Articles

Sirtuin functions and modulation: from chemistry to the clinic

Sirtuins are NAD⁺-dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, senescence, proliferatio...

Authors: Vincenzo Carafa, Dante Rotili, Mariantonietta Forgione, Francesca Cuomo, Enrica Serretiello, Gebremedhin Solomon Hailu, Elina Jarho, Maija Lahtela-Kakkonen, Antonello Mai and Lucia Altucci

Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy

The term epigenetics is defined as heritable changes in gene expression that are not due to alterations of the DNA sequence. In the last years, it has become more and more evident that dysregulated epigenetic ...

Authors: Ludovica Morera, Michael Lübbert and Manfred Jung

Disagreement between two common biomarkers of global DNA methylation

The quantification of global DNA methylation has been established in epigenetic screening. As more practicable alternatives to the HPLC-based gold standard, the methylation analysis of CpG islands in repeatabl...

Authors: Claudia Knothe, Hiromi Shiratori, Eduard Resch, Alfred Ultsch, Gerd Geisslinger, Alexandra Doehring and Jörn Lötsch

Epigenetic drugs: from chemistry via biology to medicine and back

Authors: Lucia Altucci and Marianne G. Rots

MeCP2 and the enigmatic organization of brain chromatin. Implications for depression and cocaine addiction

Methyl CpG binding protein 2 (MeCP2) is a highly abundant chromosomal protein within the brain. It is hence not surprising that perturbations in its genome-wide distribution, and at particular loci within this...

Authors: Juan Ausió

DNA methylation mediates the effect of exposure to prenatal maternal stress on cytokine production in children at age 13½ years: Project Ice Storm

Prenatal maternal stress (PNMS) is an important programming factor of postnatal immunity. We tested here the hypothesis that DNA methylation of genes in the NF-κB signaling pathway in T cells mediates the effe...

Authors: Lei Cao-Lei, Franz Veru, Guillaume Elgbeili, Moshe Szyf, David P. Laplante and Suzanne King

RRx-001, an epigenetic-based radio- and chemosensitizer, has vascular normalizing effects on SCCVII and U87 tumors

The tumor-specific microregional effects of the anticancer agent RRx-001, a novel epigenetic-based radio/chemosensitizer with nitrogen oxide-donating properties in phase II clinical trials, were investigated w...

Authors: Bryan Oronsky, Jan Scicinski, Pedro Cabrales and Andrew Minchinton

Hypomethylation of FAM63B in bipolar disorder patients

Bipolar disorder (BD) and schizophrenia (SZ) are known to share common genetic and psychosocial risk factors. A recent epigenome-wide association study performed on blood samples from SZ patients found signifi...

Authors: Anna Starnawska, Ditte Demontis, Andrew McQuillin, Niamh L. O’Brien, Nicklas H. Staunstrup, Ole Mors, Anders L. Nielsen, Anders D. Børglum and Mette Nyegaard

Obesity-related DNA methylation at imprinted genes in human sperm: Results from the TIEGER study

Epigenetic reprogramming in mammalian gametes resets methylation marks that regulate monoallelic expression of imprinted genes. In males, this involves erasure of the maternal methylation marks and establishme...

Authors: Adelheid Soubry, Lisa Guo, Zhiqing Huang, Cathrine Hoyo, Stephanie Romanus, Thomas Price and Susan K. Murphy

CREBBP is a target of epigenetic, but not genetic, modification in juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm of childhood whose clinical heterogeneity is only poorly represented by gene sequence alterations. It was previously shown that aberrant...

Authors: Silvia Fluhr, Melanie Boerries, Hauke Busch, Aikaterini Symeonidi, Tania Witte, Daniel B Lipka, Oliver Mücke, Peter Nöllke, Christopher Felix Krombholz, Charlotte M Niemeyer, Christoph Plass and Christian Flotho

MGMT promoter methylation determined by HRM in comparison to MSP and pyrosequencing for predicting high-grade glioma response

The DNA repair protein O⁶-methylguanine-DNA methyltransferase (MGMT) causes resistance of cancer cells to alkylating agents and, therefore, is a well-established predictive marker for high-grade gliomas that are ...

Authors: Olivier J. Switzeny, Markus Christmann, Mirjam Renovanz, Alf Giese, Clemens Sommer and Bernd Kaina

DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease

Chronic hepatitis B infection is characterized by hepatic immune and inflammatory response with considerable variation in the rates of progression to cirrhosis. Genetic variants and environmental cues influenc...

Authors: Müjdat Zeybel, Sezgin Vatansever, Timothy Hardy, Ayşegül Akder Sarı, Fulya Cakalağaoğlu, Arzu Avcı, Gemma Louise Zeybel, Serçin Karahüseyinoğlu, Matthew Bashton, John C. Mathers, Belkıs Ünsal and Jelena Mann

Kaiso mediates human ICR1 methylation maintenance and H19 transcriptional fine regulation

Genomic imprinting evolved in a common ancestor to marsupials and eutherian mammals and ensured the transcription of developmentally important genes from defined parental alleles. The regulation of imprinted g...

Authors: Florian Bohne, David Langer, Ursula Martiné, Claudia S. Eider, Regina Cencic, Matthias Begemann, Miriam Elbracht, Luzie Bülow, Thomas Eggermann, Ulrich Zechner, Jerry Pelletier, Bernhard Ulrich Zabel, Thorsten Enklaar and Dirk Prawitt

Vitamin C enhances epigenetic modifications induced by 5-azacytidine and cell cycle arrest in the hepatocellular carcinoma cell lines HLE and Huh7

5-Azacytidine (5-AZA), a DNA methyl transferase inhibitor, is a clinically used epigenetic drug for cancer therapy. Recently, we have shown that 5-AZA upregulates ten-eleven translocation (TET) protein express...

Authors: Sahar Olsadat Sajadian, Chaturvedula Tripura, Fazel Sahraneshin Samani, Marc Ruoss, Steven Dooley, Hossein Baharvand and Andreas K. Nussler

Establishing an analytic pipeline for genome-wide DNA methylation

The need for research investigating DNA methylation (DNAm) in clinical studies has increased, leading to the evolution of new analytic methods to improve accuracy and reproducibility of the interpretation of r...

Authors: Michelle L. Wright, Mikhail G. Dozmorov, Aaron R. Wolen, Colleen Jackson-Cook, Angela R. Starkweather, Debra E. Lyon and Timothy P. York

Analysis of RET promoter CpG island methylation using methylation-specific PCR (MSP), pyrosequencing, and methylation-sensitive high-resolution melting (MS-HRM): impact on stage II colon cancer patient outcome

Already since the 1990s, promoter CpG island methylation markers have been considered promising diagnostic, prognostic, and predictive cancer biomarkers. However, so far, only a limited number of DNA methylati...

Authors: Muriel X. G. Draht, Kim M. Smits, Valérie Jooste, Benjamin Tournier, Martijn Vervoort, Chantal Ramaekers, Caroline Chapusot, Matty P. Weijenberg, Manon van Engeland and Veerle Melotte

The detective, prognostic, and predictive value of DNA methylation in human esophageal squamous cell carcinoma

Esophageal cancer is one of the most common malignancies in the world. Squamous cell carcinoma accounts for approximately 90 % of esophageal cancer cases. Genetic and epigenetic changes have been found to accu...

Authors: Kai Ma, Baoping Cao and Mingzhou Guo

The bromodomain inhibitor N-methyl pyrrolidone reduced fat accumulation in an ovariectomized rat model

Weight gain is one of the consequences of estrogen deficiency and constitutes a major health problem. The present study highlights the effects of N-methyl pyrrolidone (NMP) on adipogenesis in osteoporosis indu...

Authors: Bebeka Gjoksi, Chafik Ghayor, Indranil Bhattacharya, Marcy Zenobi-Wong and Franz E. Weber

Quantitative methylation analysis reveals distinct association between PAX6 methylation and clinical characteristics with different viral infections in hepatocellular carcinoma

Related to genetic alteration, frequent promoter hypermethylation is also a contributing factor in the development of human cancers. Recently, we discovered numerous novel genes that were aberrantly methylated...

Authors: Yu-Lueng Shih, Chih-Chi Kuo, Ming-De Yan, Ya-Wen Lin, Chung-Bao Hsieh and Tsai-Yuan Hsieh

Erratum to: A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver–Russell and Beckwith–Wiedemann syndromes

Authors: Silvia Russo, Luciano Calzari, Alessandro Mussa, Ester Mainini, Matteo Cassina, Stefania Di Candia, Maurizio Clementi, Sara Guzzetti, Silvia Tabano, Monica Miozzo, Silvia Sirchia, Palma Finelli, Paolo Prontera, Silvia Maitz, Giovanni Sorge, Annalisa Calcagno…

Defining the criteria for identifying constitutional epimutations

In the January 2016 issue of Clinical Epigenetics, Quiñonez-Silva et al. (Clin Epigenetics 8:1, 2016) described a possible constitutional epimutation of the RB1 gene as a cause of hereditary predisposition to ret...

Authors: Mathew A. Sloane, Robyn L. Ward and Luke B. Hesson

The epigenetic modifier JMJD6 is amplified in mammary tumors and cooperates with c-Myc to enhance cellular transformation, tumor progression, and metastasis

Oncogene overexpression in primary cells often triggers the induction of a cellular safeguard response promoting senescence or apoptosis. Secondary cooperating genetic events are generally required for oncogen...

Authors: Olga Aprelikova, Kenny Chen, Lara H. El Touny, Constance Brignatz-Guittard, Justin Han, Tinghu Qiu, Howard H. Yang, Maxwell P. Lee, Min Zhu and Jeffrey E. Green

TREM2 upregulation correlates with 5-hydroxymethycytosine enrichment in Alzheimer’s disease hippocampus

Recent genome-wide association studies revealed TREM2 rs75932628-T variant to be associated with Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the role that TREM2 plays in sporadic AD is...

Authors: Naiara Celarain, Javier Sánchez-Ruiz de Gordoa, María Victoria Zelaya, Miren Roldán, Rosa Larumbe, Laura Pulido, Carmen Echavarri and Maite Mendioroz

Associations and prognostic implications of Eastern Cooperative Oncology Group performance status and tumoral LINE-1 methylation status in stage III colon cancer patients

Low methylation status of LINE-1 in tumors is associated with poor survival in patients with colon cancer. Eastern Cooperative Oncology Group performance status (ECOG-PS) is a method to assess the functional stat...

Authors: Duo Chen, Xianyu Wen, Young Seok Song, Ye-Young Rhee, Tae Hun Lee, Nam Yun Cho, Sae-Won Han, Tae-You Kim and Gyeong Hoon Kang

Detection and monitoring of hypermethylated RASSF1A in serum from patients with metastatic breast cancer

Circulating hypermethylated RASSF1A could be a novel and potential useful marker for monitoring patients with metastatic breast cancer. Technical obstacles include fragmentation of the circulating DNA, fluctuatio...

Authors: Søren Kristiansen, Dorte Nielsen and György Sölétormos

Global histone modification profiling reveals the epigenomic dynamics during malignant transformation in a four-stage breast cancer model

Epigenetic regulation has emerged to be the critical steps for tumorigenesis and metastasis. Multiple histone methyltransferase and demethylase have been implicated as tumor suppressors or oncogenes recently. ...

Authors: Quan-Yi Zhao, Pin-Ji Lei, Xiaoran Zhang, Jun-Yi Zheng, Hui-Yi Wang, Jiao Zhao, Yi-Ming Li, Mei Ye, Lianyun Li, Gang Wei and Min Wu

Splicing-dependent expression of microRNAs of mirtron origin in human digestive and excretory system cancer cells

An abundant class of intronic microRNAs (miRNAs) undergoes atypical Drosha-independent biogenesis in which the spliceosome governs the excision of hairpin miRNA precursors, called mirtrons. Although nearly 500...

Authors: Stasė Butkytė, Laurynas Čiupas, Eglė Jakubauskienė, Laurynas Vilys, Paulius Mocevicius, Arvydas Kanopka and Giedrius Vilkaitis

Dynamic interplay between locus-specific DNA methylation and hydroxymethylation regulates distinct biological pathways in prostate carcinogenesis

Despite the significant global loss of DNA hydroxymethylation marks in prostate cancer tissues, the locus-specific role of hydroxymethylation in prostate tumorigenesis is unknown. We characterized hydroxymethy...

Authors: Shivani N. Kamdar, Linh T. Ho, Ken J. Kron, Ruth Isserlin, Theodorus van der Kwast, Alexandre R. Zlotta, Neil E. Fleshner, Gary Bader and Bharati Bapat

5-Hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma

Primary hyperparathyroidism is characterized by enlarged parathyroid glands due to an adenoma (80–85 %) or multiglandular disease (~15 %) causing hypersecretion of parathyroid hormone (PTH) and generally hyper...

Authors: Elham Barazeghi, Anthony J. Gill, Stan Sidhu, Olov Norlén, Roberto Dina, F. Fausto Palazzo, Per Hellman, Peter Stålberg and Gunnar Westin

Genome-wide analysis of DNA methylation and gene expression defines molecular characteristics of Crohn’s disease-associated fibrosis

Fibrosis of the intestine is a common and poorly understood complication of Crohn’s disease (CD) characterized by excessive deposition of extracellular matrix and accompanied by narrowing and obstruction of th...

Authors: Tammy Sadler, Jeffrey M. Bhasin, Yaomin Xu, Jill Barnholz-Sloan, Yanwen Chen, Angela H. Ting and Eleni Stylianou

Discovery of new methylation markers to improve screening for cervical intraepithelial neoplasia grade 2/3

Assessment of DNA promoter methylation markers in cervical scrapings for the detection of cervical intraepithelial neoplasia (CIN) and cervical cancer is feasible, but finding methylation markers with both hig...

Authors: A. Boers, R. Wang, R. W. van Leeuwen, H. G. Klip, G. H. de Bock, H. Hollema, W. van Criekinge, T. de Meyer, S. Denil, A. G J. van der Zee, E. Schuuring and G. B. A. Wisman

Hsa-miR-375 is a predictor of local control in early stage breast cancer

A long-term analysis by the Early Breast Cancer Trialist Group (EBCTG) revealed a strong correlation between local control and cancer-specific mortality. MicroRNAs (miRs), short (20–25 nucleotides) non-coding ...

Authors: Franz Zehentmayr, Cornelia Hauser-Kronberger, Barbara Zellinger, Falk Hlubek, Claudia Schuster, Ulrich Bodenhofer, Gerd Fastner, Heinz Deutschmann, Philipp Steininger, Roland Reitsamer, Thorsten Fischer and Felix Sedlmayer

Erratum to: Imprinting disorders: a group of congenital disorders with overlapping patterns of molecular changes affecting imprinted loci

Authors: Thomas Eggermann, Guiomar Perez de Nanclares, Eamonn R. Maher, I. Karen Temple, Zeynep Tümer, David Monk, Deborah J. G. Mackay, Karen Grønskov, Andrea Riccio, Agnès Linglart and Irène Netchine

MSRE-HTPrimer: a high-throughput and genome-wide primer design pipeline optimized for epigenetic research

Methylation-sensitive restriction enzymes—polymerase chain reaction (MSRE-PCR) has been used in epigenetic research to identify genome-wide and gene-specific DNA methylation. Currently, epigenome-wide discover...

Authors: Ram Vinay Pandey, Walter Pulverer, Rainer Kallmeyer, Gabriel Beikircher, Stephan Pabinger, Albert Kriegner and Andreas Weinhäusel

Different definitions of CpG island methylator phenotype and outcomes of colorectal cancer: a systematic review

Contradictory results were reported for the prognostic role of CpG island methylator phenotype (CIMP) among colorectal cancer (CRC) patients. Differences in the definitions of CIMP were the most common explana...

Authors: Min Jia, Xu Gao, Yan Zhang, Michael Hoffmeister and Hermann Brenner

Diagnostic and prognostic value of SHOX2 and SEPT9 DNA methylation and cytology in benign, paramalignant, and malignant ascites

Cytology remains the gold standard for the detection of malignant cells in ascites. However, its sensitivity is limited. The aim of this study was to evaluate DNA methylation biomarkers for the differential di...

Authors: Maria Jung, Svenja Pützer, Heidrun Gevensleben, Sebastian Meller, Glen Kristiansen and Dimo Dietrich

A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver–Russell and Beckwith–Wiedemann syndromes

Multiple (epi)genetic defects affecting the expression of the imprinted genes within the 11p15.5 chromosomal region underlie Silver–Russell (SRS) and Beckwith–Wiedemann (BWS) syndromes. The molecular diagnosis...

Authors: Silvia Russo, Luciano Calzari, Alessandro Mussa, Ester Mainini, Matteo Cassina, Stefania Di Candia, Maurizio Clementi, Sara Guzzetti, Silvia Tabano, Monica Miozzo, Silvia Sirchia, Palma Finelli, Paolo Prontera, Silvia Maitz, Giovanni Sorge, Annalisa Calcagno…

Expression of epigenetic machinery genes is sensitive to maternal obesity and weight loss in relation to fetal growth in mice

Maternal obesity impacts fetal growth and pregnancy outcomes. To counteract the deleterious effects of obesity on fertility and pregnancy issue, preconceptional weight loss is recommended to obese women. Wheth...

Authors: Polina E. Panchenko, Sarah Voisin, Mélanie Jouin, Luc Jouneau, Audrey Prézelin, Simon Lecoutre, Christophe Breton, Hélène Jammes, Claudine Junien and Anne Gabory

Frailty is associated with the epigenetic clock but not with telomere length in a German cohort

The epigenetic clock, in particular epigenetic pre-aging quantified by the so-called DNA methylation age acceleration, has recently been suggested to closely correlate with a variety of disease phenotypes. The...

Authors: Lutz Philipp Breitling, Kai-Uwe Saum, Laura Perna, Ben Schöttker, Bernd Holleczek and Hermann Brenner

X chromosome-wide analysis identifies DNA methylation sites influenced by cigarette smoking

Tobacco smoking is a major cause of chronic disease worldwide. Smoking may induce cellular and molecular changes including epigenetic modification, with both short-term and long-term modification patterns that...

Authors: Daniella Klebaner, Yunfeng Huang, Qin Hui, Jacquelyn Y. Taylor, Jack Goldberg, Viola Vaccarino and Yan V. Sun

Development of 5‘ LTR DNA methylation of latent HIV-1 provirus in cell line models and in long-term-infected individuals

Human immunodeficiency virus type 1 (HIV-1) latency represents the major barrier to virus eradication in infected individuals because cells harboring latent HIV-1 provirus are not affected by current antiretro...

Authors: Kateřina Trejbalová, Denisa Kovářová, Jana Blažková, Ladislav Machala, David Jilich, Jan Weber, Dana Kučerová, Ondřej Vencálek, Ivan Hirsch and Jiří Hejnar

Reviewer acknowledgement 2016

The editors of Clinical Epigenetics would like to thank all our reviewers who have contributed to the journal in Volume 7 (2015).

Authors: Ulrich Mahlknecht

DNA methylation and hormone receptor status in breast cancer

We examined whether differences in tumor DNA methylation were associated with more aggressive hormone receptor-negative breast cancer in an ethnically diverse group of patients in the Breast Cancer Care in Chi...

Authors: Elizaveta V. Benevolenskaya, Abul B. M. M. K. Islam, Habibul Ahsan, Muhammad G. Kibriya, Farzana Jasmine, Ben Wolff, Umaima Al-Alem, Elizabeth Wiley, Andre Kajdacsy-Balla, Virgilia Macias and Garth H. Rauscher

Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer

While localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence suggests that ab...

Authors: Pier-Luc Clermont, Francesco Crea, Yan Ting Chiang, Dong Lin, Amy Zhang, James Z. L. Wang, Abhijit Parolia, Rebecca Wu, Hui Xue, Yuwei Wang, Jiarui Ding, Kelsie L. Thu, Wan L. Lam, Sohrab P. Shah, Colin C. Collins, Yuzhuo Wang…

Reciprocal changes in DNA methylation and hydroxymethylation and a broad repressive epigenetic switch characterize FMR1 transcriptional silencing in fragile X syndrome

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability, resulting from the loss of function of the fragile X mental retardation 1 (FMR1) gene. The molecular pathways associated with...

Authors: Sarah Brasa, Arne Mueller, Sébastien Jacquemont, Florian Hahne, Izabela Rozenberg, Thomas Peters, Yunsheng He, Christine McCormack, Fabrizio Gasparini, Salah-Dine Chibout, Olivier Grenet, Jonathan Moggs, Baltazar Gomez-Mancilla and Rémi Terranova

H3K4 tri-methylation breadth at transcription start sites impacts the transcriptome of systemic lupus erythematosus

The autoimmune disease systemic lupus erythematosus (SLE) has a modified epigenome with modified tri-methylation of histone H3 lysine 4 (H3K4me3) at specific loci across the genome. H3K4me3 is a canonical chro...

Authors: Zhe Zhang, Lihua Shi, Noor Dawany, Judith Kelsen, Michelle A. Petri and Kathleen E. Sullivan

Epigenetic associations of type 2 diabetes and BMI in an Arab population

The prevalence of type 2 diabetes (T2D) and obesity has dramatically increased within a few generations, reaching epidemic levels. In addition to genetic risk factors, epigenetic mechanisms triggered by changi...

Authors: Wadha A. Al Muftah, Mashael Al-Shafai, Shaza B. Zaghlool, Alessia Visconti, Pei-Chien Tsai, Pankaj Kumar, Tim Spector, Jordana Bell, Mario Falchi and Karsten Suhre

The cardiovascular and hypothalamus-pituitary-adrenal axis response to stress is controlled by glucocorticoid receptor sequence variants and promoter methylation

Gender, genetic makeup, and prior experience interact to determine physiological responses to an external perceived stressor. Here, we investigated the contribution of both genetic variants and promoter methyl...

Authors: Ting Li-Tempel, Mauro F. Larra, Estelle Sandt, Sophie B. Mériaux, Andrea B. Schote, Hartmut Schächinger, Claude P. Muller and Jonathan D. Turner

Insulin-like growth factor axis in pregnancies affected by fetal growth disorders

Insulin-like growth factors 1 and 2 (IGF1 and IGF2) and their binding proteins (IGFBPs) are expressed in the placenta and known to regulate fetal growth. DNA methylation is an epigenetic mechanism which involv...

Authors: Aamod R. Nawathe, Mark Christian, Sung Hye Kim, Mark Johnson, Makrina D. Savvidou and Vasso Terzidou

Loss of nuclear localization of TET2 in colorectal cancer

5-Hydroxymethylcytosine (5hmC) is lost in multiple human cancers, including colorectal cancer (CRC). Decreased ten-eleven translocation 1 (TET1) messenger RNA (mRNA), but not other two TET family members, has ...

Authors: Yuji Huang, Guanghui Wang, Zhonglin Liang, Yili Yang, Long Cui and Chen-Ying Liu