemma C, Gianotti TF, et al., 2007, Effects of rotating shift work on biomarkers of metabolic syndrome and inflammation, JOURNAL OF INTERNAL MEDICINE, Vol: 261, Pages: 285-292, ISSN: 0954-6820
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- Citations: 214
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