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Zhang Y, Zhang D, Xie Z, Xia T, Zou L, Wang T, Zhong L, Zeng Z, Wang L, Chen G, Liang X. Integrated transcriptomic and metabolomic analysis reveals the effects of EMMPRIN on nucleotide metabolism and 1C metabolism in AS mouse BMDMs. Front Mol Biosci 2025; 11:1460186. [PMID: 40125455 PMCID: PMC11927532 DOI: 10.3389/fmolb.2024.1460186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 12/27/2024] [Indexed: 03/25/2025] Open
Abstract
Background Extracellular matrix metalloproteinase inducer (EMMPRIN) has been considered as a key promoting factor in atherosclerosis (AS). Some studies have shown that regulating EMMPRIN expression in bone marrow-derived macrophages (BMDMs) of ApoE-/- mice can affect plaque stability, but the mechanism was not clear. Methods AS model mice were built from high-fat-feeding ApoE -/- mice, and were divided into siE group and CON group. The BMDMs and aortas from AS mice were harvested following in vivo treatment with either EMMPRIN short interfering (si)RNA (siEMMPRIN) or negative control siRNA. Transcriptomic and metabolomic profiles were analyzed using RNA-sequencing and Liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively. The efficacy of siEMMPRIN was assessed through real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting (WB). Immunofluorescence staining was employed to measure EMMPRIN expression within aortic atherosclerotic plaques. Cell proliferation was monitored using the Cell Counting Kit-8 (CCK8), while flow cytometry was utilized to analyze the cell cycle. Additionally, seahorse analysis and oil red O staining were conducted to verify glucose and lipid metabolism, respectively. Results A total of 3,282 differentially expressed metabolites (DEMs) and 16,138 differentially expressed genes (DEGs) were identified between the CON group and siE group. The nucleotide metabolism and one-carbon (1C) metabolism were identified as major altered pathways at both the transcriptional and metabolic levels. Metabolomic results identified increased levels of glycine, serine, betaine and S-adenosyl-L-methionine (SAM) to S-adenosyl-L-homocysteine (SAH) ratio and decreased levels of dimethylglycine (DMG) and SAH in 1C metabolism, accompanied by the accumulation of nucleotides, nucleosides, and bases in nucleotide metabolism. Transcriptomics results shown that Dnmt, Mthfd2 and Dhfr were downregulated, while Mthfr were upregulated in 1C metabolism. And numerous genes involved in de novo nucleotide synthesis, pentose phosphate pathway (PPP) and dNTP production were significantly inhibited, which may be associated with decreased BMDMs proliferation and cell cycle arrest in the G0/G1 phase in siE group. Multi-omics results also showed changes in glucose and lipid metabolism. Seahorse assay confirmed reduced glycolysis and oxidative phosphorylation (OXPHOS) levels and the Oil Red O staining confirmed the decrease of lipid droplets in siE group. Conclusion The integrated metabolomic and transcriptomic analysis suggested that nucleotide metabolism and 1C metabolism may be major metabolic pathways affected by siEMMPRIN in AS mouse BMDMs. Our study contributes to a better understanding of the role of EMMPRIN in AS development.
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Affiliation(s)
- Yun Zhang
- First Clinical College, Chongqing Medical University, Chongqing, China
| | - Diyuan Zhang
- Second Clinical College, Chongqing Medical University, Chongqing, China
| | - Zulong Xie
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tianli Xia
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lili Zou
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tao Wang
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Li Zhong
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhuo Zeng
- First Clinical College, Chongqing Medical University, Chongqing, China
| | - Lingying Wang
- First Clinical College, Chongqing Medical University, Chongqing, China
| | - Guozhu Chen
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xing Liang
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Li S, Liang X, Shao Q, Wang G, Huang Y, Wen P, Jiang D, Zeng X. Research hotspots and trends of epigenetic therapy in oncology: a bibliometric analysis from 2004 to 2023. Front Pharmacol 2024; 15:1465954. [PMID: 39329125 PMCID: PMC11424529 DOI: 10.3389/fphar.2024.1465954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 08/30/2024] [Indexed: 09/28/2024] Open
Abstract
Background Epigenetics denotes heritable alterations in gene expression patterns independent of changes in DNA sequence. Epigenetic therapy seeks to reprogram malignant cells to a normal phenotype and has been extensively investigated in oncology. This study conducts a bibliometric analysis of epigenetic therapy in cancer, providing a comprehensive overview of current research, identifying trends, and highlighting key areas of investigation. Methods Publications concerning epigenetic inhibitors in cancer spanning 2004 to 2023 were retrieved from the Web of Science Core Collection (WoSCC). Co-occurrence analysis using VOSviewer assessed current status and focal points. Evolutionary trends and bursts in the knowledge domain were analyzed using CiteSpace. Bibliometrix facilitated topic evolution and revealed trends in keywords. National, institutional, and author affiliations and collaborations were also examined. Results A total of 2,153 articles and reviews on epigenetic therapy in oncology were identified, demonstrating a consistent upward trend over time. The United States (745 papers), University of Texas MD Anderson Cancer Center (57 papers), and Stephen B. Baylin (27 papers) emerged as the most productive country, institution, and author, respectively. Keyword co-occurrence analysis identified five primary clusters: tumor, DNA methylation, epigenetic therapy, expression, and immunotherapy. In the past 5 years, newly emerging themes with increased centrality and density include "drug resistance," "immunotherapy," and "combination therapy." The most cited publication reviewed current understanding of potential causes of epigenetic diseases and proposed future therapeutic strategies. Conclusion In the past two decades, the importance of epigenetic therapy in cancer research has become increasingly prominent. The United States occupies a key position in this field, while China, despite having published a large number of related papers, still has relatively limited influence. Current research focuses on the "combination therapy" of epigenetic drugs. Future studies should further explore the sequencing and scheduling of combination therapies, optimize trial designs and dosing regimens to improve clinical efficacy.
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Affiliation(s)
- Sisi Li
- Department of Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
- Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer (iCQBC), Chongqing University Cancer Hospital, Chongqing, China
| | - Xinrui Liang
- Department of Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Qing Shao
- Department of Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
- Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer (iCQBC), Chongqing University Cancer Hospital, Chongqing, China
| | - Guanwen Wang
- Department of Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
- Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer (iCQBC), Chongqing University Cancer Hospital, Chongqing, China
| | - Yuxin Huang
- School of Medicine, Chongqing University, Chongqing, China
| | - Ping Wen
- School of Medicine, Chongqing University, Chongqing, China
| | - Dongping Jiang
- School of Medicine, Chongqing University, Chongqing, China
| | - Xiaohua Zeng
- Department of Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
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Cheng JC, Swarup N, Morselli M, Huang WL, Aziz M, Caggiano C, Kordi M, Patel A, Chia D, Kim Y, Li F, Wei F, Zaitlen N, Krysan K, Dubinett S, Pellegrini M, Wong DW. Single-stranded pre-methylated 5mC adapters uncover the methylation profile of plasma ultrashort Single-stranded cell-free DNA. Nucleic Acids Res 2024; 52:e50. [PMID: 38797520 PMCID: PMC11194076 DOI: 10.1093/nar/gkae276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 03/21/2024] [Accepted: 04/15/2024] [Indexed: 05/29/2024] Open
Abstract
Whole-genome bisulfite sequencing (BS-Seq) measures cytosine methylation changes at single-base resolution and can be used to profile cell-free DNA (cfDNA). In plasma, ultrashort single-stranded cfDNA (uscfDNA, ∼50 nt) has been identified together with 167 bp double-stranded mononucleosomal cell-free DNA (mncfDNA). However, the methylation profile of uscfDNA has not been described. Conventional BS-Seq workflows may not be helpful because bisulfite conversion degrades larger DNA into smaller fragments, leading to erroneous categorization as uscfDNA. We describe the '5mCAdpBS-Seq' workflow in which pre-methylated 5mC (5-methylcytosine) single-stranded adapters are ligated to heat-denatured cfDNA before bisulfite conversion. This method retains only DNA fragments that are unaltered by bisulfite treatment, resulting in less biased uscfDNA methylation analysis. Using 5mCAdpBS-Seq, uscfDNA had lower levels of DNA methylation (∼15%) compared to mncfDNA and was enriched in promoters and CpG islands. Hypomethylated uscfDNA fragments were enriched in upstream transcription start sites (TSSs), and the intensity of enrichment was correlated with expressed genes of hemopoietic cells. Using tissue-of-origin deconvolution, we inferred that uscfDNA is derived primarily from eosinophils, neutrophils, and monocytes. As proof-of-principle, we show that characteristics of the methylation profile of uscfDNA can distinguish non-small cell lung carcinoma from non-cancer samples. The 5mCAdpBS-Seq workflow is recommended for any cfDNA methylation-based investigations.
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Affiliation(s)
- Jordan C Cheng
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Neeti Swarup
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Marco Morselli
- Department of Molecular, Cell, and Developmental Biology, Life Sciences Division, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
| | - Wei-Lun Huang
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan
| | - Mohammad Aziz
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Christa Caggiano
- Department of Computational Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Misagh Kordi
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Abhijit A Patel
- Department of Therapeutic Radiology, Yale University, New Haven, CT, USA
| | - David Chia
- Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Yong Kim
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Feng Li
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Fang Wei
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Noah Zaitlen
- Department of Computational Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Kostyantyn Krysan
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Steve Dubinett
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Matteo Pellegrini
- Department of Molecular, Cell, and Developmental Biology, Life Sciences Division, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - David T W Wong
- School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
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Lee Y, Chowdhury T, Kim S, Yu HJ, Kim KM, Kang H, Kim MS, Kim JW, Kim YH, Ji SY, Hwang K, Han JH, Hwang J, Yoo SK, Lee KS, Choe G, Won JK, Park SH, Lee YK, Shin JH, Park CK, Kim CY, Kim JI. Central neurocytoma exhibits radial glial cell signatures with FGFR3 hypomethylation and overexpression. Exp Mol Med 2024; 56:975-986. [PMID: 38609519 PMCID: PMC11059271 DOI: 10.1038/s12276-024-01204-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 12/01/2023] [Accepted: 01/30/2024] [Indexed: 04/14/2024] Open
Abstract
We explored the genomic events underlying central neurocytoma (CN), a rare neoplasm of the central nervous system, via multiomics approaches, including whole-exome sequencing, bulk and single-nuclei RNA sequencing, and methylation sequencing. We identified FGFR3 hypomethylation leading to FGFR3 overexpression as a major event in the ontogeny of CN that affects crucial downstream events, such as aberrant PI3K-AKT activity and neuronal development pathways. Furthermore, we found similarities between CN and radial glial cells based on analyses of gene markers and CN tumor cells and postulate that CN tumorigenesis is due to dysregulation of radial glial cell differentiation into neurons. Our data demonstrate the potential role of FGFR3 as one of the leading drivers of tumorigenesis in CN.
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Affiliation(s)
- Yeajina Lee
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea
| | - Tamrin Chowdhury
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Sojin Kim
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hyeon Jong Yu
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Kyung-Min Kim
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Ho Kang
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Min-Sung Kim
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jin Wook Kim
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Yong-Hwy Kim
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - So Young Ji
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Kihwan Hwang
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Jung Ho Han
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Jinha Hwang
- Department of Laboratory Medicine, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Seong-Keun Yoo
- The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Kyu Sang Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Gheeyoung Choe
- Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Jae-Kyung Won
- Department of Pathology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Sung-Hye Park
- Department of Pathology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Yong Kyu Lee
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA
| | - Joo Heon Shin
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA
- Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Chul-Kee Park
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
| | - Chae-Yong Kim
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea.
| | - Jong-Il Kim
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea.
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
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5
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Lanciano S, Philippe C, Sarkar A, Pratella D, Domrane C, Doucet AJ, van Essen D, Saccani S, Ferry L, Defossez PA, Cristofari G. Locus-level L1 DNA methylation profiling reveals the epigenetic and transcriptional interplay between L1s and their integration sites. CELL GENOMICS 2024; 4:100498. [PMID: 38309261 PMCID: PMC10879037 DOI: 10.1016/j.xgen.2024.100498] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 07/20/2023] [Accepted: 01/09/2024] [Indexed: 02/05/2024]
Abstract
Long interspersed element 1 (L1) retrotransposons are implicated in human disease and evolution. Their global activity is repressed by DNA methylation, but deciphering the regulation of individual copies has been challenging. Here, we combine short- and long-read sequencing to unveil L1 methylation heterogeneity across cell types, families, and individual loci and elucidate key principles involved. We find that the youngest primate L1 families are specifically hypomethylated in pluripotent stem cells and the placenta but not in most tumors. Locally, intronic L1 methylation is intimately associated with gene transcription. Conversely, the L1 methylation state can propagate to the proximal region up to 300 bp. This phenomenon is accompanied by the binding of specific transcription factors, which drive the expression of L1 and chimeric transcripts. Finally, L1 hypomethylation alone is typically insufficient to trigger L1 expression due to redundant silencing pathways. Our results illuminate the epigenetic and transcriptional interplay between retrotransposons and their host genome.
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Affiliation(s)
- Sophie Lanciano
- University Cote d'Azur, INSERM, CNRS, Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France
| | - Claude Philippe
- University Cote d'Azur, INSERM, CNRS, Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France
| | - Arpita Sarkar
- University Cote d'Azur, INSERM, CNRS, Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France
| | - David Pratella
- University Cote d'Azur, INSERM, CNRS, Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France
| | - Cécilia Domrane
- University Paris Cité, CNRS, Epigenetics and Cell Fate, Paris, France
| | - Aurélien J Doucet
- University Cote d'Azur, INSERM, CNRS, Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France
| | - Dominic van Essen
- University Cote d'Azur, INSERM, CNRS, Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France
| | - Simona Saccani
- University Cote d'Azur, INSERM, CNRS, Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France
| | - Laure Ferry
- University Paris Cité, CNRS, Epigenetics and Cell Fate, Paris, France
| | | | - Gael Cristofari
- University Cote d'Azur, INSERM, CNRS, Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France.
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Edwards S, Adams J, Tchernikov A, Edwards JG. Low-dose X-ray radiation induces an adaptive response: A potential countermeasure to galactic cosmic radiation exposure. Exp Physiol 2024. [PMID: 38180298 DOI: 10.1113/ep091350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 12/21/2023] [Indexed: 01/06/2024]
Abstract
Space exploration involves many dangers including galactic cosmic radiation (GCR). This class of radiation includes high-energy protons and heavy ionizing ions. NASA has defined GCR as a carcinogenic risk for long-duration space missions. To date, no clear strategy has been developed to counter chronic GCR exposure. We hypothesize that preconditioning cells with low levels of radiation will be protective from subsequent higher radiation exposures. H9C2 cells were pretreated with 0.1 to 1.0 Gy X-rays. The challenge radiation exposure consisted of either 8 Gy X-rays or 75 cGy of GCR, using a five-ion GCRsim protocol. A cell doubling time assay was used to determine cell viability. An 8 Gy X-ray challenge alone significantly (P < 0.05) increased cell doubling time compared to the no-radiation control group. Low-dose radiation pre-treatment ameliorated the 8 Gy X-ray-induced increases in cell doubling time. A 75 cGy GCR challenge alone significantly increased cell doubling time compared to the no-radiation group. Following the 75 cGy challenge, only the 0.5 and 1.0 Gy pre-treatment ameliorated the 75 cGy-induced increases in cell doubling time. DNA damage or pathological oxidant stress will delay replicative functions and increase cell doubling time. Our results suggested that pretreatment with low-dose X-rays induced an adaptive response which offered a small but significant protection against a following higher radiation challenge. Although perhaps not a practical countermeasure, these findings may serve to offer insight into cell signalling pathways activated in response to low-dose irradiation and targeted for countermeasure development.
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Switzer CH. Non-canonical nitric oxide signalling and DNA methylation: Inflammation induced epigenetic alterations and potential drug targets. Br J Pharmacol 2023. [PMID: 38116806 DOI: 10.1111/bph.16302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/29/2023] [Accepted: 09/20/2023] [Indexed: 12/21/2023] Open
Abstract
DNA methylation controls DNA accessibility to transcription factors and other regulatory proteins, thereby affecting gene expression and hence cellular identity and function. As epigenetic modifications control the transcriptome, epigenetic dysfunction is strongly associated with pathological conditions and ageing. The development of pharmacological agents that modulate the activity of major epigenetic proteins are in pre-clinical development and clinical use. However, recent publications have identified novel redox-based signalling pathways, and therefore novel drug targets, that may exert epigenetic effects. This review will discuss the recent developments in nitric oxide (NO) signalling on DNA methylation as well as potential epigenetic drug targets that have emerged from the intersection of inflammation/redox biology and epigenetic regulation.
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Affiliation(s)
- Christopher H Switzer
- William Harvey Research Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Department of Molecular and Cell Biology, University of Leicester, Leicester, UK
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Nguyen VTC, Nguyen TH, Doan NNT, Pham TMQ, Nguyen GTH, Nguyen TD, Tran TTT, Vo DL, Phan TH, Jasmine TX, Nguyen VC, Nguyen HT, Nguyen TV, Nguyen THH, Huynh LAK, Tran TH, Dang QT, Doan TN, Tran AM, Nguyen VH, Nguyen VTA, Ho LMQ, Tran QD, Pham TTT, Ho TD, Nguyen BT, Nguyen TNV, Nguyen TD, Phu DTB, Phan BHH, Vo TL, Nai THT, Tran TT, Truong MH, Tran NC, Le TK, Tran THT, Duong ML, Bach HPT, Kim VV, Pham TA, Tran DH, Le TNA, Pham TVN, Le MT, Vo DH, Tran TMT, Nguyen MN, Van TTV, Nguyen AN, Tran TT, Tran VU, Le MP, Do TT, Phan TV, Nguyen HDL, Nguyen DS, Cao VT, Do TTT, Truong DK, Tang HS, Giang H, Nguyen HN, Phan MD, Tran LS. Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization. eLife 2023; 12:RP89083. [PMID: 37819044 PMCID: PMC10567114 DOI: 10.7554/elife.89083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2023] Open
Abstract
Despite their promise, circulating tumor DNA (ctDNA)-based assays for multi-cancer early detection face challenges in test performance, due mostly to the limited abundance of ctDNA and its inherent variability. To address these challenges, published assays to date demanded a very high-depth sequencing, resulting in an elevated price of test. Herein, we developed a multimodal assay called SPOT-MAS (screening for the presence of tumor by methylation and size) to simultaneously profile methylomics, fragmentomics, copy number, and end motifs in a single workflow using targeted and shallow genome-wide sequencing (~0.55×) of cell-free DNA. We applied SPOT-MAS to 738 non-metastatic patients with breast, colorectal, gastric, lung, and liver cancer, and 1550 healthy controls. We then employed machine learning to extract multiple cancer and tissue-specific signatures for detecting and locating cancer. SPOT-MAS successfully detected the five cancer types with a sensitivity of 72.4% at 97.0% specificity. The sensitivities for detecting early-stage cancers were 73.9% and 62.3% for stages I and II, respectively, increasing to 88.3% for non-metastatic stage IIIA. For tumor-of-origin, our assay achieved an accuracy of 0.7. Our study demonstrates comparable performance to other ctDNA-based assays while requiring significantly lower sequencing depth, making it economically feasible for population-wide screening.
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Srivastava A, Srivastava A, Singh RK. Insight into the Epigenetics of Kaposi's Sarcoma-Associated Herpesvirus. Int J Mol Sci 2023; 24:14955. [PMID: 37834404 PMCID: PMC10573522 DOI: 10.3390/ijms241914955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/25/2023] [Accepted: 07/28/2023] [Indexed: 10/15/2023] Open
Abstract
Epigenetic reprogramming represents a series of essential events during many cellular processes including oncogenesis. The genome of Kaposi's sarcoma-associated herpesvirus (KSHV), an oncogenic herpesvirus, is predetermined for a well-orchestrated epigenetic reprogramming once it enters into the host cell. The initial epigenetic reprogramming of the KSHV genome allows restricted expression of encoded genes and helps to hide from host immune recognition. Infection with KSHV is associated with Kaposi's sarcoma, multicentric Castleman's disease, KSHV inflammatory cytokine syndrome, and primary effusion lymphoma. The major epigenetic modifications associated with KSHV can be labeled under three broad categories: DNA methylation, histone modifications, and the role of noncoding RNAs. These epigenetic modifications significantly contribute toward the latent-lytic switch of the KSHV lifecycle. This review gives a brief account of the major epigenetic modifications affiliated with the KSHV genome in infected cells and their impact on pathogenesis.
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Affiliation(s)
- Anusha Srivastava
- Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
| | - Ankit Srivastava
- Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
| | - Rajnish Kumar Singh
- Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
- Faculty of Medical Sciences, Charotar University of Science and Technology, Changa 388421, Gujarat, India
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Otsuka K, Iwasaki T. Insights into radiation carcinogenesis based on dose-rate effects in tissue stem cells. Int J Radiat Biol 2023; 99:1503-1521. [PMID: 36971595 DOI: 10.1080/09553002.2023.2194398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 03/16/2023] [Indexed: 03/29/2023]
Abstract
PURPOSE Increasing epidemiological and biological evidence suggests that radiation exposure enhances cancer risk in a dose-dependent manner. This can be attributed to the 'dose-rate effect,' where the biological effect of low dose-rate radiation is lower than that of the same dose at a high dose-rate. This effect has been reported in epidemiological studies and experimental biology, although the underlying biological mechanisms are not completely understood. In this review, we aim to propose a suitable model for radiation carcinogenesis based on the dose-rate effect in tissue stem cells. METHODS We surveyed and summarized the latest studies on the mechanisms of carcinogenesis. Next, we summarized the radiosensitivity of intestinal stem cells and the role of dose-rate in the modulation of stem-cell dynamics after irradiation. RESULTS Consistently, driver mutations can be detected in most cancers from past to present, supporting the hypothesis that cancer progression is initiated by the accumulation of driver mutations. Recent reports demonstrated that driver mutations can be observed even in normal tissues, which suggests that the accumulation of mutations is a necessary condition for cancer progression. In addition, driver mutations in tissue stem cells can cause tumors, whereas they are not sufficient when they occur in non-stem cells. For non-stem cells, tissue remodeling induced by marked inflammation after the loss of tissue cells is important in addition to the accumulation of mutations. Therefore, the mechanism of carcinogenesis differs according to the cell type and magnitude of stress. In addition, our results indicated that non-irradiated stem cells tend to be eliminated from three-dimensional cultures of intestinal stem cells (organoids) composed of irradiated and non-irradiated stem cells, supporting the stem-cell competition. CONCLUSIONS We propose a unique scheme in which the dose-rate dependent response of intestinal stem cells incorporates the concept of the threshold of stem-cell competition and context-dependent target shift from stem cells to whole tissue. The concept highlights four key issues that should be considered in radiation carcinogenesis: i.e. accumulation of mutations; tissue reconstitution; stem-cell competition; and environmental factors like epigenetic modifications.
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Affiliation(s)
- Kensuke Otsuka
- Biology and Environmental Chemistry Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry, Tokyo, Japan
| | - Toshiyasu Iwasaki
- Strategy and Planning Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry, Tokyo, Japan
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11
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Identification of Prognostic Biomarkers for Suppressing Tumorigenesis and Metastasis of Hepatocellular Carcinoma through Transcriptome Analysis. Diagnostics (Basel) 2023; 13:diagnostics13050965. [PMID: 36900109 PMCID: PMC10001411 DOI: 10.3390/diagnostics13050965] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/16/2023] [Indexed: 03/06/2023] Open
Abstract
Cancer is one of the deadliest diseases developed through tumorigenesis and could be fatal if it reaches the metastatic phase. The novelty of the present investigation is to explore the prognostic biomarkers in hepatocellular carcinoma (HCC) that could develop glioblastoma multiforme (GBM) due to metastasis. The analysis was conducted using RNA-seq datasets for both HCC (PRJNA494560 and PRJNA347513) and GBM (PRJNA494560 and PRJNA414787) from Gene Expression Omnibus (GEO). This study identified 13 hub genes found to be overexpressed in both GBM and HCC. A promoter methylation study showed these genes to be hypomethylated. Validation through genetic alteration and missense mutations resulted in chromosomal instability, leading to improper chromosome segregation, causing aneuploidy. A 13-gene predictive model was obtained and validated using a KM plot. These hub genes could be prognostic biomarkers and potential therapeutic targets, inhibition of which could suppress tumorigenesis and metastasis.
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12
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Liu S, Morihiro K, Takeuchi F, Li Y, Okamoto A. Interstrand crosslinking oligonucleotides elucidate the effect of metal ions on the methylation status of repetitive DNA elements. Front Chem 2023; 11:1122474. [PMID: 36711237 PMCID: PMC9881727 DOI: 10.3389/fchem.2023.1122474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 01/02/2023] [Indexed: 01/15/2023] Open
Abstract
DNA methylation plays an important physiological function in cells, and environmental changes result in fluctuations in DNA methylation levels. Metal ions have become both environmental and health concerns, as they have the potential to disrupt the genomic DNA methylation status, even on specific sequences. In the current research, the methylation status of two typical repetitive DNA elements, i.e., long-interspersed nuclear element-1 (LINE-1) and alpha satellite (α-sat), was imaged and assessed using methylation-specific fluorescence in situ hybridization (MeFISH). This technique elucidated the effect of several metal ions on the methylation levels of repetitive DNA sequences. The upregulation and downregulation of the methylation levels of repetitive DNA elements by various metal ions were confirmed and depended on their concentration. This is the first example to investigate the effects of metal ions on DNA methylation in a sequence-specific manner.
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Affiliation(s)
- Shan Liu
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Kunihiko Morihiro
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Fumika Takeuchi
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Yufeng Li
- The Key Laboratory of Molecular Oncology of Hebei Province, Tangshan People’s Hospital, Tangshan, Hebei, China
| | - Akimitsu Okamoto
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan,*Correspondence: Akimitsu Okamoto,
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13
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Ukey S, Jain A, Dwivedi S, Vishnoi JR, Chugh A, Purohit P, Pareek P, Elhence P, Misra S, Sharma P. Global and promoter specific hypermethylation of tumor suppressor genes P16, SOCS1, and SHP1 in oral squamous cell carcinoma and oral submucous fibrosis. J Cancer Res Ther 2023; 19:S551-S559. [PMID: 38384018 DOI: 10.4103/jcrt.jcrt_689_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 07/04/2022] [Indexed: 02/23/2024]
Abstract
Aberrant methylation pattern leads to altered gene expression, that is, involved in the transformation of various cancers, including oral squamous cell carcinoma (OSCC). In the present study, an attempt has been made to examine the association of global and promoter-specific methylation of tumor suppressor genes in patients with OSCC and oral submucous fibrosis (OSMF). Promoter-specific methylation of tumor suppressor genes P16, SOCS1, and SHP1 had been studied earlier for their aberrant methylation patterns in other cancers; however, these studies were mainly conducted in-vitro or in animal models, and as such, only a few studies are available on human samples. In the present study evaluation of promoter-specific methylation of genes P16, SOCS1, and SHP1 in 76 patients' blood and tissue samples was done and compared with methylation of 35 healthy control samples using qPCR. Further, these samples were analyzed for global methylation patterns using ELISA. The results have shown a significant decreasing trend of promoter methylation (OSCC > OSMF > Controls); the methylation indices (MI) were significantly higher in OSCC than in the controls. The median MI of three genes for OSCC were P16MI (0.96), SHP1MI (0.79), and SOCS1 (0.80). Similarly, median MIs for OSMF were P16MI (0.18), SHP1 MI (0.19), and SOCS1 MI (0.5) against controls with MI (0) for each of the three genes. The global methylation %mC values were 1.9, 0.5, and 0.1, respectively. The values of MI and %mC were found to correlate with various risk factors such as tobacco, smoking, and alcohol consumption, which are positively involved in OSMF pathogenesis followed by oral cancer progression. Further, the methylation trend in tissue was reflected in blood samples, proving a window for methylation load to be used as a lesser invasive biomarker. The sensitivity and specificity of methylation load were also found reasonable. Therefore, the current study suggests that there may be a role of global and promoter-specific methylation load in the transition of OSMF to OSCC.
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Affiliation(s)
- Shweta Ukey
- All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Ankit Jain
- All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Shailendra Dwivedi
- All India Institute of Medical Sciences, Gorakhpur, Uttar Pradesh, India
| | | | - Ankita Chugh
- All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Purvi Purohit
- All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Puneet Pareek
- All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Poonam Elhence
- All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Sanjeev Misra
- All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Praveen Sharma
- All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
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14
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Nguyen HT, Khoa Huynh LA, Nguyen TV, Tran DH, Thu Tran TT, Khang Le ND, Le NAT, Pham TVN, Le MT, Quynh Pham TM, Nguyen TH, Van Nguyen TC, Nguyen TD, Tran Nguyen BQ, Phan MD, Giang H, Tran LS. Multimodal analysis of ctDNA methylation and fragmentomic profiles enhances detection of nonmetastatic colorectal cancer. Future Oncol 2022; 18:3895-3912. [PMID: 36524960 DOI: 10.2217/fon-2022-1041] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Aims: Early detection of colorectal cancer (CRC) provides substantially better survival rates. This study aimed to develop a blood-based screening assay named SPOT-MAS ('screen for the presence of tumor by DNA methylation and size') for early CRC detection with high accuracy. Methods: Plasma cell-free DNA samples from 159 patients with nonmetastatic CRC and 158 healthy controls were simultaneously analyzed for fragment length and methylation profiles. We then employed a deep neural network with fragment length and methylation signatures to build a classification model. Results: The model achieved an area under the curve of 0.989 and a sensitivity of 96.8% at 97% specificity in detecting CRC. External validation of our model showed comparable performance, with an area under the curve of 0.96. Conclusion: SPOT-MAS based on integration of cancer-specific methylation and fragmentomic signatures could provide high accuracy for early-stage CRC detection.
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Affiliation(s)
| | - Le Anh Khoa Huynh
- Medical Genetics Institute, Ho Chi Minh City, Vietnam.,Department of Biostatistics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA
| | | | - Duc Huy Tran
- University Medical Center, Ho Chi Minh City, Vietnam
| | - Thuy Thi Thu Tran
- Medical Genetics Institute, Ho Chi Minh City, Vietnam.,Gene Solutions, Ho Chi Minh City, Vietnam
| | - Nguyen Duy Khang Le
- Medical Genetics Institute, Ho Chi Minh City, Vietnam.,Gene Solutions, Ho Chi Minh City, Vietnam
| | | | | | - Minh-Triet Le
- University Medical Center, Ho Chi Minh City, Vietnam
| | - Thi Mong Quynh Pham
- Medical Genetics Institute, Ho Chi Minh City, Vietnam.,Gene Solutions, Ho Chi Minh City, Vietnam
| | - Trong Hieu Nguyen
- Medical Genetics Institute, Ho Chi Minh City, Vietnam.,Gene Solutions, Ho Chi Minh City, Vietnam
| | - Thien Chi Van Nguyen
- Medical Genetics Institute, Ho Chi Minh City, Vietnam.,Gene Solutions, Ho Chi Minh City, Vietnam
| | - Thanh Dat Nguyen
- Medical Genetics Institute, Ho Chi Minh City, Vietnam.,Gene Solutions, Ho Chi Minh City, Vietnam
| | - Bui Que Tran Nguyen
- Medical Genetics Institute, Ho Chi Minh City, Vietnam.,Gene Solutions, Ho Chi Minh City, Vietnam
| | - Minh-Duy Phan
- Medical Genetics Institute, Ho Chi Minh City, Vietnam.,Gene Solutions, Ho Chi Minh City, Vietnam
| | - Hoa Giang
- Medical Genetics Institute, Ho Chi Minh City, Vietnam.,Gene Solutions, Ho Chi Minh City, Vietnam
| | - Le Son Tran
- Medical Genetics Institute, Ho Chi Minh City, Vietnam.,Gene Solutions, Ho Chi Minh City, Vietnam
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15
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Szigeti KA, Kalmár A, Galamb O, Valcz G, Barták BK, Nagy ZB, Zsigrai S, Felletár I, V Patai Á, Micsik T, Papp M, Márkus E, Tulassay Z, Igaz P, Takács I, Molnár B. Global DNA hypomethylation of colorectal tumours detected in tissue and liquid biopsies may be related to decreased methyl-donor content. BMC Cancer 2022; 22:605. [PMID: 35655145 PMCID: PMC9164347 DOI: 10.1186/s12885-022-09659-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 05/03/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hypomethylation of long interspersed nuclear element 1 (LINE-1) is characteristic of various cancer types, including colorectal cancer (CRC). Malfunction of several factors or alteration of methyl-donor molecules' (folic acid and S-adenosylmethionine) availability can contribute to DNA methylation changes. Detection of epigenetic alterations in liquid biopsies can assist in the early recognition of CRC. Following the investigations of a Hungarian colon tissue sample set, our goal was to examine the LINE-1 methylation of blood samples along the colorectal adenoma-carcinoma sequence and in inflammatory bowel disease. Moreover, we aimed to explore the possible underlying mechanisms of global DNA hypomethylation formation on a multi-level aspect. METHODS LINE-1 methylation of colon tissue (n = 183) and plasma (n = 48) samples of healthy controls and patients with colorectal tumours were examined with bisulfite pyrosequencing. To investigate mRNA expression, microarray analysis results were reanalysed in silico (n = 60). Immunohistochemistry staining was used to validate DNA methyltransferases (DNMTs) and folate receptor beta (FOLR2) expression along with the determination of methyl-donor molecules' in situ level (n = 40). RESULTS Significantly decreased LINE-1 methylation level was observed in line with cancer progression both in tissue (adenoma: 72.7 ± 4.8%, and CRC: 69.7 ± 7.6% vs. normal: 77.5 ± 1.7%, p ≤ 0.01) and liquid biopsies (adenoma: 80.0 ± 1.7%, and CRC: 79.8 ± 1.3% vs. normal: 82.0 ± 2.0%, p ≤ 0.01). However, no significant changes were recognized in inflammatory bowel disease cases. According to in silico analysis of microarray data, altered mRNA levels of several DNA methylation-related enzymes were detected in tumours vs. healthy biopsies, namely one-carbon metabolism-related genes-which met our analysing criteria-showed upregulation, while FOLR2 was downregulated. Using immunohistochemistry, DNMTs, and FOLR2 expression were confirmed. Moreover, significantly diminished folic acid and S-adenosylmethionine levels were observed in parallel with decreasing 5-methylcytosine staining in tumours compared to normal adjacent to tumour tissues (p ≤ 0.05). CONCLUSION Our results suggest that LINE-1 hypomethylation may have a distinguishing value in precancerous stages compared to healthy samples in liquid biopsies. Furthermore, the reduction of global DNA methylation level could be linked to reduced methyl-donor availability with the contribution of decreased FOLR2 expression.
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Affiliation(s)
- Krisztina A Szigeti
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary.
| | - Alexandra Kalmár
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
- Molecular Medicine Research Group, Eötvös Loránd Research Network, 1083, Budapest, Hungary
| | - Orsolya Galamb
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
- Molecular Medicine Research Group, Eötvös Loránd Research Network, 1083, Budapest, Hungary
| | - Gábor Valcz
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
- Molecular Medicine Research Group, Eötvös Loránd Research Network, 1083, Budapest, Hungary
| | - Barbara K Barták
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
| | - Zsófia B Nagy
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
| | - Sára Zsigrai
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
| | - Ildikó Felletár
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
| | - Árpád V Patai
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, 1082, Budapest, Hungary
- Interdisciplinary Gastroenterology (IGA) Working Group, Semmelweis University, 1082, Budapest, Hungary
| | - Tamás Micsik
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085, Budapest, Hungary
| | - Márton Papp
- Centre for Bioinformatics, University of Veterinary Medicine Budapest, 1078, Budapest, Hungary
| | - Eszter Márkus
- Department of Anaesthesia and Intensive Care, Pest County Flor Ferenc Hospital, 2143, Kistarcsa, Hungary
| | - Zsolt Tulassay
- Molecular Medicine Research Group, Eötvös Loránd Research Network, 1083, Budapest, Hungary
- Department of Internal Medicine and Hematology, Faculty of Medicine, Semmelweis University, 1088, Budapest, Hungary
| | - Peter Igaz
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
- Molecular Medicine Research Group, Eötvös Loránd Research Network, 1083, Budapest, Hungary
- Department of Endocrinology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
| | - István Takács
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
| | - Béla Molnár
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
- Molecular Medicine Research Group, Eötvös Loránd Research Network, 1083, Budapest, Hungary
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16
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Lin W, Huang Z, Ping S, Zhang S, Wen X, He Y, Ren Y. Toxicological effects of atenolol and venlafaxine on zebrafish tissues: Bioaccumulation, DNA hypomethylation, and molecular mechanism. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 299:118898. [PMID: 35081461 DOI: 10.1016/j.envpol.2022.118898] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 01/02/2022] [Accepted: 01/22/2022] [Indexed: 06/14/2023]
Abstract
The beta-blocker atenolol (ATE), and the selective serotonin and norepinephrine reuptake inhibitor, venlafaxine (VEN) are frequently detected in municipal wastewater effluents, but little is known about their ecotoxicological effect on aquatic animals. Herein, ATE and VEN were selected to explore their accumulation and global DNA methylation (GDM) in zebrafish tissues after a 30-day exposure. Molecular dynamics (MD) stimulation was used to investigate the toxic mechanism of ATE and VEN exposure. The results demonstrated that ATE and VEN could reduce the condition factor of zebrafish. The bioaccumulation capacity for ATE and VEN was in the order of liver > gut > gill > brain and liver > gut > brain > gill, respectively. After a 30-day recovery, ATE and VEN could still be detected in zebrafish tissues when exposure concentrations were ≥10 μg/L. Moreover, ATE and VEN induced global DNA hypomethylation in different tissues with a dose-dependent manner and their main target tissues were liver and brain. When the exposure concentrations of ATE and VEN were increased to 100 μg/L, the global DNA hypomethylation of liver and brain were reduced to 27% and 18%, respectively. In the same tissue exposed to the same concentration, DNA hypomethylation induced by VEN was more serious than that of ATE. After a 30-day recovery, the global DNA hypomethylations caused by the two drugs were still persistent, and the recovery of VEN was slower than that of ATE. The MD simulation results showed that both ATE and VEN could reduce the catalytic activity of DNA Methyltransferase 1 (DNMT1), while the effect of VEN on the 3D conformational changes of the DNMT1 domain was more significant, resulting in a lower DNA methylation rate. The current study shed new light on the toxic mechanism and potential adverse impacts of ATE and VEN on zebrafish, providing essential information to the further ecotoxicological risk assessment of these drugs in the aquatic environment.
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Affiliation(s)
- Wenting Lin
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, PR China
| | - Zhishan Huang
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, PR China
| | - Senwen Ping
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, PR China
| | - Shuan Zhang
- School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, PR China
| | - Xiufang Wen
- School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, PR China
| | - Yuhe He
- School of Energy and Environment, City University of Hong Kong, Hong Kong, China
| | - Yuan Ren
- School of Environment and Energy, South China University of Technology, Guangzhou, 510006, PR China; The Key Lab of Pollution Control and Ecosystem Restoration in Industry Clusters, Ministry of Education, China; The Key Laboratory of Environmental Protection and Eco-Remediation of Guangdong Regular Higher Education Institutions, China.
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17
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Noro F, Marotta A, Bonaccio M, Costanzo S, Santonastaso F, Orlandi S, Tirozzi A, Parisi R, De Curtis A, Persichillo M, Gianfagna F, Di Castelnuovo A, Donati MB, Cerletti C, de Gaetano G, Iacoviello L, Gialluisi A, Izzi B. Fine-grained investigation of the relationship between human nutrition and global DNA methylation patterns. Eur J Nutr 2021; 61:1231-1243. [PMID: 34741648 DOI: 10.1007/s00394-021-02716-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 10/18/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE Nutrition is an important, modifiable, environmental factor affecting human health by modulating epigenetic processes, including DNA methylation (5mC). Numerous studies investigated the association of nutrition with global and gene-specific DNA methylation and evidences on animal models highlighted a role in DNA hydroxymethylation (5hmC) regulation. However, a more comprehensive analysis of different layers of nutrition in association with global levels of 5mC and 5hmC is lacking. We investigated the association between global levels of 5mC and 5hmC and human nutrition, through the stratification and analysis of dietary patterns into different nutritional layers: adherence to Mediterranean diet (MD), main food groups, macronutrients and micronutrients intake. METHODS ELISA technique was used to measure global 5mC and 5hmC levels in 1080 subjects from the Moli-sani cohort. Food intake during the 12 months before enrolment was assessed using the semi-quantitative EPIC food frequency questionnaire. Complementary approaches involving both classical statistics and supervised machine learning analyses were used to investigate the associations between global 5mC and 5hmC levels and adherence to Mediterranean diet, main food groups, macronutrients and micronutrients intake. RESULTS We found that global DNA methylation, but not hydroxymethylation, was associated with daily intake of zinc and vitamin B3. Random Forests algorithms predicting 5mC and 5hmC through intakes of food groups, macronutrients and micronutrients revealed a significant contribution of zinc, while vitamin B3 was reported among the most influential features. CONCLUSION We found that nutrition may affect global DNA methylation, suggesting a contribution of micronutrients previously implicated as cofactors in methylation pathways.
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Affiliation(s)
- Fabrizia Noro
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Annalisa Marotta
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Marialaura Bonaccio
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Simona Costanzo
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Federica Santonastaso
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Sabatino Orlandi
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Alfonsina Tirozzi
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Roberta Parisi
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Amalia De Curtis
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Mariarosaria Persichillo
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Francesco Gianfagna
- Mediterranea Cardiocentro, Naples, Italy.,Department of Medicine and Surgery, EPIMED Research Center, University of Insubria, Varese, Italy
| | | | - Maria Benedetta Donati
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Chiara Cerletti
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Giovanni de Gaetano
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Licia Iacoviello
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy. .,Department of Medicine and Surgery, EPIMED Research Center, University of Insubria, Varese, Italy.
| | - Alessandro Gialluisi
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
| | - Benedetta Izzi
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Via dell'Elettronica, 86077, Pozzilli, IS, Italy
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18
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Lee YR, Kim G, Lee HW, Tak WY, Park SY, Jang SY, Kweon YO, Park JG, Han YS, Chun JM, Han JR, Hur K. Long interspersed nuclear element-1 hypomethylation is associated with poor outcomes via the activation of ST18 in human hepatocellular carcinoma. Medicine (Baltimore) 2021; 100:e25552. [PMID: 33879706 PMCID: PMC8078304 DOI: 10.1097/md.0000000000025552] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 03/25/2021] [Indexed: 01/04/2023] Open
Abstract
The level of long interspersed nuclear element-1 (LINE-1) methylation, representing the global deoxyribonucleic acid methylation level, could contribute to the prognosis of cancer via the activation of oncogenes. This study was performed to evaluate the prognostic implications of LINE-1 hypomethylation in patients with hepatocellular carcinoma (HCC) and the possible mechanisms related to oncogene activation.Seventy-seven HCC patients between October 2014 and September 2015 were enrolled in this prospective study. Quantitative pyrosequencing was performed to assess the LINE-1 methylation level of HCC and matched non-HCC tissue samples. The expression of suppression of tumorigenicity 18 was measured by immunohistochemistry and its correlation with LINE-1 methylation levels was examined.LINE-1 was significantly hypomethylated in the HCC tissue compared with the matched nontumor tissue (64.0 ± 11.6% vs 75.6 ± 4.0%, P < .001). LINE-1 hypomethylation was an independent risk factor for overall survival (hazard ratio = 27.291, P = .032) and disease progression (hazard ratio = 5.298, P = .005). The expression of suppression of tumorigenicity 18 was higher in the hypomethylated LINE-1 HCC tissue than the hypermethylated LINE-1 tumor tissue (P = .030).LINE-1 hypomethylation may serve as a potential prognostic marker for patients with HCC.
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Affiliation(s)
- Yu Rim Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital
| | - Gyeonghwa Kim
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University
| | - Hye Won Lee
- Department of Pathology, Keimyung University School of Medicine
| | - Won Young Tak
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital
| | - Se Young Jang
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital
| | - Young Oh Kweon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital
| | - Jung Gil Park
- Department of Internal Medicine, College of Medicine, Yeungnam University
| | - Young Seok Han
- Department of Surgery, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
| | - Jae Min Chun
- Department of Surgery, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
| | - Ja Ryung Han
- Department of Surgery, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
| | - Keun Hur
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University
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19
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Martisova A, Holcakova J, Izadi N, Sebuyoya R, Hrstka R, Bartosik M. DNA Methylation in Solid Tumors: Functions and Methods of Detection. Int J Mol Sci 2021; 22:ijms22084247. [PMID: 33921911 PMCID: PMC8073724 DOI: 10.3390/ijms22084247] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/16/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
DNA methylation, i.e., addition of methyl group to 5′-carbon of cytosine residues in CpG dinucleotides, is an important epigenetic modification regulating gene expression, and thus implied in many cellular processes. Deregulation of DNA methylation is strongly associated with onset of various diseases, including cancer. Here, we review how DNA methylation affects carcinogenesis process and give examples of solid tumors where aberrant DNA methylation is often present. We explain principles of methods developed for DNA methylation analysis at both single gene and whole genome level, based on (i) sodium bisulfite conversion, (ii) methylation-sensitive restriction enzymes, and (iii) interactions of 5-methylcytosine (5mC) with methyl-binding proteins or antibodies against 5mC. In addition to standard methods, we describe recent advances in next generation sequencing technologies applied to DNA methylation analysis, as well as in development of biosensors that represent their cheaper and faster alternatives. Most importantly, we highlight not only advantages, but also disadvantages and challenges of each method.
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20
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Szu J, Wojcinski A, Jiang P, Kesari S. Impact of the Olig Family on Neurodevelopmental Disorders. Front Neurosci 2021; 15:659601. [PMID: 33859549 PMCID: PMC8042229 DOI: 10.3389/fnins.2021.659601] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 03/08/2021] [Indexed: 12/13/2022] Open
Abstract
The Olig genes encode members of the basic helix-loop-helix (bHLH) family of transcription factors. Olig1, Olig2, and Olig3 are expressed in both the developing and mature central nervous system (CNS) and strictly regulate cellular specification and differentiation. Extensive studies have established functional roles of Olig1 and Olig2 in directing neuronal and glial formation during different stages in development. Recently, Olig2 overexpression was implicated in neurodevelopmental disorders down syndrome (DS) and autism spectrum disorder (ASD) but its influence on cognitive and intellectual defects remains unknown. In this review, we summarize the biological functions of the Olig family and how it uniquely promotes cellular diversity in the CNS. This is followed up with a discussion on how abnormal Olig2 expression impacts brain development and function in DS and ASD. Collectively, the studies described here emphasize vital features of the Olig members and their distinctive potential roles in neurodevelopmental disease states.
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Affiliation(s)
- Jenny Szu
- Department of Translational Neurosciences and Neurotherapeutics, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, United States
| | - Alexandre Wojcinski
- Department of Translational Neurosciences and Neurotherapeutics, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, United States
| | - Peng Jiang
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
| | - Santosh Kesari
- Department of Translational Neurosciences and Neurotherapeutics, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, United States.,Pacific Neuroscience Institute, Providence Saint John's Health Center, Santa Monica, CA, United States
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21
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Conconi D, Redaelli S, Lissoni AA, Cilibrasi C, Perego P, Gautiero E, Sala E, Paderno M, Dalprà L, Landoni F, Lavitrano M, Roversi G, Bentivegna A. Genomic and Epigenomic Profile of Uterine Smooth Muscle Tumors of Uncertain Malignant Potential (STUMPs) Revealed Similarities and Differences with Leiomyomas and Leiomyosarcomas. Int J Mol Sci 2021; 22:1580. [PMID: 33557274 PMCID: PMC7914585 DOI: 10.3390/ijms22041580] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/24/2021] [Accepted: 02/01/2021] [Indexed: 01/20/2023] Open
Abstract
Uterine smooth muscle tumors of uncertain malignant potential (STUMPs) represent a heterogeneous group of tumors that cannot be histologically diagnosed as unequivocally benign or malignant. For this reason, many authors are working to obtain a better definition of diagnostic and prognostic criteria. In this work, we analyzed the genomic and epigenomic profile of uterine smooth muscle tumors (USMTs) in order to find similarities and differences between STUMPs, leiomyosarcomas (LMSs) and leiomyomas (LMs), and possibly identify prognostic factors in this group of tumors. Array-CGH data on 23 USMTs demonstrated the presence of a more similar genomic profile between STUMPs and LMSs. Some genes, such as PRKDC and PUM2, with a potential prognostic value, were never previously associated with STUMP. The methylation data appears to be very promising, especially with regards to the divergent profile found in the sample that relapsed, characterized by an overall CGI hypomethylation. Finally, the Gene Ontology analysis highlighted some cancer genes that could play a pivotal role in the unexpected aggressive behavior that can be found in some of these tumors. These genes could prove to be prognostic markers in the future.
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Affiliation(s)
- Donatella Conconi
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (A.A.L.); (M.P.); (L.D.); (F.L.); (M.L.); (G.R.)
| | - Serena Redaelli
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (A.A.L.); (M.P.); (L.D.); (F.L.); (M.L.); (G.R.)
| | - Andrea Alberto Lissoni
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (A.A.L.); (M.P.); (L.D.); (F.L.); (M.L.); (G.R.)
- Clinic of Obstetrics and Gynecology, San Gerardo Hospital, 20900 Monza, Italy
| | - Chiara Cilibrasi
- Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK;
| | - Patrizia Perego
- Division of Pathology, San Gerardo Hospital, 20900 Monza, Italy;
| | - Eugenio Gautiero
- Medical Genetics Laboratory, San Gerardo Hospital, 20900 Monza, Italy; (E.G.); (E.S.)
| | - Elena Sala
- Medical Genetics Laboratory, San Gerardo Hospital, 20900 Monza, Italy; (E.G.); (E.S.)
| | - Mariachiara Paderno
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (A.A.L.); (M.P.); (L.D.); (F.L.); (M.L.); (G.R.)
- Clinic of Obstetrics and Gynecology, San Gerardo Hospital, 20900 Monza, Italy
| | - Leda Dalprà
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (A.A.L.); (M.P.); (L.D.); (F.L.); (M.L.); (G.R.)
| | - Fabio Landoni
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (A.A.L.); (M.P.); (L.D.); (F.L.); (M.L.); (G.R.)
- Clinic of Obstetrics and Gynecology, San Gerardo Hospital, 20900 Monza, Italy
| | - Marialuisa Lavitrano
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (A.A.L.); (M.P.); (L.D.); (F.L.); (M.L.); (G.R.)
| | - Gaia Roversi
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (A.A.L.); (M.P.); (L.D.); (F.L.); (M.L.); (G.R.)
- Medical Genetics Laboratory, San Gerardo Hospital, 20900 Monza, Italy; (E.G.); (E.S.)
| | - Angela Bentivegna
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (S.R.); (A.A.L.); (M.P.); (L.D.); (F.L.); (M.L.); (G.R.)
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22
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Belli M, Indovina L. The Response of Living Organisms to Low Radiation Environment and Its Implications in Radiation Protection. Front Public Health 2020; 8:601711. [PMID: 33384980 PMCID: PMC7770185 DOI: 10.3389/fpubh.2020.601711] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 11/25/2020] [Indexed: 12/12/2022] Open
Abstract
Life has evolved on Earth for about 4 billion years in the presence of the natural background of ionizing radiation. It is extremely likely that it contributed, and still contributes, to shaping present form of life. Today the natural background radiation is extremely small (few mSv/y), however it may be significant enough for living organisms to respond to it, perhaps keeping memory of this exposure. A better understanding of this response is relevant not only for improving our knowledge on life evolution, but also for assessing the robustness of the present radiation protection system at low doses, such as those typically encountered in everyday life. Given the large uncertainties in epidemiological data below 100 mSv, quantitative evaluation of these health risk is currently obtained with the aid of radiobiological models. These predict a health detriment, caused by radiation-induced genetic mutations, linearly related to the dose. However a number of studies challenged this paradigm by demonstrating the occurrence of non-linear responses at low doses, and of radioinduced epigenetic effects, i.e., heritable changes in genes expression not related to changes in DNA sequence. This review is focused on the role that epigenetic mechanisms, besides the genetic ones, can have in the responses to low dose and protracted exposures, particularly to natural background radiation. Many lines of evidence show that epigenetic modifications are involved in non-linear responses relevant to low doses, such as non-targeted effects and adaptive response, and that genetic and epigenetic effects share, in part, a common origin: the reactive oxygen species generated by ionizing radiation. Cell response to low doses of ionizing radiation appears more complex than that assumed for radiation protection purposes and that it is not always detrimental. Experiments conducted in underground laboratories with very low background radiation have even suggested positive effects of this background. Studying the changes occurring in various living organisms at reduced radiation background, besides giving information on the life evolution, have opened a new avenue to answer whether low doses are detrimental or beneficial, and to understand the relevance of radiobiological results to radiation protection.
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Affiliation(s)
| | - Luca Indovina
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
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23
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An introduction to EpiPol (Epigenetic affecting Polymorphism) concept with an in silico identification of CpG-affecting SNPs in the upstream regulatory sequences of human AHR gene. Meta Gene 2020. [DOI: 10.1016/j.mgene.2020.100805] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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24
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Shademan M, Zare K, Zahedi M, Mosannen Mozaffari H, Bagheri Hosseini H, Ghaffarzadegan K, Goshayeshi L, Dehghani H. Promoter methylation, transcription, and retrotransposition of LINE-1 in colorectal adenomas and adenocarcinomas. Cancer Cell Int 2020; 20:426. [PMID: 32905102 PMCID: PMC7466817 DOI: 10.1186/s12935-020-01511-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 08/21/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The methylation of the CpG islands of the LINE-1 promoter is a tight control mechanism on the function of mobile elements. However, simultaneous quantification of promoter methylation and transcription of LINE-1 has not been performed in progressive stages of colorectal cancer. In addition, the insertion of mobile elements in the genome of advanced adenoma stage, a precancerous stage before colorectal carcinoma has not been emphasized. In this study, we quantify promoter methylation and transcripts of LINE-1 in three stages of colorectal non-advanced adenoma, advanced adenoma, and adenocarcinoma. In addition, we analyze the insertion of LINE-1, Alu, and SVA elements in the genome of patient tumors with colorectal advanced adenomas. METHODS LINE-1 hypomethylation status was evaluated by absolute quantitative analysis of methylated alleles (AQAMA) assay. To quantify the level of transcripts for LINE-1, quantitative RT-PCR was performed. To find mobile element insertions, the advanced adenoma tissue samples were subjected to whole genome sequencing and MELT analysis. RESULTS We found that the LINE-1 promoter methylation in advanced adenoma and adenocarcinoma was significantly lower than that in non-advanced adenomas. Accordingly, the copy number of LINE-1 transcripts in advanced adenoma was significantly higher than that in non-advanced adenomas, and in adenocarcinomas was significantly higher than that in the advanced adenomas. Whole-genome sequencing analysis of colorectal advanced adenomas revealed that at this stage polymorphic insertions of LINE-1, Alu, and SVA comprise approximately 16%, 51%, and 74% of total insertions, respectively. CONCLUSIONS Our correlative analysis showing a decreased methylation of LINE-1 promoter accompanied by the higher level of LINE-1 transcription, and polymorphic genomic insertions in advanced adenoma, suggests that the early and advanced polyp stages may host very important pathogenic processes concluding to cancer.
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Affiliation(s)
- Milad Shademan
- Graduate Program in Physiology, Department of Basic Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Khadijeh Zare
- Stem Cell Biology and Regenerative Medicine Research Group, Research Institute of Biotechnology, Ferdowsi University of Mashhad, Azadi Square, Mashhad, 91779-48974 Iran
| | - Morteza Zahedi
- Graduate Program in Physiology, Department of Basic Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Hooman Mosannen Mozaffari
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Gastroenterology and Hepatology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hadi Bagheri Hosseini
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Gastroenterology and Hepatology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Kamran Ghaffarzadegan
- Pathology Department, Education and Research Department, Razavi Hospital, Mashhad, Iran
| | - Ladan Goshayeshi
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hesam Dehghani
- Stem Cell Biology and Regenerative Medicine Research Group, Research Institute of Biotechnology, Ferdowsi University of Mashhad, Azadi Square, Mashhad, 91779-48974 Iran
- Division of Biotechnology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
- Department of Basic Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
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25
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Ionizing Radiation-Induced Epigenetic Modifications and Their Relevance to Radiation Protection. Int J Mol Sci 2020; 21:ijms21175993. [PMID: 32825382 PMCID: PMC7503247 DOI: 10.3390/ijms21175993] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/15/2020] [Accepted: 08/17/2020] [Indexed: 12/12/2022] Open
Abstract
The present system of radiation protection assumes that exposure at low doses and/or low dose-rates leads to health risks linearly related to the dose. They are evaluated by a combination of epidemiological data and radiobiological models. The latter imply that radiation induces deleterious effects via genetic mutation caused by DNA damage with a linear dose-dependence. This picture is challenged by the observation of radiation-induced epigenetic effects (changes in gene expression without altering the DNA sequence) and of non-linear responses, such as non-targeted and adaptive responses, that in turn can be controlled by gene expression networks. Here, we review important aspects of the biological response to ionizing radiation in which epigenetic mechanisms are, or could be, involved, focusing on the possible implications to the low dose issue in radiation protection. We examine in particular radiation-induced cancer, non-cancer diseases and transgenerational (hereditary) effects. We conclude that more realistic models of radiation-induced cancer should include epigenetic contribution, particularly in the initiation and progression phases, while the impact on hereditary risk evaluation is expected to be low. Epigenetic effects are also relevant in the dispute about possible "beneficial" effects at low dose and/or low dose-rate exposures, including those given by the natural background radiation.
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Zeggar HR, How-Kit A, Daunay A, Bettaieb I, Sahbatou M, Rahal K, Adouni O, Gammoudi A, Douik H, Deleuze JF, Kharrat M. Tumor DNA hypomethylation of LINE-1 is associated with low tumor grade of breast cancer in Tunisian patients. Oncol Lett 2020; 20:1999-2006. [PMID: 32724446 PMCID: PMC7377197 DOI: 10.3892/ol.2020.11745] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 05/19/2020] [Indexed: 12/24/2022] Open
Abstract
DNA hypomethylation of long interspersed repetitive DNA retrotransposon (LINE-1) and Alu repeats elements of short interspersed elements family (SINEs) is an early event in carcinogenesis that causes transcriptional activation and leads to chromosomal instability. In the current study, DNA methylation levels of LINE-1 and Alu repeats were analyzed in tumoral tissues of invasive breast cancer in a Tunisian cohort and its association with the clinicopathological features of patients was defined. DNA methylation of LINE-1 and Alu repeats were analyzed using pyrosequencing in 61 invasive breast cancers. Median values observed for DNA methylation of LINE-1 and Alu repeats were considered as the cut-off (59.81 and 18.49%, respectively). The results of the current study demonstrated a positive correlation between DNA methylation levels of LINE-1 and Alu repeats (rho=0.284; P<0.03). DNA hypomethylation of LINE-1 was also indicated to be associated with low grade (P=0.023). To the best of our knowledge, the current study is the first study regarding DNA methylation of LINE-1 and Alu repeats element in breast cancer of the Tunisian population. The results of the current study suggest that, since hypomethylation of LINE-1 is associated with low grade, it could be used as a biomarker for prognosis for patients with breast cancer.
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Affiliation(s)
- Hayet Radia Zeggar
- University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES10 Human Genetics Laboratory, 1007 Tunis, Tunisia
| | - Alexandre How-Kit
- Laboratoire de Génomique, Fondation Jean Dausset-CEPH, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France
| | - Antoine Daunay
- Laboratoire de Génomique, Fondation Jean Dausset-CEPH, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France
| | - Ilhem Bettaieb
- Department of Immunohistocytology, Salah Azaïz Cancer Institute, 1006 Tunis, Tunisia
| | - Mourad Sahbatou
- Laboratoire de Biostatistique, Fondation Jean Dausset-CEPH, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France
| | - Khaled Rahal
- Service de Chirurgie Carcinologique, Institut Salah Azaiz de Tunis, 1006 Tunis, Tunisia
| | - Olfa Adouni
- Department of Immunohistocytology, Salah Azaïz Cancer Institute, 1006 Tunis, Tunisia
| | - Amor Gammoudi
- Department of Immunohistocytology, Salah Azaïz Cancer Institute, 1006 Tunis, Tunisia
| | - Hayet Douik
- University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES10 Human Genetics Laboratory, 1007 Tunis, Tunisia
| | - Jean-François Deleuze
- Laboratoire de Génomique, Fondation Jean Dausset-CEPH, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France
- Centre National de Recherche en Génomique Humaine, CEA, Le Commissariat à l'énergie atomique et aux énergies alternatives-Institut François Jacob, 92265 Evry, France
| | - Maher Kharrat
- University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES10 Human Genetics Laboratory, 1007 Tunis, Tunisia
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Kaur G, Batra S. Regulation of DNA methylation signatures on NF-κB and STAT3 pathway genes and TET activity in cigarette smoke extract-challenged cells/COPD exacerbation model in vitro. Cell Biol Toxicol 2020; 36:459-480. [PMID: 32342329 DOI: 10.1007/s10565-020-09522-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 03/19/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) is a global health problem. Currently, there is a lack of knowledge about the pathobiology of this disease and available therapies are ineffective. Cigarette smoking is the leading cause of COPD; however, not all smokers develop COPD. Exacerbations of COPD caused by microbes are common and detrimental. Approximately 20-50% of patient exacerbations are caused by bacterial colonization in the lower airways. It is generally accepted that epigenetic mechanisms, especially DNA methylation, play an important role during progression of COPD. Thus, we hypothesized that DNA methylation patterns vary significantly following smoke exposure and during exacerbations caused by bacterial infections. To test our hypothesis, we used an in vitro study model that mimics COPD exacerbations and performed extensive studies to understand the role of CpG promoter methylation of NF-κB and STAT3-mediated pathway genes. Both NF-κB and STAT3 transcription factors play critical roles in orchestrating inflammatory responses during cigarette smoke exposure. In brief, human lung adenocarcinoma cells with type II alveolar epithelium characteristics (A549) were challenged with cigarette smoke extract (CSE) or DMSO (control) followed by a 3-h challenge with bacterial lipopolysaccharide (LPS; from Pseudomonas aeruginosa) prior to the termination of CSE exposure (COPD exacerbation group). The production of cytokines/chemokines, regulation of transcription factors, and DNA methylation of specific genes were then assessed. We also studied changes in the expression and activity of ten-eleven translocases (TETs), the enzymes responsible for DNA demethylation, and assessed their role in regulating DNA methylation in the CSE-challenged group. RESULTS There was a significant increase in the release of cytokines/chemokines (IL-8, MCP-1, IL-6 and CCL5) in the COPD exacerbation group as compared to the control group. Hypomethylation of NF-κB-mediated pathway genes correlated with their induction in our COPD exacerbation study model. Further, we observed an important role of TET1/2 in regulating the DNA methylation of NF-κB, STAT3, IKK, and NIK genes and cytokine/chemokine production by A549 cells during CSE challenge. CONCLUSIONS Studies to further define the role of TETs in CSE-mediated epigenetic regulation may lead to the development of better and more effective therapeutic intervention strategies for COPD.
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Affiliation(s)
- Gagandeep Kaur
- Laboratory of Pulmonary Immunotoxicology, Department of Environmental Toxicology, Southern University and A&M College, Baton Rouge, LA, 70813, USA
| | - Sanjay Batra
- Laboratory of Pulmonary Immunotoxicology, Department of Environmental Toxicology, Southern University and A&M College, Baton Rouge, LA, 70813, USA.
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Moradi Sarabi M, Mohammadrezaei Khorramabadi R, Zare Z, Eftekhar E. Polyunsaturated fatty acids and DNA methylation in colorectal cancer. World J Clin Cases 2019; 7:4172-4185. [PMID: 31911898 PMCID: PMC6940323 DOI: 10.12998/wjcc.v7.i24.4172] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 11/27/2019] [Accepted: 12/13/2019] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) has been designated a major global problem, especially due to its high prevalence in developed countries. CRC mostly occurs sporadically (75%-80%), and only 20%-25% of patients have a family history. Several processes are involved in the development of CRC such as a combination of genetic and epigenetic alterations. Epigenetic changes, including DNA methylation play a vital role in the progression of CRC. Complex interactions between susceptibility genes and environmental factors, such as a diet and sedentary lifestyle, lead to the development of CRC. Clinical and experimental studies have confirmed the beneficial effects of dietary polyunsaturated fatty acids (PUFAs) in preventing CRC. From a mechanistic viewpoint, it has been suggested that PUFAs are pleiotropic agents that alter chromatin remodeling, membrane structure and downstream cell signaling. Moreover, PUFAs can alter the epigenome via modulation of DNA methylation. In this review, we summarize recent investigations linking PUFAs and DNA methylation-associated CRC risk.
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Affiliation(s)
- Mostafa Moradi Sarabi
- Department of Biochemistry and Genetics, School of Medicine, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran
| | - Reza Mohammadrezaei Khorramabadi
- Department of Biochemistry and Genetics, School of Medicine, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran
| | - Zohre Zare
- Department of Pharmaceutics, School of Pharmacy, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran
| | - Ebrahim Eftekhar
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
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29
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Seif EA, Diab IH, Ibrahim SA, Hussein HA, Ghitani SA. Association between different parameters of child maltreatment and global DNA methylation. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1080/20905068.2019.1681178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Affiliation(s)
- Eman A Seif
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Iman H Diab
- department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Soha A Ibrahim
- department of Psychiatry, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Heba A Hussein
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Sara A Ghitani
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
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30
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Pasha HA, Rezk NA, Riad MA. Circulating Cell Free Nuclear DNA, Mitochondrial DNA and Global DNA Methylation: Potential Noninvasive Biomarkers for Breast Cancer Diagnosis. Cancer Invest 2019; 37:432-439. [PMID: 31516038 DOI: 10.1080/07357907.2019.1663864] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Eighty seven women with benign breast lesion, 120 patients with breast cancer (BC) and one hundred controls were included in the study. Quantification of mtDNA and nDNA was done by qPCR. Global DNA methylation was measured using ELISA. Circulating cell-free nDNA and mtDNA were significantly elevated in BC and benign breast lesions patients. Global methylation was significantly low in BC patients. Combining the studied parameters in one panel, nDNA/mtDNA/hypomethylation, improved their sensitivity in detecting BC to reach 92.5%. Circulating cell-free nDNA, mtDNA and global DNA hypomethylation can be used as diagnostic and prognostic markers for BC.
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Affiliation(s)
- Heba A Pasha
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University , Zagazig , Egypt
| | - Noha A Rezk
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University , Zagazig , Egypt
| | - Mohamed A Riad
- Surgery Department, Faculty of Medicine, Zagazig University , Zagazig , Egypt
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Liu C, Fennell LJ, Bettington ML, Walker NI, Dwine J, Leggett BA, Whitehall VLJ. DNA methylation changes that precede onset of dysplasia in advanced sessile serrated adenomas. Clin Epigenetics 2019; 11:90. [PMID: 31200767 PMCID: PMC6570920 DOI: 10.1186/s13148-019-0691-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 06/04/2019] [Indexed: 12/31/2022] Open
Abstract
Background Sessile serrated adenomas (SSAs) are common polyps which give rise to 20–30% of colorectal cancer (CRC). SSAs display clinicopathologic features which present challenges in surveillance, including overrepresentation in young patients, proclivity for the proximal colon and rarity of histologic dysplasia (referred to then as SSAs with dysplasia, SSADs). Once dysplasia develops, there is rapid progression to CRC, even at a small size. There is therefore a clinical need to separate the “advanced” SSAs at high risk of progression to SSAD and cancer from ordinary SSAs. Since SSAs are known to accumulate methylation over time prior to the development of dysplasia, SSAD backgrounds (the remnant SSA present within an SSAD) likely harbour additional methylation events compared with ordinary SSAs. We therefore performed MethyLight and comprehensive methylation array (Illumina MethylationEPIC) on 40 SSAD backgrounds and 40 matched ordinary SSAs, and compared the methylation results with CRC methylation, CRC expression and immunohistochemical data. Results SSAD backgrounds demonstrated significant hypermethylation of CpG islands compared with ordinary SSAs, and the proportion of hypermethylated probes decreased progressively in the shore, shelf and open sea regions. Hypomethylation occurred in concert with hypermethylation, which showed a reverse pattern, increasing progressively away from the island regions. These methylation changes were also identified in BRAF-mutant hypermethylated CRCs. When compared with CRC expression data, SV2B, MLH1/EPM2AIP1, C16orf62, RCOR3, BAIAP3, OGDHL, HDHD3 and ATP1B2 demonstrated both promoter hypermethylation and decreased expression. Although SSAD backgrounds were histologically indistinguishable from ordinary SSAs, MLH1 methylation was detectable via MethyLight in 62.9% of SSAD backgrounds, and focal immunohistochemical MLH1 loss was seen in 52.5% of SSAD backgrounds. Conclusions Significant hyper- and hypomethylation events occur during SSA progression well before the development of histologically identifiable changes. Methylation is a heterogeneous process within individual SSAs, as typified by MLH1, where both MLH1 methylation and focal immunohistochemical MLH1 loss can be seen in the absence of dysplasia. This heterogeneity is likely a generalised phenomenon and should be taken into account in future methylation-based studies and the development of clinical methylation panels. Electronic supplementary material The online version of this article (10.1186/s13148-019-0691-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Cheng Liu
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia. .,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia. .,Envoi Specialist Pathologists, Brisbane, QLD, Australia.
| | - Lochlan J Fennell
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Mark L Bettington
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Neal I Walker
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Joel Dwine
- Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Barbara A Leggett
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | - Vicki L J Whitehall
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Department of Chemical Pathology, Pathology Queensland, Brisbane, QLD, Australia
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Wanchai V, Jin J, Bircan E, Eng C, Orloff M. Genome-wide tracts of homozygosity and exome analyses reveal repetitive elements with Barrets esophagus/esophageal adenocarcinoma risk. BMC Bioinformatics 2019; 20:98. [PMID: 30871476 PMCID: PMC6419328 DOI: 10.1186/s12859-019-2622-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Barrett's esophagus (BE) is most commonly seen as the condition in which the normal squamous epithelium lining of the esophagus is replaced by goblet cells. Many studies show that BE is a predisposing factor for the development of esophageal adenocarcinoma (EAC), a particularly lethal cancer. The use of single nucleotide polymorphisms (SNPs) to map BE/EAC genes has previously provided insufficient genetic information to fully characterize the heterogeneous nature of the disease. We therefore hypothesize that rigorous interrogation of other types of genomic changes, e.g. tracts of homozygosity (TOH), repetitive elements, and insertion/deletions, may provide a comprehensive understanding of the development of BE/EAC. RESULTS First, we used a case-control framework to identify TOHs by using SNPs and tested for association with BE/EAC. Second, we used a case only approach on a validation series of eight samples subjected to exome sequencing to identify repeat elements and insertion/deletions. Third, insertion/deletions and repeat elements identified in the exomes were then mapped onto genes in the significant TOH regions. Overall, 24 TOH regions were significantly differentially represented among cases, as compared to controls (adjusted-P = 0.002-0.039). Interestingly, four BE/EAC-associated genes within the TOH regions consistently showed insertions and deletions that overlapped across eight exomes. Predictive functional analysis identified NOTCH, WNT, and G-protein inflammation pathways that affect BE and EAC. CONCLUSIONS The integration of common TOHs (cTOHs) with repetitive elements, insertions, and deletions within exomes can help functionally prioritize factors contributing to low to moderate penetrance predisposition to BE/EAC.
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Affiliation(s)
- Visanu Wanchai
- Arkansas Center for Genomic Epidemiology & Medicine and The Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Jing Jin
- The Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Emine Bircan
- The Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Charis Eng
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195 USA
| | - Mohammed Orloff
- The Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
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Mahmood N, Rabbani SA. Targeting DNA Hypomethylation in Malignancy by Epigenetic Therapies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1164:179-196. [PMID: 31576549 DOI: 10.1007/978-3-030-22254-3_14] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
DNA methylation is a chemically reversible epigenetic modification that regulates the chromatin structure and gene expression, and thereby takes part in various cellular processes like embryogenesis, genomic imprinting, X-chromosome inactivation, and genome stability. Alterations in the normal methylation levels of DNA may contribute to the development of pathological conditions like cancer. Even though both hypo- and hypermethylation-mediated abnormalities are prevalent in the cancer genome, the field of cancer epigenetics has been more focused on targeting hypermethylation. As a result, DNA hypomethylation-mediated abnormalities remained relatively less explored, and currently, there are no approved drugs that can be clinically used to target hypomethylation. Understanding the precise role of DNA hypomethylation is not only crucial from a mechanistic point of view but also for the development of pharmacological agents that can reverse the hypomethylated state of the DNA. This chapter focuses on the causes and impact of DNA hypomethylation in the development of cancer and describes the possible ways to pharmacologically target it, especially by using a naturally occurring physiologic agent S-adenosylmethionine (SAM).
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Affiliation(s)
- Niaz Mahmood
- Department of Medicine, McGill University Health Centre, Montréal, QC, Canada
| | - Shafaat A Rabbani
- Department of Medicine, McGill University Health Centre, Montréal, QC, Canada.
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Li S, Yang Q, Hou Y, Jiang T, Zong L, Wang Z, Luo X, Liang W, Zhao H, Ning Y, Zhao C. Hypomethylation of LINE-1 elements in schizophrenia and bipolar disorder. J Psychiatr Res 2018; 107:68-72. [PMID: 30326341 DOI: 10.1016/j.jpsychires.2018.10.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/01/2018] [Accepted: 10/08/2018] [Indexed: 01/08/2023]
Abstract
Schizophrenia (SCZ) and bipolar disorder (BPD) are severe mental illnesses with evidence of significant genetic and environmental etiological elements in their complex etiologies. 5'-Methylcytosine is the main epigenetic DNA modification that mediates the interplay between genetic and environmental components. In humans, most 5'-methylcytosine modifications are observed in CpG-rich regions within the long interspersed nuclear element (LINE-1). LINE-1 is a mobile retrotransposon that comprises ∼17% of the human genome, and its methylation levels are highly correlated with global DNA methylation levels. LINE-1 insertions are also reported to be mental illnesses-associated genomic risk factors. To examine the LINE-1 methylation levels in SCZ and BPD, this study employed a bisulfite conversion-specific one-label extension (BS-OLE) method to detect the methylation levels at three CpG sites (S1, S2 and S3) of LINE-1 in peripheral blood DNA from a Han Chinese cohort composed of 92 SCZ patients, 99 BPD patients and 92 controls (CON). The results showed a decreased S1 methylation level in SCZ, decreased S2 methylation level in BPD and decreased S3 methylation levels in both SCZ and BPD relative to those of the CON. A female-dependent positive correlation of the S3 methylation level with age in CON became non-significant in both SCZ and BPD. These findings demonstrated that LINE-1 methylation varied with development and disease status. The roles of LINE-1 methylation in the pathogenesis of SCZ and BPD remain to be elucidated.
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Affiliation(s)
- Shufen Li
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Qiong Yang
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, Guangdong, China
| | - Yu Hou
- Department of Pediatric Neurology, Affiliated BaYi Children's Hospital, PLA Army General Hospital, Beijing, China
| | - Tingyun Jiang
- The Third People's Hospital of Zhongshan, Zhongshan, Guangdong, China
| | - Lu Zong
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhongju Wang
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Xia Luo
- Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Wenquan Liang
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Hu Zhao
- Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
| | - Yuping Ning
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, Guangdong, China.
| | - Cunyou Zhao
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, Guangdong, China.
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Kerachian MA, Kerachian M. Long interspersed nucleotide element-1 (LINE-1) methylation in colorectal cancer. Clin Chim Acta 2018; 488:209-214. [PMID: 30445031 DOI: 10.1016/j.cca.2018.11.018] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 11/11/2018] [Accepted: 11/12/2018] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) represents a group of molecularly heterogeneous diseases characterized by genetic and epigenetic alterations. Long interspersed nuclear elements (LINEs) are a form of retrotransposable element found in many eukaryotic genomes. These LINEs, when active, can mobilize in the cell and steadily cause genomic rearrangement. Active LINE reorganization is a source of endogenous mutagenesis and polymorphism in the cell that brings about individual genomic variation. In normal somatic cells, these elements are heavily methylated and thus mostly suppressed, in turn, preventing their potential for bringing about genomic instability. When LINEs are inadequately controlled, they can play a role in the pathogenesis of several genetic diseases, such as cancer. In tumor cells, LINE hypomethylation can reactivate the mobilization of these elements and is associated with both an advanced stage and a poor prognosis. In this article, we summarize the current knowledge surrounding LINE methylation, its correlation to CRC and its application as a diagnostic, prognostic and predictive biomarker in colon cancer.
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Affiliation(s)
- Mohammad Amin Kerachian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.; Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Cancer Genetics Research Unit, Reza Radiotherapy and Oncology Center, Mashhad, Iran.
| | - Matin Kerachian
- Faculty of Medicine, McGill University, Montreal, Canada; Research Institute at McGill University Health Center, Montreal, Canada
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Bronkhorst AJ, Wentzel JF, Ungerer V, Peters DL, Aucamp J, de Villiers EP, Holdenrieder S, Pretorius PJ. Sequence analysis of cell-free DNA derived from cultured human bone osteosarcoma (143B) cells. Tumour Biol 2018; 40:1010428318801190. [PMID: 30261820 DOI: 10.1177/1010428318801190] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The true importance of cell-free DNA in human biology, together with the potential scale of its clinical utility, is tarnished by a lack of understanding of its composition and origin. In investigating the cell-free DNA present in the growth medium of cultured 143B cells, we previously demonstrated that the majority of cell-free DNA is neither a product of apoptosis nor necrosis. In the present study, we investigated the composition and origin of this cell-free DNA population using next-generation sequencing. We found that the cell-free DNA comprises mainly of repetitive DNA, including α-satellite DNA, mini satellites, and transposons that are currently active or exhibit the capacity to become reactivated. A significant portion of these cell-free DNA fragments originates from specific chromosomes, especially chromosomes 1 and 9. In healthy adult somatic cells, the centromeric and pericentromeric regions of these chromosomes are normally densely methylated. However, in many cancer types, these regions are preferentially hypomethylated. This can lead to double-stranded DNA breaks or it can directly impair the formation of proper kinetochore structures. This type of chromosomal instability is a precursor to the formation of nuclear anomalies, including lagging chromosomes and anaphase bridges. DNA fragments derived from these structures can recruit their own nuclear envelope and form secondary nuclear structures known as micronuclei, which can localize to the nuclear periphery and bud out from the membrane. We postulate that the majority of cell-free DNA present in the growth medium of cultured 143B cells originates from these micronuclei.
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Affiliation(s)
- Abel Jacobus Bronkhorst
- 1 Institute for Laboratory Medicine, German Heart Centre, Technical University Munich, Munich, Germany
| | - Johannes F Wentzel
- 2 Centre of Excellence for Nutrition (CEN), North-West University, Potchefstroom, South Africa
| | - Vida Ungerer
- 1 Institute for Laboratory Medicine, German Heart Centre, Technical University Munich, Munich, Germany
| | - Dimetrie L Peters
- 3 Human Metabolomics, Biochemistry Division, North-West University, Potchefstroom, South Africa
| | - Janine Aucamp
- 4 Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa
| | | | - Stefan Holdenrieder
- 1 Institute for Laboratory Medicine, German Heart Centre, Technical University Munich, Munich, Germany
| | - Piet J Pretorius
- 3 Human Metabolomics, Biochemistry Division, North-West University, Potchefstroom, South Africa
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Dumbović G, Biayna J, Banús J, Samuelsson J, Roth A, Diederichs S, Alonso S, Buschbeck M, Perucho M, Forcales SV. A novel long non-coding RNA from NBL2 pericentromeric macrosatellite forms a perinucleolar aggregate structure in colon cancer. Nucleic Acids Res 2018; 46:5504-5524. [PMID: 29912433 PMCID: PMC6009586 DOI: 10.1093/nar/gky263] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 03/19/2018] [Accepted: 04/03/2018] [Indexed: 12/22/2022] Open
Abstract
Primate-specific NBL2 macrosatellite is hypomethylated in several types of tumors, yet the consequences of this DNA hypomethylation remain unknown. We show that NBL2 conserved repeats are close to the centromeres of most acrocentric chromosomes. NBL2 associates with the perinucleolar region and undergoes severe demethylation in a subset of colorectal cancer (CRC). Upon DNA hypomethylation and histone acetylation, NBL2 repeats are transcribed in tumor cell lines and primary CRCs. NBL2 monomers exhibit promoter activity, and are contained within novel, non-polyA antisense lncRNAs, which we designated TNBL (Tumor-associated NBL2 transcript). TNBL is stable throughout the mitotic cycle, and in interphase nuclei preferentially forms a perinucleolar aggregate in the proximity of a subset of NBL2 loci. TNBL aggregates interact with the SAM68 perinucleolar body in a mirror-image cancer specific perinucleolar structure. TNBL binds with high affinity to several proteins involved in nuclear functions and RNA metabolism, such as CELF1 and NPM1. Our data unveil novel DNA and RNA structural features of a non-coding macrosatellite frequently altered in cancer.
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Affiliation(s)
- Gabrijela Dumbović
- Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Ctra Can Ruti, camí de les escoles s/n, Badalona, Barcelona 08916, Spain
| | - Josep Biayna
- Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Ctra Can Ruti, camí de les escoles s/n, Badalona, Barcelona 08916, Spain
- Institute for Research in Biomedicine (IRB Barcelona), Parc Científic de Barcelona, Carrer de Baldiri Reixac, 10–12, Barcelona 08028, Spain
| | - Jordi Banús
- Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Ctra Can Ruti, camí de les escoles s/n, Badalona, Barcelona 08916, Spain
| | | | - Anna Roth
- Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
| | - Sven Diederichs
- Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
- Division of Cancer Research, Dept. of Thoracic Surgery, Medical Center – University of Freiburg & Faculty of Medicine, University of Freiburg & German Cancer Consortium (DKTK), Freiburg, Germany
| | - Sergio Alonso
- Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Ctra Can Ruti, camí de les escoles s/n, Badalona, Barcelona 08916, Spain
| | - Marcus Buschbeck
- Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Ctra Can Ruti, camí de les escoles s/n, Badalona, Barcelona 08916, Spain
- Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias i Pujol, Campus Can Ruti, Badalona, Barcelona 08916, Spain
| | - Manuel Perucho
- Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Ctra Can Ruti, camí de les escoles s/n, Badalona, Barcelona 08916, Spain
- Sanford-Burnham-Prebys Medical Discovery Institute (SBP), 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Sonia-V Forcales
- Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Ctra Can Ruti, camí de les escoles s/n, Badalona, Barcelona 08916, Spain
- Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Campus of Bellvitge, University of Barcelona, Carrer de la Feixa Llarga, s/n, L’Hospitalet de Llobregat, Barcelona 08907, Spain
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Thongsroy J, Patchsung M, Pongpanich M, Settayanon S, Mutirangura A. Reduction in replication-independent endogenous DNA double-strand breaks promotes genomic instability during chronological aging in yeast. FASEB J 2018; 32:fj201800218RR. [PMID: 29812972 DOI: 10.1096/fj.201800218rr] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The mechanism that causes genomic instability in nondividing aging cells is unknown. Our previous study of mutant yeast suggested that 2 types of replication-independent endogenous DNA double-strand breaks (RIND-EDSBs) exist and that they play opposing roles. The first type, known as physiologic RIND-EDSBs, were ubiquitous in the G0 phase of both yeast and human cells in certain genomic locations and may act as epigenetic markers. Low RIND-EDSB levels were found in mutants that lacked chromatin-condensing proteins, such as the high-mobility group box (HMGB) proteins and Sir2. The second type is referred to as pathologic RIND-EDSBs. High pathological RIND-EDSB levels were found in DSB repair mutants. Under normal physiologic conditions, these excess RIND-EDSBs are repaired in much the same way as DNA lesions. Here, chronological aging in yeast reduced physiological RIND-EDSBs and cell viability. A strong correlation was observed between the reduction in RIND-EDSBs and viability in aging yeast cells ( r = 0.94, P < 0.0001). We used galactose-inducible HO endonuclease (HO) and nhp6a∆, an HMGB protein mutant, to evaluate the consequences of reduced physiological RIND-EDSB levels. The HO-induced cells exhibited a sustained reduction in RIND-EDSBs at various levels for several days. Interestingly, we found that lower physiologic RIND-EDSB levels resulted in decreased cell viability ( r = 0.69, P < 0.0001). Treatment with caffeine, a DSB repair inhibitor, increased pathological RIND-EDSBs, which were distinguished from physiologic RIND-EDSBs by their lack of sequences prior to DSB in untreated cells [odds ratio (OR) ≤1]. Caffeine treatment in both the HO-induced and nhp6a∆ cells markedly increased OR ≤1 breaks. Therefore, physiological RIND-EDSBs play an epigenetic role in preventing pathological RIND-EDSBs, a type of DNA damage. In summary, the reduction of physiological RIND-EDSB level is a genomic instability mechanism in chronologically aging cells.-Thongsroy, J., Patchsung, M., Pongpanich, M., Settayanon, S., Mutirangura, A. Reduction in replication-independent endogenous DNA double-strand breaks promotes genomic instability during chronological aging in yeast.
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Affiliation(s)
- Jirapan Thongsroy
- School of Medicine, Walailak University, Nakhon Si Thammarat, Thailand
| | - Maturada Patchsung
- Center for Excellence in Molecular Genetics of Cancer and Human Diseases, Chulalongkorn University, Bangkok, Thailand
| | - Monnat Pongpanich
- Center for Excellence in Molecular Genetics of Cancer and Human Diseases, Chulalongkorn University, Bangkok, Thailand
- Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- Omics Sciences and Bioinformatics Center, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | - Sirapat Settayanon
- Center for Excellence in Molecular Genetics of Cancer and Human Diseases, Chulalongkorn University, Bangkok, Thailand
| | - Apiwat Mutirangura
- Center for Excellence in Molecular Genetics of Cancer and Human Diseases, Chulalongkorn University, Bangkok, Thailand
- Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Wong CC, Li W, Chan B, Yu J. Epigenomic biomarkers for prognostication and diagnosis of gastrointestinal cancers. Semin Cancer Biol 2018; 55:90-105. [PMID: 29665409 DOI: 10.1016/j.semcancer.2018.04.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
Abstract
Altered epigenetic regulation is central to many human diseases, including cancer. Over the past two decade, major advances have been made in our understanding of the role of epigenetic alterations in carcinogenesis, particularly for DNA methylation, histone modifications and non-coding RNAs. Aberrant hypermethylation of DNA at CpG islands is a well-established phenomenon that mediates transcriptional silencing of tumor suppressor genes, and it is an early event integral to gastrointestinal cancer development. As such, detection of aberrant DNA methylation is being developed as biomarkers for prognostic and diagnostic purposes in gastrointestinal cancers. Diverse tissue types are suitable for the analyses of methylated DNA, such as tumor tissues, blood, plasma, and stool, and some of these markers are already utilized in the clinical setting. Recent advances in the genome-wide epigenomic approaches are enabling the comprehensive mapping of the cancer methylome, thus providing new avenues for mining novel biomarkers for disease prognosis and diagnosis. Here, we review the current knowledge on DNA methylation biomarkers for the prognostication and non-invasive diagnosis of gastrointestinal cancers and highlight their clinical application.
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Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
| | - Weilin Li
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Bertina Chan
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
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Yang P, Gong YJ, Cao WC, Wang RX, Wang YX, Liu C, Chen YJ, Huang LL, Ai SH, Lu WQ, Zeng Q. Prenatal urinary polycyclic aromatic hydrocarbon metabolites, global DNA methylation in cord blood, and birth outcomes: A cohort study in China. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2018; 234:396-405. [PMID: 29202418 DOI: 10.1016/j.envpol.2017.11.082] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Revised: 11/17/2017] [Accepted: 11/26/2017] [Indexed: 05/22/2023]
Abstract
BACKGROUND Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is a potential risk factor for adverse birth outcomes. Epigenetic mechanisms may play a key role in which PAHs exert its effects. OBJECTIVE Our study aimed to examine whether prenatal PAH exposure was associated with adverse birth outcomes and altered DNA methylation and to explore potential mediating roles of DNA methylation. METHODS Ten urinary PAH metabolites were measured from 106 pregnant women during late pregnancy in a Chinese cohort study. Cord blood DNA methylation in long interspersed nucleotide element-1 (LINE-1) and Alu repetitive elements as surrogates of global DNA methylation was analyzed by bisulfite pyrosequencing. Multivariable linear regression was used to estimate the associations of urinary PAH metabolites with birth outcomes and DNA methylation, and a mediation analysis was also conducted. RESULTS Prenatal urinary 2-hydroxynaphthalene (2-OHNa), ∑OHNa (sum of 1- and 2-OHNa), and sum of monohydroxy-PAH (∑OH-PAHs) were associated with lower birth length (e.g., -0.80%, 95% CI: -1.39%, -0.20% for the third vs. first tertile of 2-OHNa; p for trend = 0.01). Prenatal urinary 2-OHNa and 1-hydroxyphenanthrene (1-OHPh) were associated with lower Alu and LINE-1 methylation (e.g., -1.88%, 95% CI: -3.73%, -0.10% for the third vs. first tertile tertile of 2-OHNa in Alu methylation; p for trend = 0.04). Mediation analysis failed to show a mediator effect of global DNA methylation in the association between prenatal urinary OH-PAHs and birth outcomes. CONCLUSIONS Prenatal specific PAH exposures are associated with decreased birth length and global DNA methylation. However, global DNA methylation does not mediate the associations of prenatal PAH exposure with birth outcomes. Further studies are needed to confirm the results.
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Affiliation(s)
- Pan Yang
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Ya-Jie Gong
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Wen-Cheng Cao
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Rui-Xin Wang
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Yi-Xin Wang
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Chong Liu
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Ying-Jun Chen
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Li-Li Huang
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Song-Hua Ai
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Wen-Qing Lu
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Qiang Zeng
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
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Erichsen L, Beermann A, Arauzo-Bravo MJ, Hassan M, Dkhil MA, Al-Quraishy S, Hafiz TA, Fischer JC, Santourlidis S. Genome-wide hypomethylation of LINE-1 and Alu retroelements in cell-free DNA of blood is an epigenetic biomarker of human aging. Saudi J Biol Sci 2018; 25:1220-1226. [PMID: 30174526 PMCID: PMC6117241 DOI: 10.1016/j.sjbs.2018.02.005] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 01/31/2018] [Accepted: 02/11/2018] [Indexed: 11/26/2022] Open
Abstract
Aging associated DNA hypomethylation of LINE-1 and Alu retroelements may be a crucial determinant of loss of genomic integrity, deterioration and cancer. In peripheral blood LINE-1 hypomethylation has been reported to increase during aging, but other studies did not observe significant changes. We hypothesized that these apparently inconsistent reports might relate to differences between cellular and cell-free DNA. Using the technique of idiolocal normalization of real-time methylation-specific PCR (IDLN-MSP) for genetic imbalanced DNA specimens we obtained evidence that LINE-1 hypomethylation in cell-free DNA, but not cellular DNA from peripheral blood is an epigenetic biomarker for human aging. Furthermore, hypomethylation of cell-free DNA is more extensive in smokers, suggesting that it might be used as a surrogate marker for monitoring the improvement of smoking-induced adverse effects after cancelling smoking.
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Affiliation(s)
- Lars Erichsen
- Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Agnes Beermann
- Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
| | - Marcos J Arauzo-Bravo
- Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014 San Sebastián, Spain.,IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
| | - Mohamed Hassan
- Department of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA.,Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France
| | - Mohamed A Dkhil
- Department of Zoology, College of Science, King Saud University, Saudi Arabia.,Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt
| | - Saleh Al-Quraishy
- Department of Zoology, College of Science, King Saud University, Saudi Arabia
| | - Taghreed A Hafiz
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Saudi Arabia
| | - Johannes C Fischer
- Institute of Transplantation Diagnostics and Cell Therapeutics, University Hospital and Medical Faculty of the Heinrich-Heine-University Duesseldorf, Moorenstr. 5, Duesseldorf 40225, Germany
| | - Simeon Santourlidis
- Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
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43
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Patchsung M, Settayanon S, Pongpanich M, Mutirangura D, Jintarith P, Mutirangura A. Alu siRNA to increase Alu element methylation and prevent DNA damage. Epigenomics 2018; 10:175-185. [PMID: 29336607 DOI: 10.2217/epi-2017-0096] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Global DNA hypomethylation promoting genomic instability leads to cancer and deterioration of human health with age. AIM To invent a biotechnology that can reprogram this process. METHODS We used Alu siRNA to direct Alu interspersed repetitive sequences methylation in human cells. We evaluated the correlation between DNA damage and Alu methylation levels. RESULTS We observed an inverse correlation between Alu element methylation and endogenous DNA damage in white blood cells. Cells transfected with Alu siRNA exhibited high Alu methylation levels, increased proliferation, reduced endogenous DNA damage and improved resistance to DNA damaging agents. CONCLUSION Alu methylation stabilizes the genome by preventing accumulation of DNA damage. Alu siRNA could be useful for evaluating reprograming of the global hypomethylation phenotype in cancer and aging cells.
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Affiliation(s)
- Maturada Patchsung
- Inter-Department Program of Biomedical Sciences, Faculty of Graduate School, Chulalongkorn University, Bangkok, Thailand
| | - Sirapat Settayanon
- Program of Medical Science, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Monnat Pongpanich
- Department of Mathematics & Computer Science, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.,Center for Excellence in Molecular Genetics of Cancer & Human Diseases, Chulalongkorn University, Bangkok, Thailand
| | - Dharm Mutirangura
- Center for Excellence in Molecular Genetics of Cancer & Human Diseases, Chulalongkorn University, Bangkok, Thailand
| | - Pornrutsami Jintarith
- Omics Sciences & Bioinformatics Center, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | - Apiwat Mutirangura
- Center for Excellence in Molecular Genetics of Cancer & Human Diseases, Chulalongkorn University, Bangkok, Thailand.,Department of Tropical Nutrition & Food Science, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
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Mahmood N, Cheishvili D, Arakelian A, Tanvir I, Khan HA, Pépin AS, Szyf M, Rabbani SA. Methyl donor S-adenosylmethionine (SAM) supplementation attenuates breast cancer growth, invasion, and metastasis in vivo; therapeutic and chemopreventive applications. Oncotarget 2018; 9:5169-5183. [PMID: 29435170 PMCID: PMC5797041 DOI: 10.18632/oncotarget.23704] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 12/01/2017] [Indexed: 11/25/2022] Open
Abstract
DNA hypomethylation coordinately targets various signaling pathways involved in tumor growth and metastasis. At present, there are no approved therapeutic modalities that target hypomethylation. In this regard, we examined the therapeutic plausibility of using universal methyl group donor S-adenosylmethionine (SAM) to block breast cancer development, growth, and metastasis through a series of studies in vitro using two different human breast cancer cell lines (MDA-MB-231 and Hs578T) and in vivo using an MDA-MB-231 xenograft model of breast cancer. We found that SAM treatment caused a significant dose-dependent decrease in cell proliferation, invasion, migration, anchorage-independent growth and increased apoptosis in vitro. These results were recapitulated in vivo where oral administration of SAM reduced tumor volume and metastasis in green fluorescent protein (GFP)-tagged MDA-MB-231 xenograft model. Gene expression analyses validated the ability of SAM to decrease the expression of several key genes implicated in cancer progression and metastasis in both cell lines and breast tumor xenografts. SAM was found to be bioavailable in the serum of experimental animals as determined by enzyme-linked immunosorbent assay and no notable adverse side effects were seen including any change in animal behavior. The results of this study provide compelling evidence to evaluate the therapeutic potential of methylating agents like SAM in patients with breast cancer to reduce cancer-associated morbidity and mortality.
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Affiliation(s)
- Niaz Mahmood
- Department of Medicine, McGill University Health Centre, Montréal, Canada
| | - David Cheishvili
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada
| | - Ani Arakelian
- Department of Medicine, McGill University Health Centre, Montréal, Canada
| | - Imrana Tanvir
- Department of Pathology, Fatima Memorial Hospital, Lahore, Pakistan
| | | | - Anne-Sophie Pépin
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada
| | - Moshe Szyf
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada
| | - Shafaat A. Rabbani
- Department of Medicine, McGill University Health Centre, Montréal, Canada
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45
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Votino C, Laudanna C, Parcesepe P, Giordano G, Remo A, Manfrin E, Pancione M. Aberrant BLM cytoplasmic expression associates with DNA damage stress and hypersensitivity to DNA-damaging agents in colorectal cancer. J Gastroenterol 2017; 52:327-340. [PMID: 27169843 DOI: 10.1007/s00535-016-1222-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 04/26/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Bloom syndrome is a rare and recessive disorder characterized by loss-of-function mutations of the BLM gene, which encodes a RecQ 3'-5' DNA helicase. Despite its putative tumor suppressor function, the contribution of BLM to human sporadic colorectal cancer (CRC) remains poorly understood. METHODS The transcriptional regulation mechanism underlying BLM and related DNA damage response regulation in independent CRC subsets and a panel of derived cell lines was investigated by bioinformatics analysis, the transcriptomic profile, a CpG island promoter methylation assay, Western blot, and an immunolocalization assay. RESULTS In silico analysis of gene expression data sets revealed that BLM is overexpressed in poorly differentiated CRC and exhibits a close connection with shorter relapse-free survival even after adjustment for prognostic factors and pathways that respond to DNA damage response through ataxia telangiectasia mutated (ATM) signaling. Functional characterization demonstrated that CpG island promoter hypomethylation increases BLM expression and associates with cytoplasmic BLM mislocalization and increased DNA damage response both in clinical CRC samples and in derived cancer cell lines. The DNA-damaging agent S-adenosylmethionine suppresses BLM expression, leading to the inhibition of cell growth following accumulation of DNA damage. In tumor specimens, cytoplasmic accumulation of BLM correlates with DNA damage and γH2AX and phosphorylated ATM foci and predicts long-term progression-free survival in metastatic patients treated with irinotecan. CONCLUSIONS Taken together, the findings of this study provide the first evidence that cancer-linked DNA hypomethylation and cytosolic BLM mislocalization might reflect compromised levels of DNA-repair activity and enhanced hypersensitivity to DNA-damaging agents in CRC patients.
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Affiliation(s)
- Carolina Votino
- Department of Sciences and Technologies, University of Sannio, Via Port'Arsa, 11, 82100, Benevento, Italy
| | - Carmelo Laudanna
- Department of Experimental and Clinical Medicine "Gaetano Salvatore", University "Magna Grecia", 88100, Catanzaro, Italy
| | - Pietro Parcesepe
- Department of Surgery and Oncology, University of Verona, 37129, Verona, Italy
| | - Guido Giordano
- Medical Oncology Unit, Fatebenefratelli Hospital, 82100, Benevento, Italy
| | - Andrea Remo
- Department of Pathology, "Mater Salutis" Hospital, 37045, Legnago, VR, Italy
| | - Erminia Manfrin
- Medical Oncology Unit, Fatebenefratelli Hospital, 82100, Benevento, Italy
| | - Massimo Pancione
- Department of Sciences and Technologies, University of Sannio, Via Port'Arsa, 11, 82100, Benevento, Italy.
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University, Madrid, Spain.
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46
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Lee J, Kalia V, Perera F, Herbstman J, Li T, Nie J, Qu LR, Yu J, Tang D. Prenatal airborne polycyclic aromatic hydrocarbon exposure, LINE1 methylation and child development in a Chinese cohort. ENVIRONMENT INTERNATIONAL 2017; 99:315-320. [PMID: 28027800 PMCID: PMC5810919 DOI: 10.1016/j.envint.2016.12.009] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 11/15/2016] [Accepted: 12/11/2016] [Indexed: 05/17/2023]
Abstract
BACKGROUND Polycyclic aromatic hydrocarbons (PAH) are carcinogenic, neurotoxic environmental pollutants generated during incomplete combustion of fossil fuel and other organic material. PAH exposure has been associated with adverse fetal development and epigenetic alterations in cord blood. Several molecular epidemiology studies have established PAH-DNA adducts as biomarkers of PAH exposure. OBJECTIVES We investigated the relationship between LINE1 DNA methylation and PAH-DNA adduct levels in cord blood, and with neurodevelopmental outcomes. METHODS In Tongliang County, China, the current study enrolled two population-based cohorts of nonsmoking pregnant women before (2002) and after (2005) the closure of a local coal-fired power plant in May 2004. We analyzed cord blood samples collected from mothers in the two cohorts (n=110 from 2002 cohort and n=107 from 2005 cohort) for PAH-DNA adducts and genomic LINE1 DNA methylation. Neurodevelopmental data on children were collected using the Gesell Developmental Scales (GDS) at age 2 and using the Wechsler Intelligence Scale for Children (WISC) at age 5. RESULTS A significant inverse relationship was observed between PAH-DNA adducts and LINE1 DNA methylation (β=-0.010, p<0.038). A significant, positive association between LINE1 methylation and scores on WISC full scale and verbal (β=85.31, p<0.005; β=94.36, p<0.003) but not on the GDS. Mediation analysis did not find LINE1 to be a direct mediator between PAH-DNA adducts and IQ score. CONCLUSION LINE1 methylation in cord blood DNA was a positive predictor of IQ at age 5 and was decreased at higher levels of prenatal PAH exposure measured by PAH-DNA adducts in cord blood. However, the adverse effects of prenatal exposure to PAH on IQ scores did not appear to be directly mediated by altered LINE1 methylation.
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Affiliation(s)
- Joan Lee
- Department of Environmental Health Sciences, Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, New York, NY, United States
| | - Vrinda Kalia
- Department of Environmental Health Sciences, Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, New York, NY, United States
| | - Frederica Perera
- Department of Environmental Health Sciences, Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, New York, NY, United States
| | - Julie Herbstman
- Department of Environmental Health Sciences, Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, New York, NY, United States
| | - Tingyu Li
- Chirdren's Hospital, Chongqing Medical University, Chongqing, China
| | | | - L R Qu
- Department of Environmental Health Sciences, Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, New York, NY, United States
| | - Jie Yu
- Department of Environmental Health Sciences, Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, New York, NY, United States
| | - Deliang Tang
- Department of Environmental Health Sciences, Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, New York, NY, United States.
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Manzardo AM, Butler MG. Examination of Global Methylation and Targeted Imprinted Genes in Prader-Willi Syndrome. ACTA ACUST UNITED AC 2017; 2. [PMID: 28111641 DOI: 10.21767/2472-1158.100026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
CONTEXT Methylation changes observed in Prader-Willi syndrome (PWS) may impact global methylation as well as regional methylation status of imprinted genes on chromosome 15 (in cis) or other imprinted obesity-related genes on other chromosomes (in trans) leading to differential effects on gene expression impacting obesity phenotype unique to (PWS). OBJECTIVE Characterize the global methylation profiles and methylation status for select imprinted genes associated with obesity phenotype in a well-characterized imprinted, obesity-related syndrome (PWS) relative to a cohort of obese and non-obese individuals. DESIGN Global methylation was assayed using two methodologies: 1) enriched LINE-1 repeat sequences by EpigenDx and 2) ELISA-based immunoassay method sensitive to genomic 5-methylcytosine by Epigentek. Target gene methylation patterns at selected candidate obesity gene loci were determined using methylation-specific PCR. SETTING Study participants were recruited as part of an ongoing research program on obesity-related genomics and Prader-Willi syndrome. PARTICIPANTS Individuals with non-syndromic obesity (N=26), leanness (N=26) and PWS (N=39). RESULTS A detailed characterization of the imprinting status of select target genes within the critical PWS 15q11-q13 genomic region showed enhanced cis but not trans methylation of imprinted genes. No significant differences in global methylation were found between non-syndromic obese, PWS or non-obese controls. INTERVENTION None. MAIN OUTCOME MEASURES Percentage methylation and the methylation index. CONCLUSION The methylation abnormality in PWS due to errors of genomic imprinting effects both upstream and downstream effectors in the 15q11-q13 region showing enhanced cis but not trans methylation of imprinted genes. Obesity in our subject cohorts did not appear to impact global methylation levels using the described methodology.
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Affiliation(s)
- A M Manzardo
- Department of Psychiatry and Behavioral Sciences, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 4015, Kansas City, Kansas, USA
| | - M G Butler
- Department of Psychiatry and Behavioral Sciences, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 4015, Kansas City, Kansas, USA; Department of Pediatrics, University of Kansas Medical Center, Kansas City, Kansas, USA
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Whole-Genome DNA Methylation Profiling Identifies Epigenetic Signatures of Uterine Carcinosarcoma. Neoplasia 2017; 19:100-111. [PMID: 28088687 PMCID: PMC5237802 DOI: 10.1016/j.neo.2016.12.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 12/07/2016] [Accepted: 12/12/2016] [Indexed: 02/08/2023] Open
Abstract
Uterine carcinosarcoma (UCS) is a form of endometrial cancer simultaneously exhibiting carcinomatous and sarcomatous elements, but the underlying molecular and epigenetic basis of this disease is poorly understood. We generated complete DNA methylomes for both the carcinomatous and the sarcomatous components of three UCS samples separated by laser capture microdissection and compared DNA methylomes of UCS with those of normal endometrium as well as methylomes derived from endometrioid carcinoma, serous endometrial carcinoma, and endometrial stromal sarcoma. We identified epigenetic lesions specific to carcinosarcoma and specific to its two components. Hallmarks of DNA methylation abnormalities in UCS included global hypomethylation, especially in repetitive elements, and hypermethylation of tumor suppressor gene promoters. Among these, aberrant DNA methylation of MIR200 genes is a key feature of UCS. The carcinoma component of UCS was characterized by hypermethylation of promoters of EMILIN1, NEFM, and CLEC14A, genes that are associated with tumor vascularization. In contrast, DNA methylation changes of PKP3, FAM83F, and TCP11 were more characteristic of the sarcoma components. Our findings highlight the epigenetic signatures that distinguish the two components of UCS, providing a valuable resource for investigation of this disease.
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Babaian A, Mager DL. Endogenous retroviral promoter exaptation in human cancer. Mob DNA 2016; 7:24. [PMID: 27980689 PMCID: PMC5134097 DOI: 10.1186/s13100-016-0080-x] [Citation(s) in RCA: 165] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 11/11/2016] [Indexed: 12/13/2022] Open
Abstract
Cancer arises from a series of genetic and epigenetic changes, which result in abnormal expression or mutational activation of oncogenes, as well as suppression/inactivation of tumor suppressor genes. Aberrant expression of coding genes or long non-coding RNAs (lncRNAs) with oncogenic properties can be caused by translocations, gene amplifications, point mutations or other less characterized mechanisms. One such mechanism is the inappropriate usage of normally dormant, tissue-restricted or cryptic enhancers or promoters that serve to drive oncogenic gene expression. Dispersed across the human genome, endogenous retroviruses (ERVs) provide an enormous reservoir of autonomous gene regulatory modules, some of which have been co-opted by the host during evolution to play important roles in normal regulation of genes and gene networks. This review focuses on the “dark side” of such ERV regulatory capacity. Specifically, we discuss a growing number of examples of normally dormant or epigenetically repressed ERVs that have been harnessed to drive oncogenes in human cancer, a process we term onco-exaptation, and we propose potential mechanisms that may underlie this phenomenon.
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Affiliation(s)
- Artem Babaian
- Terry Fox Laboratory, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z1L3 Canada ; Department of Medical Genetics, University of British Columbia, Vancouver, BC Canada
| | - Dixie L Mager
- Terry Fox Laboratory, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z1L3 Canada ; Department of Medical Genetics, University of British Columbia, Vancouver, BC Canada
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50
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Samuelsson JK, Dumbovic G, Polo C, Moreta C, Alibés A, Ruiz-Larroya T, Giménez-Bonafé P, Alonso S, Forcales SV, Manuel P. Helicase Lymphoid-Specific Enzyme Contributes to the Maintenance of Methylation of SST1 Pericentromeric Repeats That Are Frequently Demethylated in Colon Cancer and Associate with Genomic Damage. EPIGENOMES 2016; 1. [PMID: 31867127 PMCID: PMC6924650 DOI: 10.3390/epigenomes1010002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
DNA hypomethylation at repetitive elements accounts for the genome-wide DNA hypomethylation common in cancer, including colorectal cancer (CRC). We identified a pericentromeric repeat element called SST1 frequently hypomethylated (>5% demethylation compared with matched normal tissue) in several cancers, including 28 of 128 (22%) CRCs. SST1 somatic demethylation associated with genome damage, especially in tumors with wild-type TP53. Seven percent of the 128 CRCs exhibited a higher (“severe”) level of demethylation (≥10%) that co-occurred with TP53 mutations. SST1 demethylation correlated with distinct histone marks in CRC cell lines and primary tumors: demethylated SST1 associated with high levels of the repressive histone 3 lysine 27 trimethylation (H3K27me3) mark and lower levels of histone 3 lysine 9 trimethylation (H3K9me3). Furthermore, induced demethylation of SST1 by 5-aza-dC led to increased H3K27me3 and reduced H3K9me3. Thus, in some CRCs, SST1 demethylation reflects an epigenetic reprogramming associated with changes in chromatin structure that may affect chromosomal integrity. The chromatin remodeler factor, the helicase lymphoid-specific (HELLS) enzyme, called the “epigenetic guardian of repetitive elements”, interacted with SST1 as shown by chromatin immunoprecipitation, and down-regulation of HELLS by shRNA resulted in demethylation of SST1 in vitro. Altogether these results suggest that HELLS contributes to SST1 methylation maintenance. Alterations in HELLS recruitment and function could contribute to the somatic demethylation of SST1 repeat elements undergone before and/or during CRC pathogenesis.
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Affiliation(s)
- Johanna K. Samuelsson
- Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
- Active Motif, 1914 Palomar Oaks Way, Suite 150, Carlsbad, CA 92008, USA
| | - Gabrijela Dumbovic
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Campus Can Ruti, Badalona 08916, Barcelona, Spain
| | - Cristian Polo
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Campus Can Ruti, Badalona 08916, Barcelona, Spain
| | - Cristina Moreta
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Campus Can Ruti, Badalona 08916, Barcelona, Spain
| | - Andreu Alibés
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Campus Can Ruti, Badalona 08916, Barcelona, Spain
| | | | - Pepita Giménez-Bonafé
- Departament de Ciències Fisiòlogiques, Facultat de Medicina i Ciències de la Salut, Campus Ciències de la Salut, Bellvitge, Universitat de Barcelona, Hospitalet del Llobregat 08916, Barcelona, Spain
| | - Sergio Alonso
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Campus Can Ruti, Badalona 08916, Barcelona, Spain
| | - Sonia-V. Forcales
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Campus Can Ruti, Badalona 08916, Barcelona, Spain
- Correspondence: (S.-V.F.); (M.P.)
| | - Perucho Manuel
- Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Campus Can Ruti, Badalona 08916, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain
- Correspondence: (S.-V.F.); (M.P.)
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