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Article ; Online: Cell division drives DNA methylation loss in late-replicating domains in primary human cells

Jamie L. Endicott / Paula A. Nolte / Hui Shen / Peter W. Laird

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 12

Abstract: DNA methylation loss has been observed in aging tissues and cancers for decades. Researchers from Van Andel Institute have now provided experimental evidence that this process is directly driven by cell division. ...

Abstract	DNA methylation loss has been observed in aging tissues and cancers for decades. Researchers from Van Andel Institute have now provided experimental evidence that this process is directly driven by cell division.
Keywords	Science ; Q
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Effects of folylpolyglutamate synthase modulation on global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

Kim, Sung-Eun / Daniel J. Weisenberger / Kyoung-Jin Sohn / Michael S. Kim / Peter W. Laird / Robert C. Cho / Toshinori Hinoue / Young-In Kim

Journal of nutritional biochemistry. 2016 Mar., v. 29

2016

Abstract: Folylpolyglutamate synthase (FPGS) plays a critical role in intracellular folate homeostasis. FPGS-induced polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group ... ...

Abstract	Folylpolyglutamate synthase (FPGS) plays a critical role in intracellular folate homeostasis. FPGS-induced polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence FPGS modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression and aberrant DNA methylation is mechanistically linked cancer development. We investigated whether FPGS modulation would affect global and gene-specific promoter DNA methylation with consequent functional effects on gene expression profiles in HCT116 colon and MDA-MB-435 breast cancer cells. Although FPGS modulation altered global DNA methylation and DNA methyltransferases (DNMT) activity, the effects of FPGS modulation on global DNA methylation and DNMT activity could not be solely explained by intracellular folate concentrations and content of long-chain folylpolyglutamates, and it may be cell-specific. FPGS modulation influenced differential gene expression and promoter cytosine-guanine dinucleotide sequences (CpG) DNA methylation involved in cellular development, cell cycle, cell death and molecular transport. Some of the altered gene expression was associated with promoter CpG DNA methylation changes. In both the FPGS-overexpressed HCT116 and MDA-MB-435 cell lines, we identified several differentially expressed genes involved in folate biosynthesis and one-carbon metabolism, which might in part have contributed to the observed increased efficacy of 5-fluorouracil in response to FPGS overexpression. Our data suggest that FPGS modulation affects global and promoter CpG DNA methylation and expression of several genes involved in important biological pathways. The potential role of FPGS modulation in DNA methylation and its associated downstream functional effects warrants further studies.
Keywords	biosynthesis ; breast neoplasms ; carcinogenesis ; cell cycle ; cell death ; colon ; DNA methylation ; epigenetics ; fluorouracil ; folic acid ; gene expression regulation ; gene overexpression ; genes ; homeostasis ; humans ; methyltransferases ; neoplasm cells ; S-adenosylmethionine ; tetrahydrofolate synthase
Language	English
Dates of publication	2016-03
Size	p. 27-35.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1014929-6
ISSN	1873-4847 ; 0955-2863
ISSN (online)	1873-4847
ISSN	0955-2863
DOI	10.1016/j.jnutbio.2015.10.019
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Analysis of germline-driven ancestry-associated gene expression in cancers

Nyasha Chambwe / Rosalyn W. Sayaman / Donglei Hu / Scott Huntsman / Anab Kemal / Samantha Caesar-Johnson / Jean C. Zenklusen / Elad Ziv / Rameen Beroukhim / Andrew D. Cherniack / Jian Carrot-Zhang / Ashton C. Berger / Seunghun Han / Matthew Meyerson / Jeffrey S. Damrauer / Katherine A. Hoadley / Ina Felau / John A. Demchok / Michael K.A. Mensah /

STAR Protocols, Vol 3, Iss 3, Pp 101586- (2022)

2022

Abstract: Summary: Differential mRNA expression between ancestry groups can be explained by both genetic and environmental factors. We outline a computational workflow to determine the extent to which germline genetic variation explains cancer-specific molecular ... ...

Abstract	Summary: Differential mRNA expression between ancestry groups can be explained by both genetic and environmental factors. We outline a computational workflow to determine the extent to which germline genetic variation explains cancer-specific molecular differences across ancestry groups. Using multi-omics datasets from The Cancer Genome Atlas (TCGA), we enumerate ancestry-informative markers colocalized with cancer-type-specific expression quantitative trait loci (e-QTLs) at ancestry-associated genes. This approach is generalizable to other settings with paired germline genotyping and mRNA expression data for a multi-ethnic cohort.For complete details on the use and execution of this protocol, please refer to Carrot-Zhang et al. (2020), Robertson et al. (2021), and Sayaman et al. (2021). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
Keywords	Bioinformatics ; Sequence analysis ; Cancer ; Genomics ; RNAseq ; Gene Expression ; Science (General) ; Q1-390
Language	English
Publishing date	2022-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: DNA methylation as a biomarker for cardiovascular disease risk.

Myungjin Kim / Tiffany I Long / Kazuko Arakawa / Renwei Wang / Mimi C Yu / Peter W Laird

PLoS ONE, Vol 5, Iss 3, p e

2010 Volume 9692

Abstract: Elevated serum homocysteine is associated with an increased risk of cardiovascular disease (CVD). This may reflect a reduced systemic remethylation capacity, which would be expected to cause decreased genomic DNA methylation in peripheral blood ... ...

Abstract	Elevated serum homocysteine is associated with an increased risk of cardiovascular disease (CVD). This may reflect a reduced systemic remethylation capacity, which would be expected to cause decreased genomic DNA methylation in peripheral blood leukocytes (PBL).We examined the association between prevalence of CVD (myocardial infarction, stroke) and its predisposing conditions (hypertension, diabetes) and PBL global genomic DNA methylation as represented by ALU and Satellite 2 (AS) repetitive element DNA methylation in 286 participants of the Singapore Chinese Health Study, a population-based prospective investigation of 63,257 men and women aged 45-74 years recruited during 1993-1998. Men exhibited significantly higher global DNA methylation [geometric mean (95% confidence interval (CI)): 159 (143, 178)] than women [133 (121, 147)] (P = 0.01). Global DNA methylation was significantly elevated in men with a history of CVD or its predisposing conditions at baseline (P = 0.03) but not in women (P = 0.53). Fifty-two subjects (22 men, 30 women) who were negative for these CVD/predisposing conditions at baseline acquired one or more of these conditions by the time of their follow-up I interviews, which took place on average about 5.8 years post-enrollment. Global DNA methylation levels of the 22 incident cases in men were intermediate (AS, 177) relative to the 56 male subjects who remained free of CVD/predisposing conditions at follow-up (lowest AS, 132) and the 51 male subjects with a diagnosis of CVD or predisposing conditions reported at baseline (highest AS 184) (P for trend = 0.0008) No such association was observed in women (P = 0.91). Baseline body mass index was positively associated with AS in both men and women (P = 0.007).Our findings indicate that elevated, not decreased, PBL DNA methylation is positively associated with prevalence of CVD/predisposing conditions and obesity in Singapore Chinese.
Keywords	Medicine ; R ; Science ; Q
Subject code	360
Language	English
Publishing date	2010-03-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Whole-genome characterization of lung adenocarcinomas lacking alterations in the RTK/RAS/RAF pathway

Jian Carrot-Zhang / Xiaotong Yao / Siddhartha Devarakonda / Aditya Deshpande / Jeffrey S. Damrauer / Tiago Chedraoui Silva / Christopher K. Wong / Hyo Young Choi / Ina Felau / A. Gordon Robertson / Mauro A.A. Castro / Lisui Bao / Esther Rheinbay / Eric Minwei Liu / Tuan Trieu / David Haan / Christina Yau / Toshinori Hinoue / Yuexin Liu /

Ofer Shapira / Kiran Kumar / Karen L. Mungall / Hailei Zhang / Jake June-Koo Lee / Ashton Berger / Galen F. Gao / Binyamin Zhitomirsky / Wen-Wei Liang / Meng Zhou / Sitapriya Moorthi / Alice H. Berger / Eric A. Collisson / Michael C. Zody / Li Ding / Andrew D. Cherniack / Gad Getz / Olivier Elemento / Christopher C. Benz / Josh Stuart / J.C. Zenklusen / Rameen Beroukhim / Jason C. Chang / Joshua D. Campbell / D. Neil Hayes / Lixing Yang / Peter W. Laird / John N. Weinstein / David J. Kwiatkowski / Ming S. Tsao / William D. Travis

Cell Reports, Vol 34, Iss 8, Pp 108784- (2021)

2021

Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Analytical protocol to identify local ancestry-associated molecular features in cancer

Jian Carrot-Zhang / Seunghun Han / Wanding Zhou / Jeffrey S. Damrauer / Anab Kemal / Andrew D. Cherniack / Rameen Beroukhim / Ashton C. Berger / Matthew Meyerson / Katherine A. Hoadley / Ina Felau / Samantha Caesar-Johnson / John A. Demchok / Michael K.A. Mensah / Roy Tarnuzzer / Zhining Wang / Liming Yang / Jean C. Zenklusen / Nyasha Chambwe /

STAR Protocols, Vol 2, Iss 4, Pp 100766- (2021)

2021

Abstract: Summary: People of different ancestries vary in cancer risk and outcome, and their molecular differences may indicate sources of these variations. Determining the “local” ancestry composition at each genetic locus across ancestry-admixed populations can ... ...

Abstract	Summary: People of different ancestries vary in cancer risk and outcome, and their molecular differences may indicate sources of these variations. Determining the “local” ancestry composition at each genetic locus across ancestry-admixed populations can suggest causal associations. We present a protocol to identify local ancestry and detect the associated molecular changes, using data from the Cancer Genome Atlas. This workflow can be applied to cancer cohorts with matched tumor and normal data from admixed patients to examine germline contributions to cancer.For complete details on the use and execution of this protocol, please refer to Carrot-Zhang et al. (2020).
Keywords	Bioinformatics ; Cancer ; Genomics ; Science (General) ; Q1-390
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Role of DNA Methylation in the Development and Progression of Lung Adenocarcinoma

Keith M. Kerr / Janice S. Galler / Jeffrey A. Hagen / Peter W. Laird / Ite A. Laird-Offringa

Disease Markers, Vol 23, Iss 1-2, Pp 5-

2007 Volume 30

Abstract: Lung cancer, caused by smoking in ∼87% of cases, is the leading cause of cancer death in the United States and Western Europe. Adenocarcinoma is now the most common type of lung cancer in men and women in the United States, and the histological subtype ... ...

Abstract	Lung cancer, caused by smoking in ∼87% of cases, is the leading cause of cancer death in the United States and Western Europe. Adenocarcinoma is now the most common type of lung cancer in men and women in the United States, and the histological subtype most frequently seen in never-smokers and former smokers. The increasing frequency of adenocarcinoma, which occurs more peripherally in the lung, is thought to be at least partially related to modifications in cigarette manufacturing that have led to a change in the depth of smoke inhalation. The rising incidence of lung adenocarcinoma and its lethal nature underline the importance of understanding the development and progression of this disease. Alterations in DNA methylation are recognized as key epigenetic changes in cancer, contributing to chromosomal instability through global hypomethylation, and aberrant gene expression through alterations in the methylation levels at promoter CpG islands. The identification of sequential changes in DNA methylation during progression and metastasis of lung adenocarcinoma, and the elucidation of their interplay with genetic changes, will broaden our molecular understanding of this disease, providing insights that may be applicable to the development of targeted drugs, as well as powerful markers for early detection and patient classification.
Keywords	Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2007-01-01T00:00:00Z
Publisher	Hindawi Publishing Corporation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Widespread epigenetic abnormalities suggest a broad DNA methylation erasure defect in abnormal human sperm.

Sahar Houshdaran / Victoria K Cortessis / Kimberly Siegmund / Allen Yang / Peter W Laird / Rebecca Z Sokol

PLoS ONE, Vol 2, Iss 12, p e

2007 Volume 1289

Abstract: Background Male-factor infertility is a common condition, and etiology is unknown for a high proportion of cases. Abnormal epigenetic programming of the germline is proposed as a possible mechanism compromising spermatogenesis of some men currently ... ...

Abstract	Background Male-factor infertility is a common condition, and etiology is unknown for a high proportion of cases. Abnormal epigenetic programming of the germline is proposed as a possible mechanism compromising spermatogenesis of some men currently diagnosed with idiopathic infertility. During germ cell maturation and gametogenesis, cells of the germ line undergo extensive epigenetic reprogramming. This process involves widespread erasure of somatic-like patterns of DNA methylation followed by establishment of sex-specific patterns by de novo DNA methylation. Incomplete reprogramming of the male germ line could, in theory, result in both altered sperm DNA methylation and compromised spermatogenesis. Methodology/principal finding We determined concentration, motility and morphology of sperm in semen samples collected by male members of couples attending an infertility clinic. Using MethyLight and Illumina assays we measured methylation of DNA isolated from purified sperm from the same samples. Methylation at numerous sequences was elevated in DNA from poor quality sperm. Conclusions This is the first report of a broad epigenetic defect associated with abnormal semen parameters. Our results suggest that the underlying mechanism for these epigenetic changes may be improper erasure of DNA methylation during epigenetic reprogramming of the male germ line.
Keywords	Medicine ; R ; Science ; Q
Subject code	310
Language	English
Publishing date	2007-12-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence

Cell Reports, Vol 23, Iss 2, Pp 637-

2018 Volume 651

Abstract: Summary: Glioma diagnosis is based on histomorphology and grading; however, such classification does not have predictive clinical outcome after glioblastomas have developed. To date, no bona fide biomarkers that significantly translate into a survival ... ...

Abstract	Summary: Glioma diagnosis is based on histomorphology and grading; however, such classification does not have predictive clinical outcome after glioblastomas have developed. To date, no bona fide biomarkers that significantly translate into a survival benefit to glioblastoma patients have been identified. We previously reported that the IDH mutant G-CIMP-high subtype would be a predecessor to the G-CIMP-low subtype. Here, we performed a comprehensive DNA methylation longitudinal analysis of diffuse gliomas from 77 patients (200 tumors) to enlighten the epigenome-based malignant transformation of initially lower-grade gliomas. Intra-subtype heterogeneity among G-CIMP-high primary tumors allowed us to identify predictive biomarkers for assessing the risk of malignant recurrence at early stages of disease. G-CIMP-low recurrence appeared in 9.5% of all gliomas, and these resembled IDH-wild-type primary glioblastoma. G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, mesenchymal stem cell-like epigenomic phenotype, and genomic instability. Molecular abnormalities of longitudinal G-CIMP offer possibilities to defy glioblastoma progression. : IDH-mutant lower-grade glioma glioblastoma often progresses to a more aggressive phenotype upon recurrence. de Souza et al. examines the intra-subtype heterogeneity of initial G-CIMP-high and use this information to identify predictive biomarkers for assessing the risk of recurrence and malignant transformation. Keywords: longitudinal gliomas, DNA methylation, IDH mutation, G-CIMP-high, intra-subtype heterogeneity, malignant transformation and recurrence, G-CIMP-low, stem cell-like glioblastoma, predictive biomarkers
Keywords	Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2018-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Epigenetic subgroups of esophageal and gastric adenocarcinoma with differential GATA5 DNA methylation associated with clinical and lifestyle factors.

Xinhui Wang / Gyeong Hoon Kang / Mihaela Campan / Daniel J Weisenberger / Tiffany I Long / Wendy Cozen / Leslie Bernstein / Anna H Wu / Kimberly D Siegmund / Darryl Shibata / Peter W Laird

PLoS ONE, Vol 6, Iss 10, p e

2011 Volume 25985

Abstract: Adenocarcinomas located near the gastroesophageal junction have unclear etiology and are difficult to classify. We used DNA methylation analysis to identify subtype-specific markers and new subgroups of gastroesophageal adenocarcinomas, and studied their ...

Abstract	Adenocarcinomas located near the gastroesophageal junction have unclear etiology and are difficult to classify. We used DNA methylation analysis to identify subtype-specific markers and new subgroups of gastroesophageal adenocarcinomas, and studied their association with epidemiological risk factors and clinical outcomes.We used logistic regression models and unsupervised hierarchical cluster analysis of 74 DNA methylation markers on 45 tumor samples (44 patients) of esophageal and gastric adenocarcinomas obtained from a population-based case-control study to uncover epigenetic markers and cluster groups of gastroesophageal adenocarcinomas. No distinct epigenetic differences were evident between subtypes of gastric and esophageal cancers. However, we identified two gastroesophageal adenocarcinoma subclusters based on DNA methylation profiles. Group membership was best predicted by GATA5 DNA methylation status. We analyzed the associations between these two epigenetic groups and exposure using logistic regression, and the associations with survival time using Cox regression in a larger set of 317 tumor samples (278 patients). There were more males with esophageal and gastric cardia cancers in Cluster Group 1 characterized by higher GATA5 DNA methylation values (all p<0.05). This group also showed associations of borderline statistical significance with having ever smoked (p-value = 0.07), high body mass index (p-value = 0.06), and symptoms of gastroesophageal reflux (p-value = 0.07). Subjects in cluster Group 1 showed better survival than those in Group 2 after adjusting for tumor differentiation grade, but this was not found to be independent of tumor stage.DNA methylation profiling can be used in population-based studies to identify epigenetic subclasses of gastroesophageal adenocarcinomas and class-specific DNA methylation markers that can be linked to epidemiological data and clinical outcome. Two new epigenetic subgroups of gastroesophageal adenocarcinomas were identified that differ to some extent in ...
Keywords	Medicine ; R ; Science ; Q
Subject code	310
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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