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Journal ArticleDOI

Clinical epigenetics: seizing opportunities for translation.

01 Feb 2019-Nature Reviews Genetics (Nat Rev Genet)-Vol. 20, Iss: 2, pp 109-127
TL;DR: Beyond helping to understand disease biology, clinical epigenetics is being incorporated into patient management in oncology, as well as being explored for clinical applicability for other human pathologies such as neurological and infectious diseases and immune system disorders.
Abstract: Biomarker discovery and validation are necessary for improving the prediction of clinical outcomes and patient monitoring. Despite considerable interest in biomarker discovery and development, improvements in the range and quality of biomarkers are still needed. The main challenge is how to integrate preclinical data to obtain a reliable biomarker that can be measured with acceptable costs in routine clinical practice. Epigenetic alterations are already being incorporated as valuable candidates in the biomarker field. Furthermore, their reversible nature offers a promising opportunity to ameliorate disease symptoms by using epigenetic-based therapy. Thus, beyond helping to understand disease biology, clinical epigenetics is being incorporated into patient management in oncology, as well as being explored for clinical applicability for other human pathologies such as neurological and infectious diseases and immune system disorders.
Citations
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01 Feb 2015
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

4,409 citations

Journal ArticleDOI
TL;DR: The timeline of epigenetic drug discovery and development is described, beginning with the early design based solely on phenotypic observations to the state-of-the-art rational epigenetics drug discovery using validated targets.
Abstract: The flexibility of the epigenome has generated an enticing argument to explore its reversion through pharmacological treatments as a strategy to ameliorate disease phenotypes. All three families of epigenetic proteins—readers, writers, and erasers—are druggable targets that can be addressed through small-molecule inhibitors. At present, a few drugs targeting epigenetic enzymes as well as analogues of epigenetic modifications have been introduced into the clinic use (e.g. to treat haematological malignancies), and a wide range of epigenetic-based drugs are undergoing clinical trials. Here, we describe the timeline of epigenetic drug discovery and development beginning with the early design based solely on phenotypic observations to the state-of-the-art rational epigenetic drug discovery using validated targets. Finally, we will highlight some of the major aspects that need further research and discuss the challenges that need to be overcome to implement epigenetic drug discovery into clinical management of human disorders. To turn into reality, researchers from various disciplines (chemists, biologists, clinicians) need to work together to optimise the drug engineering, read-out assays, and clinical trial design.

240 citations


Cites background from "Clinical epigenetics: seizing oppor..."

  • ...The potential of epigenetic drugs is extending to other pathologies, from infectious diseases to brain diseases, cardiovascular and metabolic disorders [5, 116]....

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  • ...Their use is restricted to CTCL and PTCL patients when other treatment options have failed [5]....

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Journal ArticleDOI
TL;DR: The importance of the epigenetic alterations identified in human cancer, which have led to the appearance of biomarkers or epigenetic drugs in precision medicine, are summarized, and the transport and release systems of theigenetic drugs that have been developed to date are described.
Abstract: The emergence of nanotechnology applied to medicine has revolutionized the treatment of human cancer. As in the case of classic drugs for the treatment of cancer, epigenetic drugs have evolved in terms of their specificity and efficiency, especially because of the possibility of using more effective transport and delivery systems. The use of nanoparticles (NPs) in oncology management offers promising advantages in terms of the efficacy of cancer treatments, but it is still unclear how these NPs may be affecting the epigenome such that safe routine use is ensured. In this work, we summarize the importance of the epigenetic alterations identified in human cancer, which have led to the appearance of biomarkers or epigenetic drugs in precision medicine, and we describe the transport and release systems of the epigenetic drugs that have been developed to date.

138 citations


Cites background from "Clinical epigenetics: seizing oppor..."

  • ...One of the best-characterized epigenetic markers is the hypermethylation of the glutathione S-transferase (GSTP1) gene in the biological fluids of prostate cancer patients [42, 44, 45]....

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  • ...Although at present only two classes of epigenetic drugs have been approved by the US Food and Drug Administration (FDA)—DNA methylation inhibitors (iDNMTs) and histone deacetylase inhibitors (iHDACs)—several new targets are in late-stage clinical trials and show therapeutic promise [31, 42, 47, 66] (Fig....

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  • ...Epigenetic biomarkers can be useful to predict therapeutic drug response [42, 44, 45]....

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Journal ArticleDOI
TL;DR: This review will summarize key advances in epigenetic clocks and their potential application in precision health, and highlight the importance of prospective study designs to identify and confirm epigenetic biomarkers of disease.
Abstract: Recent research efforts provided compelling evidence of genome-wide DNA methylation alterations in aging and age-related disease. It is currently well established that DNA methylation biomarkers can determine biological age of any tissue across the entire human lifespan, even during development. There is growing evidence suggesting epigenetic age acceleration to be strongly linked to common diseases or occurring in response to various environmental factors. DNA methylation based clocks are proposed as biomarkers of early disease risk as well as predictors of life expectancy and mortality. In this review, we will summarize key advances in epigenetic clocks and their potential application in precision health. We will also provide an overview of progresses in epigenetic biomarker discovery in Alzheimer's, type 2 diabetes, and cardiovascular disease. Furthermore, we will highlight the importance of prospective study designs to identify and confirm epigenetic biomarkers of disease.

118 citations


Cites background from "Clinical epigenetics: seizing oppor..."

  • ...DNA methylation modifications are highly stable compared to RNA- or proteinbased biomarkers, relatively easy to measure using non-invasive biospecimen, and are quantifiable marks on the DNA that can track the influences of various environmental and lifestyle factors (Berdasco and Esteller, 2019)....

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Journal ArticleDOI
TL;DR: A comprehensive up-to-date view of potential epigenetic biomarkers in immunotherapy is presented and their advantages over other indicators are discussed.

113 citations

References
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Journal ArticleDOI
08 Oct 2009-Nature
TL;DR: This paper examined potential sources of missing heritability and proposed research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

7,797 citations

Journal ArticleDOI
TL;DR: Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylation of theMGMT promoter did notHave such a benefit and were assigned to only radiotherapy.
Abstract: background Epigenetic silencing of the MGMT (O 6 -methylguanine–DNA methyltransferase) DNArepair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. methods We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. results The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. conclusions Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.

6,018 citations

Journal ArticleDOI
Anshul Kundaje1, Wouter Meuleman1, Wouter Meuleman2, Jason Ernst3, Misha Bilenky4, Angela Yen1, Angela Yen2, Alireza Heravi-Moussavi4, Pouya Kheradpour1, Pouya Kheradpour2, Zhizhuo Zhang2, Zhizhuo Zhang1, Jianrong Wang1, Jianrong Wang2, Michael J. Ziller2, Viren Amin5, John W. Whitaker, Matthew D. Schultz6, Lucas D. Ward1, Lucas D. Ward2, Abhishek Sarkar2, Abhishek Sarkar1, Gerald Quon1, Gerald Quon2, Richard Sandstrom7, Matthew L. Eaton1, Matthew L. Eaton2, Yi-Chieh Wu2, Yi-Chieh Wu1, Andreas R. Pfenning1, Andreas R. Pfenning2, Xinchen Wang1, Xinchen Wang2, Melina Claussnitzer1, Melina Claussnitzer2, Yaping Liu1, Yaping Liu2, Cristian Coarfa5, R. Alan Harris5, Noam Shoresh2, Charles B. Epstein2, Elizabeta Gjoneska2, Elizabeta Gjoneska1, Danny Leung8, Wei Xie8, R. David Hawkins8, Ryan Lister6, Chibo Hong9, Philippe Gascard9, Andrew J. Mungall4, Richard A. Moore4, Eric Chuah4, Angela Tam4, Theresa K. Canfield7, R. Scott Hansen7, Rajinder Kaul7, Peter J. Sabo7, Mukul S. Bansal1, Mukul S. Bansal10, Mukul S. Bansal2, Annaick Carles4, Jesse R. Dixon8, Kai How Farh2, Soheil Feizi2, Soheil Feizi1, Rosa Karlic11, Ah Ram Kim2, Ah Ram Kim1, Ashwinikumar Kulkarni12, Daofeng Li13, Rebecca F. Lowdon13, Ginell Elliott13, Tim R. Mercer14, Shane Neph7, Vitor Onuchic5, Paz Polak15, Paz Polak2, Nisha Rajagopal8, Pradipta R. Ray12, Richard C Sallari2, Richard C Sallari1, Kyle Siebenthall7, Nicholas A Sinnott-Armstrong1, Nicholas A Sinnott-Armstrong2, Michael Stevens13, Robert E. Thurman7, Jie Wu16, Bo Zhang13, Xin Zhou13, Arthur E. Beaudet5, Laurie A. Boyer1, Philip L. De Jager2, Philip L. De Jager15, Peggy J. Farnham17, Susan J. Fisher9, David Haussler18, Steven J.M. Jones4, Steven J.M. Jones19, Wei Li5, Marco A. Marra4, Michael T. McManus9, Shamil R. Sunyaev15, Shamil R. Sunyaev2, James A. Thomson20, Thea D. Tlsty9, Li-Huei Tsai2, Li-Huei Tsai1, Wei Wang, Robert A. Waterland5, Michael Q. Zhang21, Lisa Helbling Chadwick22, Bradley E. Bernstein15, Bradley E. Bernstein6, Bradley E. Bernstein2, Joseph F. Costello9, Joseph R. Ecker11, Martin Hirst4, Alexander Meissner2, Aleksandar Milosavljevic5, Bing Ren8, John A. Stamatoyannopoulos7, Ting Wang13, Manolis Kellis1, Manolis Kellis2 
19 Feb 2015-Nature
TL;DR: It is shown that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

5,037 citations

01 Feb 2015
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

4,409 citations

Journal ArticleDOI
TL;DR: Dysregulation of these ncRNAs is being found to have relevance not only to tumorigenesis, but also to neurological, cardiovascular, developmental and other diseases, and there is great interest in therapeutic strategies to counteract these perturbations.
Abstract: The role of non-coding RNAs (ncRNAs) in disease is best understood for microRNAs in cancer. However, there is increasing interest in the disease-related roles of other ncRNAs — including piRNAs, snoRNAs, T-UCRs and lncRNAs — and in using this knowledge for therapy.

4,016 citations