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Lo EKW, Idrizi A, Tryggvadottir R, Zhou W, Hou W, Ji H, Cahan P, Feinberg AP. DNA methylation memory of pancreatic acinar-ductal metaplasia transition state altering Kras-downstream PI3K and Rho GTPase signaling in the absence of Kras mutation. Genome Med 2025; 17:32. [PMID: 40156071 PMCID: PMC11951614 DOI: 10.1186/s13073-025-01452-6] [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: 10/01/2024] [Accepted: 03/10/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND A critical area of recent cancer research is the emergence of transition states between normal and cancer that exhibit increased cell plasticity which underlies tumor cell heterogeneity. Pancreatic ductal adenocarcinoma (PDAC) can arise from the combination of a transition state termed acinar-to-ductal metaplasia (ADM) and a gain-of-function mutation in the proto-oncogene KRAS. During ADM, digestive enzyme-producing acinar cells acquire a transient ductal epithelium-like phenotype while maintaining their geographical acinar organization. One route of ADM initiation is the overexpression of the Krüppel-like factor 4 gene (KLF4) in the absence of oncogenic driver mutations. Here, we asked to what extent cells acquire and retain an epigenetic memory of the ADM transition state in the absence of oncogene mutation. METHODS We profiled the DNA methylome and transcriptome of KLF4-induced ADM in transgenic mice at various timepoints during and after recovery from ADM. We validated the identified DNA methylation and transcriptomic signatures in the widely used caerulein model of inducible pancreatitis. RESULTS We identified differential DNA methylation at Kras-downstream PI3K and Rho/Rac/Cdc42 GTPase pathway genes during ADM, as well as a corresponding gene expression increase in these pathways. Importantly, differential methylation persisted after gene expression returned to normal. Caerulein exposure, which induces widespread digestive system changes in addition to ADM, showed similar changes in DNA methylation in ADM cells. Regions of differential methylation were enriched for motifs of KLF and AP-1 family transcription factors, as were those of human pancreatic intraepithelial neoplasia (PanIN) samples, demonstrating the relevance of this epigenetic transition state memory in human carcinogenesis. Finally, single-cell spatial transcriptomics revealed that these ADM transition cells were enriched for PI3K pathway and AP1 family members. CONCLUSIONS Our comprehensive study of DNA methylation in the acinar-ductal metaplasia transition state links epigenetic memory to cancer-related cell plasticity even in the absence of oncogenic mutation.
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Affiliation(s)
- Emily K W Lo
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA
- Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Medicine, Johns Hopkins University School of Medicine, 1830 E. Monument Street, Baltimore, MD, USA
| | - Adrian Idrizi
- Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Medicine, Johns Hopkins University School of Medicine, 1830 E. Monument Street, Baltimore, MD, USA
| | - Rakel Tryggvadottir
- Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Medicine, Johns Hopkins University School of Medicine, 1830 E. Monument Street, Baltimore, MD, USA
| | - Weiqiang Zhou
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Wenpin Hou
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Hongkai Ji
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Patrick Cahan
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Andrew P Feinberg
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.
- Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Medicine, Johns Hopkins University School of Medicine, 1830 E. Monument Street, Baltimore, MD, USA.
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Wang TW, Nakanishi M. Immune surveillance of senescence: potential application to age-related diseases. Trends Cell Biol 2025; 35:248-257. [PMID: 39025762 DOI: 10.1016/j.tcb.2024.06.007] [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: 03/27/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 07/20/2024]
Abstract
Several lines of evidence suggest that the age-dependent accumulation of senescent cells leads to chronic tissue microinflammation, which in turn contributes to age-related pathologies. In general, senescent cells can be eliminated by the host's innate and adaptive immune surveillance system, including macrophages, NK cells, and T cells. Impaired immune surveillance leads to the accumulation of senescent cells and accelerates the aging process. Recently, senescent cells, like cancer cells, have been shown to express certain types of immune checkpoint proteins as well as non-classical immune-tolerant MHC variants, leading to immune escape from surveillance systems. Thus, immune checkpoint blockade (ICB) may be a promising strategy to enhance immune surveillance of senescence, leading to the amelioration of some age-related diseases and tissue dysfunction.
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Affiliation(s)
- Teh-Wei Wang
- Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | - Makoto Nakanishi
- Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
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de Melo Viana TC, Nakamura ET, Park A, Filardi KFXC, de Almeida Leite RM, Baltazar LFSR, Usón Junior PLS, Tustumi F. Molecular Abnormalities and Carcinogenesis in Barrett's Esophagus: Implications for Cancer Treatment and Prevention. Genes (Basel) 2025; 16:270. [PMID: 40149421 PMCID: PMC11942460 DOI: 10.3390/genes16030270] [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: 01/29/2025] [Revised: 02/16/2025] [Accepted: 02/23/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Barrett's esophagus (BE) is described by the transformation of the normal squamous epithelium into metaplastic columnar epithelium, driven by chronic gastroesophageal reflux disease (GERD). BE is a recognized premalignant condition and the main precursor to esophageal adenocarcinoma (EAC). Understanding the molecular mechanisms underlying BE carcinogenesis is crucial for improving prevention, surveillance, and treatment strategies. METHODS This narrative review examines the molecular abnormalities associated with the progression of BE to EAC. RESULTS This study highlights inflammatory, genetic, epigenetic, and chromosomal alterations, emphasizing key pathways and biomarkers. BE progression follows a multistep process involving dysplasia and genetic alterations such as TP53 and CDKN2A (p16) mutations, chromosomal instability, and dysregulation of pathways like PI3K/AKT/mTOR. Epigenetic alterations, including aberrant microRNA expression or DNA methylation, further contribute to this progression. These molecular changes are stage-specific, with some alterations occurring early in BE during the transition to high-grade dysplasia or EAC. Innovations in chemoprevention, such as combining proton pump inhibitors and aspirin, and the potential of antireflux surgery to halt disease progression are promising. Incorporating molecular biomarkers into surveillance strategies and advancing precision medicine may enable earlier detection and personalized treatments. CONCLUSIONS BE is the primary preneoplastic condition for EAC. A deeper understanding of its molecular transformation can enhance surveillance protocols, optimize the management of gastroesophageal reflux inflammation, and refine prevention and therapeutic strategies, ultimately contributing to a reduction in the global burden of EAC.
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Affiliation(s)
| | | | - Amanda Park
- Department of Evidenced-Based Medicine, Centro Universitário Lusíada, Santos 11050-071, Brazil
| | | | | | | | | | - Francisco Tustumi
- Department of Gastroenterology, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil
- Department of Health Sciences, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil
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Goldberg DC, Cloud C, Lee SM, Barnes B, Gruber S, Kim E, Pottekat A, Westphal MS, McAuliffe L, Majounie E, KalayilManian M, Zhu Q, Tran C, Hansen M, Stojakovic J, Parker JB, Kohli RM, Porecha R, Renke N, Zhou W. Scalable Screening of Ternary-Code DNA Methylation Dynamics Associated with Human Traits. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.05.17.594606. [PMID: 38826316 PMCID: PMC11142114 DOI: 10.1101/2024.05.17.594606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Epigenome-wide association studies (EWAS) are transforming our understanding of the interplay between epigenetics and complex human traits and phenotypes. We introduce the Methylation Screening Array (MSA), a new iteration of the Infinium technology for scalable and quantitative screening of trait associations of nuanced ternary-code cytosine modifications in larger, more inclusive, and stratified human populations. MSA integrates EWAS, single-cell, and cell-type-resolved methylome profiles, covering diverse human traits and diseases. Our first MSA applications yield multiple biological insights: we revealed a previously unappreciated role of 5-hydroxymethylcytosine (5hmC) in trait associations and epigenetic clocks. We demonstrated that 5hmCs complement 5-methylcytosines (5mCs) in defining tissues and cells' epigenetic identities. In-depth analyses highlighted the cell type context of EWAS and GWAS hits. Using this platform, we conducted a comprehensive human 5hmC aging EWAS, discovering tissue-invariant and tissue-specific aging dynamics, including distinct tissue-specific rates of mitotic hyper- and hypomethylation rates. These findings chart a landscape of the complex interplay of the two forms of cytosine modifications in diverse human tissues and their roles in health and disease.
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Wagner RT, Hlady RA, Pan X, Wang L, Kim S, Zhao X, El Khoury LY, Shaikh S, Zhong J, Lee JH, Grembecka J, Cierpicki T, Ho TH, Robertson KD. SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation. Genome Biol 2025; 26:22. [PMID: 39910618 PMCID: PMC11800516 DOI: 10.1186/s13059-025-03483-z] [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: 05/09/2024] [Accepted: 01/24/2025] [Indexed: 02/07/2025] Open
Abstract
BACKGROUND SETD2 is the sole epigenetic factor responsible for catalyzing histone 3, lysine 36, tri-methylation (H3K36me3) in mammals. Its role in regulating cellular processes such as RNA splicing, DNA repair, and spurious transcription initiation underlies its broader tumor suppressor function. SETD2 mutation promotes the epithelial-mesenchymal transition and is clinically associated with adverse outcomes highlighting a therapeutic need to develop targeted therapies against this dangerous mutation. RESULTS We employ an unbiased genome-wide synthetic lethal screen, which identifies another H3K36me writer, NSD1, as a synthetic lethal modifier in SETD2-mutant cells. Confirmation of this synthetic lethal interaction is performed in isogenic clear cell renal cell carcinoma and immortalized renal epithelial cell lines, in mouse and human backgrounds. Depletion of NSD1 using a CRISPRi targeting approach promotes the loss of SETD2-mutant cells coincident with elevated levels of DNA damage and apoptosis. Surprisingly, only suppression of NSD1, but not related H3K36-methyltransferases, promotes synthetic lethality in these models. Mapping of genomic H3K36me2 targeting by NSD1 and NSD2 individually highlights the independent functions of these epigenetic writers. Furthermore, as a proof-of-principle, we demonstrate the therapeutic feasibility of targeting this synthetic lethal interaction by recapitulating the phenotype using BT5, a first-in-class pharmacologic inhibitor against NSD1. CONCLUSIONS These findings unify genome-wide screening approaches with the latest genetic and pharmacologic modeling methodologies to reveal an entirely novel epigenetic approach to individualize therapies against a challenging loss-of-function SETD2 mutation in cancer.
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Affiliation(s)
- Ryan T Wagner
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Stabile 12-70, Rochester, MN, 55905, USA
| | - Ryan A Hlady
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Stabile 12-70, Rochester, MN, 55905, USA
| | - Xiaoyu Pan
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Stabile 12-70, Rochester, MN, 55905, USA
| | - Liguo Wang
- Division of Computational Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Sungho Kim
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Stabile 12-70, Rochester, MN, 55905, USA
| | - Xia Zhao
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Stabile 12-70, Rochester, MN, 55905, USA
| | - Louis Y El Khoury
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Stabile 12-70, Rochester, MN, 55905, USA
| | - Shafiq Shaikh
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Jian Zhong
- Epigenomics Development Laboratory, Mayo Clinic, CIM Epigenomics Program, Rochester, MN, USA
| | - Jeong-Heon Lee
- Epigenomics Development Laboratory, Mayo Clinic, CIM Epigenomics Program, Rochester, MN, USA
| | | | - Tomasz Cierpicki
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Thai H Ho
- Division of Hematology and Oncology, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC, 29425, USA.
| | - Keith D Robertson
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Stabile 12-70, Rochester, MN, 55905, USA.
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Bai H, Dang Q, Chen G, Xie L, Wang S, Jiang N, Wu X, Zhang S, Wang X. MyD88 inhibitor TJ-M2010-5 alleviates spleen impairment and inflammation by inhibiting the PI3K/miR-136-5p/AKT3 pathway in the early infection of Trichinella spiralis. Vet Res 2025; 56:28. [PMID: 39905552 DOI: 10.1186/s13567-025-01459-2] [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: 08/20/2024] [Accepted: 09/30/2024] [Indexed: 02/06/2025] Open
Abstract
Trichinella spiralis (T. spiralis) has been reported to induce inflammation, which can cause immune system dysregulation. Myeloid differentiation primary response gene 88 (MyD88) is implicated in inflammation signalling pathways. TJ-M2010-5 is a novel MyD88 inhibitor with remarkable protective effects against several diseases. However, the precise mechanism of TJ-M2010-5's involvement in spleen impairment and inflammation in the early infection of T. spiralis has yet to be fully elucidated. This study analysed histological, inflammation, and macrophage polarisation of the early T. spiralis-infected mice treated with TJ-M2010-5. MyD88 promoter methylation results showed that the methylation levels in the 5 d group were lower compared to the control group (P < 0.05). Furthermore, the methylation led to an imbalance in anti-inflammatory regulation in the infected mice. After TJ-M2010-5 treatment, spleen impairment was reduced. Sequencing analysis showed that TJ-M2010-5 significantly up-regulated 9 and down-regulated 10 miRNAs compared with the 5 d group. A dual-luciferase reporter assay further revealed that miR-136-5p is involved in the TJ-M2010-5 treatment by targeting AKT3. In RAW264.7 cells, TJ-M2010-5 pre-treatment significantly reversed the M1 polarisation and inhibited nitric oxide (NO) production. LC-MS/MS results showed TJ-M2010-5 was hepatosplenic-targeted. In conclusion, the study demonstrates that TJ-M2010-5 could effectively alleviate spleen impairment and reduce inflammation in mice infected with T. spiralis in its early stages by blocking the activation of PI3K/miR-136-5p/AKT3.
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Affiliation(s)
- Huifang Bai
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Qianqian Dang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Guoliang Chen
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Lingfeng Xie
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Saining Wang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Ning Jiang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Xiaoxia Wu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Shuyan Zhang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Xuelin Wang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China.
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Yusoff NA, Abd Hamid Z, Taib IS, Abdul Razak SR, Budin SB. Exploring Epigenetic Complexity in Regulation of Hematopoietic Stem Cells Niche: A Mechanistic Journey from Normal to Malignant Hematopoiesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025. [PMID: 39841383 DOI: 10.1007/5584_2024_846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2025]
Abstract
Epigenetic regulation in hematopoietic stem cells (HSCs) research has emerged as a transformative molecular approach that enhances understanding of hematopoiesis and hematological disorders. This chapter investigates the intricate epigenetic mechanisms that control HSCs function, including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. It also explores the role of non-coding ribonucleic acid (RNAs) as epigenetic regulators, highlighting how changes in gene expression can occur without alterations to the DNA sequence. Epigenetic mechanisms play a pivotal in regulating HSC self-renewal and differentiation, processes essential for maintaining a balanced hematopoietic system in which lineage-specific hematopoietic stem and progenitor cells (HSPCs) pool is sustained. Recent advancements in epigenetic mapping and sequencing technologies have illuminated the dynamic epigenetic landscapes that characterize HSCs and their progeny. Numerous studies have revealed that dysregulation of epigenetic pathways is a hallmark of various hematological malignancies, including leukemias, lymphomas, and myelodysplastic syndromes. This review highlights key findings that demonstrate the impact of epigenetic abnormalities on the disruption of HSPC niches and the progression of oncogenesis in hematological malignancies. Furthermore, this chapter explores the therapeutic potential of targeting epigenetic modifications that are critical in formation and progression of hematologic malignancies. It also discusses the latest developments in epigenetic therapies, including the use of DNA methyltransferase inhibitors, histone deacetylase inhibitors, and emerging drugs targeting other epigenetic regulators. These therapies represent a promising strategy for resetting aberrant epigenetic states, potentially restoring normal hematopoiesis. Conclusively, this chapter offers a thorough overview of the current landscape and future directions of epigenetic research related to the maintenance of the HSPC niches. The insights presented here aim to contribute significantly to the field, offering a reference point for molecular approaches that enhance our understanding of hematopoiesis and its associated hematological malignancies.
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Affiliation(s)
- Nur Afizah Yusoff
- Centre for Diagnostic, Therapeutic and Investigative Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Zariyantey Abd Hamid
- Centre for Diagnostic, Therapeutic and Investigative Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
| | - Izatus Shima Taib
- Centre for Diagnostic, Therapeutic and Investigative Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Siti Razila Abdul Razak
- Department of Biomedical Science, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Pulau Pinang, Malaysia
| | - Siti Balkis Budin
- Centre for Diagnostic, Therapeutic and Investigative Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Magnani E, Macchi F, Randic T, Chen C, Madakashira B, Ranjan S, Eski SE, Singh SP, Sadler KC. Epigenetic Disordering Drives Stemness, Senescence Escape and Tumor Heterogeneity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.29.629346. [PMID: 39763773 PMCID: PMC11703240 DOI: 10.1101/2024.12.29.629346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Tumor heterogeneity is the substrate for tumor evolution and the linchpin of treatment resistance. Cancer cell heterogeneity is largely attributed to distinct genetic changes within each cell population. However, the widespread epigenome repatterning that characterizes most cancers is also highly heterogenous within tumors and could generate cells with diverse identities and malignant features. We show that high levels of the epigenetic regulator and oncogene, UHRF1, in zebrafish hepatocytes rapidly induced methylome disordering, loss of heterochromatin, and DNA damage, resulting in cell cycle arrest, senescence, and acquisition of stemness. Reducing UHRF1 expression transitions these cells from senescent to proliferation-competent. The expansion of these damaged cells results in hepatocellular carcinomas (HCC) that have immature cancer cells intermingled with fibroblasts, immune and senescent cells expressing high UHRF1 levels, which serve as reservoirs for new cancer cells. This defines a distinct and heterogenous HCC subtype resulting from epigenetic changes, stemness and senescence escape.
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Affiliation(s)
- Elena Magnani
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Filippo Macchi
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Tijana Randic
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Charlene Chen
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Bhavani Madakashira
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Shashi Ranjan
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Sema Elif Eski
- Laboratory of Regeneration and Stress Biology, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM-Jacques E. Dumont), Université libre de Bruxelles, 1070 Brussels, Belgium
| | - Sumeet P. Singh
- Laboratory of Regeneration and Stress Biology, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM-Jacques E. Dumont), Université libre de Bruxelles, 1070 Brussels, Belgium
| | - Kirsten C. Sadler
- Program in Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
- Center for Genomics and Systems Biology, NYU Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
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Tsai WJ, Hsieh WS, Chen PC, Liu CY. Prenatal Perfluoroalkyl Substance Exposure in Association with Global Histone Post-Translational Methylation in 2-Year-Old Children. TOXICS 2024; 12:876. [PMID: 39771091 PMCID: PMC11679469 DOI: 10.3390/toxics12120876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/26/2024] [Accepted: 11/28/2024] [Indexed: 01/11/2025]
Abstract
Perfluoroalkyl substances (PFASs) have elimination half-lives in years in humans and are persistent in the environment. PFASs can cross the placenta and impact fetal development. Exposure to PFASs may lead to adverse effects through epigenetic mechanisms. This study aimed to investigate whether prenatal exposure to perfluorooctyl sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluoroundecanoic acid (PFUA) was associated with global histone methylation level changes among the 130 2-year-old children followed-up in a birth cohort study in Taiwan. PFOS, PFOA, PFNA, and PFUA were measured by UHPLC/MS/MS in cord blood. Global histone methylation levels were measured from the blood leukocytes of 2-year-old children by Western blotting. Multivariable regression analyses were applied to adjust for potential confounding effects. Among the 2-year-old children, an IQR increase in the natural log-transformed PFUA exposure was associated with an increased H3K4me3 level by 2.76-fold (95%CI = (0.79, 4.73), p = 0.007). PFOA and PFNA exposures was associated with a decreased H3K27me3 level by 2.35-fold (95%CI = (-4.29, -0.41), p = 0.01) and 2.01-fold (95%CI = (-4.00, -0.03), p = 0.04), respectively. Our findings suggest that prenatal PFAS exposure affected histone post-translational modifications.
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Affiliation(s)
- Wan-Ju Tsai
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei 100, Taiwan (P.-C.C.)
| | - Wu-Shiun Hsieh
- Department of Pediatrics, Cathay General Hospital, Taipei 106, Taiwan;
- Department of Pediatrics, National Taiwan University College of Medicine, Taipei 100, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Pau-Chung Chen
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei 100, Taiwan (P.-C.C.)
- Department of Environmental and Occupational Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan
- National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli 350, Taiwan
- Department of Public Health, College of Public Health, National Taiwan University, Taipei 100, Taiwan
| | - Chen-Yu Liu
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei 100, Taiwan (P.-C.C.)
- Department of Public Health, College of Public Health, National Taiwan University, Taipei 100, Taiwan
- Global Health Program, College of Public Health, National Taiwan University, Taipei 100, Taiwan
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10
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Gezer U, Özgür E, Yörüker EE, Polatoglou E, Holdenrieder S, Bronkhorst A. LINE-1 cfDNA Methylation as an Emerging Biomarker in Solid Cancers. Cancers (Basel) 2024; 16:3725. [PMID: 39594682 PMCID: PMC11592170 DOI: 10.3390/cancers16223725] [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: 10/08/2024] [Revised: 11/01/2024] [Accepted: 11/03/2024] [Indexed: 11/28/2024] Open
Abstract
Epigenetic dysregulation is a hallmark of many human malignancies, with DNA methylation being a primary mechanism influencing gene expression and maintaining genomic stability. Genome-wide hypomethylation, characteristic of many cancers, is partly attributed to the demethylation of repetitive elements, including LINE-1, a prevalent non-LTR retrotransposon. The methylation status of LINE-1 is closely associated with overall genomic methylation levels in tumors. cfDNA comprises extracellular DNA fragments found in bodily fluids such as plasma, serum, and urine, offering a dynamic snapshot of the genetic and epigenetic landscape of tumors. This real-time sampling provides a minimally invasive avenue for cancer diagnostics, prognostics, and monitoring. The methylation status of LINE-1 in cfDNA has emerged as a promising biomarker, with several studies highlighting its potential in diagnosing and predicting outcomes in cancer patients. Recent research also suggests that cfDNA-based LINE-1 methylation analysis could serve as a valuable tool in evaluating the efficacy of cancer therapies, including immunotherapy. The growing clinical significance of cfDNA calls for a closer examination of its components, particularly repetitive elements like LINE-1. Despite their importance, the role of LINE-1 elements in cfDNA has not been thoroughly gauged. We aim to address this gap by reviewing the current literature on LINE-1 cfDNA assays, focusing on their potential applications in diagnostics and disease monitoring.
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Affiliation(s)
- Ugur Gezer
- Department of Basic Oncology, Oncology Institute, Istanbul University, 34093 Istanbul, Türkiye; (U.G.); (E.Ö.); (E.E.Y.)
| | - Emre Özgür
- Department of Basic Oncology, Oncology Institute, Istanbul University, 34093 Istanbul, Türkiye; (U.G.); (E.Ö.); (E.E.Y.)
| | - Ebru E. Yörüker
- Department of Basic Oncology, Oncology Institute, Istanbul University, 34093 Istanbul, Türkiye; (U.G.); (E.Ö.); (E.E.Y.)
| | - Eleni Polatoglou
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, 80636 Munich, Germany (S.H.)
| | - Stefan Holdenrieder
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, 80636 Munich, Germany (S.H.)
| | - Abel Bronkhorst
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, 80636 Munich, Germany (S.H.)
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11
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Lo EKW, Idrizi A, Tryggvadottir R, Zhou W, Hou W, Ji H, Cahan P, Feinberg AP. DNA methylation memory of pancreatic acinar-ductal metaplasia transition state altering Kras-downstream PI3K and Rho GTPase signaling in the absence of Kras mutation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.26.620414. [PMID: 39553977 PMCID: PMC11565792 DOI: 10.1101/2024.10.26.620414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
A critical area of recent cancer research is the emergence of transition states between normal and cancer that exhibit increased cell plasticity which underlies tumor cell heterogeneity. Pancreatic ductal adenocarcinoma (PDAC) can arise from the combination of a transition state termed acinar-to-ductal metaplasia (ADM) and a gain-of-function mutation in the proto-oncogene KRAS . During ADM, digestive enzyme-producing acinar cells acquire a transient ductal epithelium-like phenotype while maintaining their geographical acinar organization. One route of ADM initiation is the overexpression of the Krüppel-like factor 4 gene ( KLF4 ) in the absence of oncogenic driver mutations. Here, we asked to what extent cells acquire and retain an epigenetic memory of the ADM transition state in the absence of oncogene mutation. We identified differential DNA methylation at Kras-downstream PI3K and Rho / Rac / Cdc42 GTPase pathway genes during ADM, as well as a corresponding gene expression increase in these pathways. Importantly, differential methylation persisted after gene expression returned to normal. Caerulein exposure, which induces widespread digestive system changes in addition to ADM, showed similar changes in DNA methylation in ADM cells. Regions of differential methylation were enriched for motifs of KLF and AP-1 family transcription factors, as were those of human pancreatic intraepithelial neoplasia (PanIN) samples, demonstrating the relevance of this epigenetic transition state memory in human carcinogenesis. Finally, single-cell spatial transcriptomics revealed that these ADM transition cells were enriched for PI3K pathway and AP1 family members, linking epigenetic memory to cancer cell plasticity even in the absence of oncogene mutation.
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12
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Xiong Y, Lei X, Xiong Y, Liu Y, Dong Z, Zhao J, Yu Q, Ma X. Factors contributing to organelle genomes size variation and the intracellular DNA transfer in Polygonaceae. BMC Genomics 2024; 25:994. [PMID: 39443865 PMCID: PMC11515532 DOI: 10.1186/s12864-024-10914-x] [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: 04/11/2024] [Accepted: 10/17/2024] [Indexed: 10/25/2024] Open
Abstract
The use of complete organelle genomes, including chloroplast and mitochondrial genomes, is a powerful molecular method for studying biological evolution and gene transfer. However, in the case of Polygonaceae, an important family with numerous edible, medicinal, and ornamental species, the mitochondrial genomes of only three species have been sequenced and analyzed. In this study, we present the mitochondrial and chloroplast genomes of two important Tibetan medicinal plants, Bistorta viviparum and B. macrophyllum. All the organelle genomes are assembled into a single circular structure and contain a common set of 32 protein-coding genes (PCGs). Some genes such as rps2 and ndhF were found to have high nucleotide polymorphism (Pi) in the chloroplast genomes, while cox1, mttB and rps12 showed pronounced Pi values in the mitochondrial genomes. Furthermore, our analysis revealed that most chloroplast genes and mitochondrial PCGs in Polygonaceae plants are under purifying selection. However, a few genes, including the chloroplast gene psaJ and the mitochondrial genes ccmFc, atp8 and nad4, showed positive selection in certain Polygonaceae plants, as indicated by a Ka/Ks ratio greater than one. Structural variation analysis revealed a wealth of differences between the mitochondrial genomes of five Polygonaceae species, with a particularly notable large-scale inversion observed between Reynoutria japonica and Fallopia aubertii. Furthermore, an analysis of the homologous sequences in the chloroplast and mitochondrial genomes revealed that the rps7 has been transferred from the chloroplast to the mitochondrial genome in all five Polygonaceae species. Finally, ecological niche models were constructed for B. viviparum and B. macrophyllum, indicating that mean annual temperature and altitude are the main climatic factors influencing the distribution of both species. Although the current distribution of B. viviparum is significantly wider than that of B. macrophyllum, projections suggest that the optimal growth ranges of both species will expand in the future, with B. macrophyllum potentially exceeding B. viviparum. This study not only contributes to the plastid genome database for Polygonaceae plants, but also provides theoretical insights into the adaptive evolution of these plants.
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Affiliation(s)
- Yi Xiong
- College of Grassland Science and Technology, Sichuan Agricultural University, Chengdu, 611130, Sichuan, China
| | - Xiong Lei
- Sichuan Academy of Grassland Sciences, Chengdu, 611700, Sichuan, China
| | - Yanli Xiong
- College of Grassland Science and Technology, Sichuan Agricultural University, Chengdu, 611130, Sichuan, China
| | - Yingjie Liu
- College of Grassland Science and Technology, Sichuan Agricultural University, Chengdu, 611130, Sichuan, China
| | - Zhixiao Dong
- College of Grassland Science and Technology, Sichuan Agricultural University, Chengdu, 611130, Sichuan, China
| | - Junming Zhao
- College of Grassland Science and Technology, Sichuan Agricultural University, Chengdu, 611130, Sichuan, China
| | - Qingqing Yu
- Sichuan Academy of Grassland Sciences, Chengdu, 611700, Sichuan, China.
| | - Xiao Ma
- College of Grassland Science and Technology, Sichuan Agricultural University, Chengdu, 611130, Sichuan, China.
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13
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Wu Z, Zhou R, Li B, Cao M, Wang W, Li X. Methylation modifications in tRNA and associated disorders: Current research and potential therapeutic targets. Cell Prolif 2024; 57:e13692. [PMID: 38943267 PMCID: PMC11503269 DOI: 10.1111/cpr.13692] [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: 03/02/2024] [Revised: 05/14/2024] [Accepted: 06/03/2024] [Indexed: 07/01/2024] Open
Abstract
High-throughput sequencing has sparked increased research interest in RNA modifications, particularly tRNA methylation, and its connection to various diseases. However, the precise mechanisms underpinning the development of these diseases remain largely elusive. This review sheds light on the roles of several tRNA methylations (m1A, m3C, m5C, m1G, m2G, m7G, m5U, and Nm) in diverse biological functions, including metabolic processing, stability, protein interactions, and mitochondrial activities. It further outlines diseases linked to aberrant tRNA modifications, related enzymes, and potential underlying mechanisms. Moreover, disruptions in tRNA regulation and abnormalities in tRNA-derived small RNAs (tsRNAs) contribute to disease pathogenesis, highlighting their potential as biomarkers for disease diagnosis. The review also delves into the exploration of drugs development targeting tRNA methylation enzymes, emphasizing the therapeutic prospects of modulating these processes. Continued research is imperative for a comprehensive comprehension and integration of these molecular mechanisms in disease diagnosis and treatment.
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Affiliation(s)
- Zhijing Wu
- Department of General Surgery, Xiangya HospitalCentral South UniversityChangshaHunanChina
- National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Ruixin Zhou
- Department of General Surgery, Xiangya HospitalCentral South UniversityChangshaHunanChina
- National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Baizao Li
- Department of General Surgery, Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Mingyu Cao
- Department of General Surgery, Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Wenlong Wang
- Department of Breast Surgery, Xiangya HospitalCentral South UniversityChangshaHunanChina
- Clinical Research Center for Breast Cancer in Hunan ProvinceChangshaHunanChina
| | - Xinying Li
- Department of General Surgery, Xiangya HospitalCentral South UniversityChangshaHunanChina
- National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaHunanChina
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14
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Abolghasemi Fard A, Mahmoodzadeh A. Unraveling the Progression of Colon Cancer Pathogenesis Through Epigenetic Alterations and Genetic Pathways. Cureus 2024; 16:e59503. [PMID: 38826873 PMCID: PMC11143495 DOI: 10.7759/cureus.59503] [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] [Accepted: 05/02/2024] [Indexed: 06/04/2024] Open
Abstract
In the modern age, colon cancer has attained a widespread status, affecting a considerable number of people. It develops due to the progressive accumulation of genetic and epigenetic alterations. While genetic mutations have been extensively studied in the context of colon cancer, emerging evidence highlights the pivotal role of epigenetic alterations in its pathogenesis. These alterations ultimately result in the transformation of normal colonic epithelium into colon adenocarcinoma. Key mechanisms of epigenetic modifications include DNA methylation, histone modification, and nucleosome positioning. Research findings have linked these modifications to the development, progression, or metastasis of tumors. Through the assessment of the colon cancer epigenome, it has been discovered that practically all colorectal cancers (CRCs) display gene methylation abnormalities and changes in miRNA expression. Advancements in this area indicate that epigenetic modifications will likely be commonly used in the near future to direct the prevention and treatment of CRC. The maintenance of genome stability is essential for preserving cellular integrity. The development of CRC is primarily influenced by the loss of genomic stability, which allows for the emergence of new mutations contributing to tumor characteristics. Although genetic mutations have been extensively researched in the realm of colon cancer, recent evidence underscores the pivotal role of epigenetic changes in its pathogenesis. The following types of genomic instability will be discussed: chromosomal instability, microsatellite instability, CpG island methylation phenotype, and aberrant DNA methylation.
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Affiliation(s)
- Asal Abolghasemi Fard
- Department of Cellular and Molecular Biology, Faculty of Modern Science and Technologies, Tehran Medical Sciences, Islamic Azad University, Tehran, IRN
| | - Afshin Mahmoodzadeh
- Department of Biology, Roudehen Branch, Islamic Azad University, Tehran, IRN
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15
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Qin Q, Zhou Y, Guo J, Chen Q, Tang W, Li Y, You J, Li Q. Conserved methylation signatures associate with the tumor immune microenvironment and immunotherapy response. Genome Med 2024; 16:47. [PMID: 38566132 PMCID: PMC10985907 DOI: 10.1186/s13073-024-01318-3] [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: 03/16/2023] [Accepted: 03/20/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Aberrant DNA methylation is a major characteristic of cancer genomes. It remains unclear which biological processes determine epigenetic reprogramming and how these processes influence the variants in the cancer methylome, which can further impact cancer phenotypes. METHODS We performed pairwise permutations of 381,900 loci in 569 paired DNA methylation profiles of cancer tissue and matched normal tissue from The Cancer Genome Atlas (TCGA) and defined conserved differentially methylated positions (DMPs) based on the resulting null distribution. Then, we derived independent methylation signatures from 2,465 cancer-only methylation profiles from the TCGA and 241 cell line-based methylation profiles from the Genomics of Drug Sensitivity in Cancer (GDSC) cohort using nonnegative matrix factorization (NMF). We correlated DNA methylation signatures with various clinical and biological features, including age, survival, cancer stage, tumor immune microenvironment factors, and immunotherapy response. We inferred the determinant genes of these methylation signatures by integrating genomic and transcriptomic data and evaluated the impact of these signatures on cancer phenotypes in independent bulk and single-cell RNA/methylome cohorts. RESULTS We identified 7,364 differentially methylated positions (2,969 Hyper-DMPs and 4,395 Hypo-DMPs) in nine cancer types from the TCGA. We subsequently retrieved three highly conserved, independent methylation signatures (Hyper-MS1, Hypo-MS1, and Hypo-MS4) from cancer tissues and cell lines based on these Hyper and Hypo-DMPs. Our data suggested that Hypo-MS4 activity predicts poor survival and is associated with immunotherapy response and distant tumor metastasis, and Hypo-MS4 activity is related to TP53 mutation and FOXA1 binding specificity. In addition, we demonstrated a correlation between the activities of Hypo-MS4 in cancer cells and the fractions of regulatory CD4 + T cells with the expression levels of immunological genes in the tumor immune microenvironment. CONCLUSIONS Our findings demonstrated that the methylation signatures of distinct biological processes are associated with immune activity in the cancer microenvironment and predict immunotherapy response.
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Affiliation(s)
- Qingqing Qin
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, China
- School of Medicine, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, 361102, China
- Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Ying Zhou
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, China
- School of Medicine, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, 361102, China
- Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Jintao Guo
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, China
- School of Medicine, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, 361102, China
- Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Qinwei Chen
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, China
- School of Medicine, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, 361102, China
| | - Weiwei Tang
- Department of Medical Oncology, School of Medicine, The First Affiliated Hospital of Xiamen University and Institute of Hematology, Xiamen University, Xiamen, 361003, China
- Xiamen Key Laboratory of Antitumor Drug Transformation Research, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, The School of Clinical Medicine of Fujian, Medical University, Xiamen, 361003, China
| | - Yuchen Li
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, China
- School of Medicine, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, 361102, China
- Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, 361003, China
| | - Jun You
- Department of Gastrointestinal Oncology Surgery, The First Affiliated Hospital of Xiamen University, Cancer Center, Xiamen, 361003, China
| | - Qiyuan Li
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, China.
- School of Medicine, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, 361102, China.
- Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, 361003, China.
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16
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Kanai Y. Molecular pathological approach to cancer epigenomics and its clinical application. Pathol Int 2024; 74:167-186. [PMID: 38482965 PMCID: PMC11551818 DOI: 10.1111/pin.13418] [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: 01/09/2024] [Revised: 02/15/2024] [Accepted: 02/26/2024] [Indexed: 04/11/2024]
Abstract
Careful microscopic observation of histopathological specimens, accumulation of large numbers of high-quality tissue specimens, and analysis of molecular pathology in relation to morphological features are considered to yield realistic data on the nature of multistage carcinogenesis. Since the morphological hallmark of cancer is disruption of the normal histological structure maintained through cell-cell adhesiveness and cellular polarity, attempts have been made to investigate abnormalities of the cadherin-catenin cell adhesion system in human cancer cells. It has been shown that the CDH1 tumor suppressor gene encoding E-cadherin is silenced by DNA methylation, suggesting that a "double hit" involving DNA methylation and loss of heterozygosity leads to carcinogenesis. Therefore, in the 1990s, we focused on epigenomic mechanisms, which until then had not received much attention. In chronic hepatitis and liver cirrhosis associated with hepatitis virus infection, DNA methylation abnormalities were found to occur frequently, being one of the earliest indications that such abnormalities are present even in precancerous tissue. Aberrant expression and splicing of DNA methyltransferases, such as DNMT1 and DNMT3B, was found to underlie the mechanism of DNA methylation alterations in various organs. The CpG island methylator phenotype in renal cell carcinoma was identified for the first time, and its therapeutic targets were identified by multilayer omics analysis. Furthermore, the DNA methylation profile of nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma was clarified in groundbreaking studies. Since then, we have developed diagnostic markers for carcinogenesis risk in NASH patients and noninvasive diagnostic markers for upper urinary tract cancer, as well as developing a new high-performance liquid chromatography-based diagnostic system for DNA methylation diagnosis. Research on the cancer epigenome has revealed that DNA methylation alterations occur from the precancerous stage as a result of exposure to carcinogenic factors such as inflammation, smoking, and viral infections, and continuously contribute to multistage carcinogenesis through aberrant expression of cancer-related genes and genomic instability. DNA methylation alterations at the precancerous stages are inherited by or strengthened in cancers themselves and determine the clinicopathological aggressiveness of cancers as well as patient outcome. DNA methylation alterations have applications as biomarkers, and are expected to contribute to diagnosis, as well as preventive and preemptive medicine.
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Affiliation(s)
- Yae Kanai
- Department of PathologyKeio University School of MedicineTokyoJapan
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17
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Akram F, Tanveer R, Andleeb S, Shah FI, Ahmad T, Shehzadi S, Akhtar AM, Syed G. Deciphering the Epigenetic Symphony of Cancer: Insights and Epigenetic Therapies Implications. Technol Cancer Res Treat 2024; 23:15330338241250317. [PMID: 38780251 PMCID: PMC11119348 DOI: 10.1177/15330338241250317] [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: 12/31/2023] [Revised: 04/01/2024] [Accepted: 04/08/2024] [Indexed: 05/25/2024] Open
Abstract
Epigenetic machinery is a cornerstone in normal cell development, orchestrating tissue-specific gene expression in mammalian cells. Aberrations in this intricate landscape drive substantial changes in gene function, emerging as a linchpin in cancer etiology and progression. While cancer was conventionally perceived as solely a genetic disorder, its contemporary definition encompasses genetic alterations intertwined with disruptive epigenetic abnormalities. This review explores the profound impact of DNA methylation, histone modifications, and noncoding RNAs on fundamental cellular processes. When these pivotal epigenetic mechanisms undergo disruption, they intricately guide the acquisition of the 6 hallmark characteristics of cancer within seemingly normal cells. Leveraging the latest advancements in decoding these epigenetic intricacies holds immense promise, heralding a new era in developing targeted and more efficacious treatment modalities against cancers driven by aberrant epigenetic modifications.
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Affiliation(s)
- Fatima Akram
- Institute of Industrial Biotechnology, Government College University, Lahore, Pakistan
| | - Rida Tanveer
- School of Biological Sciences, University of the Punjab, Lahore, Pakistan
| | - Sahar Andleeb
- School of Biological Sciences, University of the Punjab, Lahore, Pakistan
| | - Fatima Iftikhar Shah
- Department of Medical Lab Technology, The University of Lahore, Lahore, Pakistan
| | - Tayyab Ahmad
- Department of Medicine, Fatima Memorial Hospital, Lahore, Pakistan
| | - Somia Shehzadi
- Department of Medical Lab Technology, The University of Lahore, Lahore, Pakistan
| | | | - Ghania Syed
- Centre for Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
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18
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Li F, Liu P, Mi W, Li L, Anderson NM, Lesner NP, Burrows M, Plesset J, Majer A, Wang G, Li J, Zhu L, Keith B, Simon MC. Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer. NATURE CANCER 2024; 5:131-146. [PMID: 38168934 PMCID: PMC11277537 DOI: 10.1038/s43018-023-00671-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 10/16/2023] [Indexed: 01/05/2024]
Abstract
Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is essential for liver tumor growth, and its inhibition can be exploited as an improved pro-senescence strategy for combination with senolytic agents to treat liver cancer.
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Affiliation(s)
- Fuming Li
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Pingyu Liu
- Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai, China
| | - Wen Mi
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| | - Liucheng Li
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| | - Nicole M Anderson
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Nicholas P Lesner
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Michelle Burrows
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jacqueline Plesset
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ariana Majer
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Guanlin Wang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| | - Jinyang Li
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| | - Lingzhi Zhu
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| | - Brian Keith
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - M Celeste Simon
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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19
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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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20
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Li S, Zhang H, Zhu M, Kuang Z, Li X, Xu F, Miao S, Zhang Z, Lou X, Li H, Xia F. Electrochemical Biosensors for Whole Blood Analysis: Recent Progress, Challenges, and Future Perspectives. Chem Rev 2023. [PMID: 37262362 DOI: 10.1021/acs.chemrev.1c00759] [Citation(s) in RCA: 66] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Whole blood, as one of the most significant biological fluids, provides critical information for health management and disease monitoring. Over the past 10 years, advances in nanotechnology, microfluidics, and biomarker research have spurred the development of powerful miniaturized diagnostic systems for whole blood testing toward the goal of disease monitoring and treatment. Among the techniques employed for whole-blood diagnostics, electrochemical biosensors, as known to be rapid, sensitive, capable of miniaturization, reagentless and washing free, become a class of emerging technology to achieve the target detection specifically and directly in complex media, e.g., whole blood or even in the living body. Here we are aiming to provide a comprehensive review to summarize advances over the past decade in the development of electrochemical sensors for whole blood analysis. Further, we address the remaining challenges and opportunities to integrate electrochemical sensing platforms.
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Affiliation(s)
- Shaoguang Li
- State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Hongyuan Zhang
- State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Man Zhu
- State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Zhujun Kuang
- State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Xun Li
- State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Fan Xu
- State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Siyuan Miao
- State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Zishuo Zhang
- State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Xiaoding Lou
- State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Hui Li
- State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Fan Xia
- State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
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D'Amico F, Graziano R, D'Aria F, Russomanno P, Di Fonzo S, Amato J, Pagano B. Cytosine epigenetic modifications and conformational changes in G-quadruplex DNA: An ultraviolet resonance Raman spectroscopy study. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2023; 300:122901. [PMID: 37244027 DOI: 10.1016/j.saa.2023.122901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/26/2023] [Accepted: 05/17/2023] [Indexed: 05/29/2023]
Abstract
Epigenetic modifications of DNA are known to play important regulatory roles in biological systems, especially in regulation of gene expression, and are associated with many types of human diseases, including cancer. Alternative DNA secondary structures, such as G-quadruplexes, can also influence gene transcription, thus suggesting that such structures may represent a distinctive layer of epigenetic information. G-quadruplex structures and DNA epigenetic modifications often go side by side, and recent evidence reveals that cytosine modifications within loops of G-quadruplexes can play a role in modulating their stability and structural polymorphism. Therefore, the development and validation of experimental techniques that can easily and reliably analyse G-quadruplex structures are highly desirable. In the present study, we propose to exploit the advantages of UV resonance Raman (UVRR) spectroscopy to investigate cytosine epigenetic modifications along with conformational changes in G-quadruplex-forming DNA. Our findings show that clear and specific spectral changes occur when there is a change in a G-quadruplex structure. Moreover, UVRR spectral analysis can indirectly distinguish the spectral variations occurring because of modifications in the guanine glycosidic conformations, as well as detect changes in the loops induced by H-bond formation or hydration of nitrogenous bases. The results further underscore the utility of UVRR spectroscopy for G-quadruplex structure elucidation under biologically relevant solution conditions.
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Affiliation(s)
- Francesco D'Amico
- Elettra-Sincrotrone Trieste S. C. p. A., Science Park, Trieste I-34149, Italy
| | - Raffaele Graziano
- Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy
| | - Federica D'Aria
- Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy
| | - Pasquale Russomanno
- Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy
| | - Silvia Di Fonzo
- Elettra-Sincrotrone Trieste S. C. p. A., Science Park, Trieste I-34149, Italy
| | - Jussara Amato
- Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.
| | - Bruno Pagano
- Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.
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22
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Besselink N, Keijer J, Vermeulen C, Boymans S, de Ridder J, van Hoeck A, Cuppen E, Kuijk E. The genome-wide mutational consequences of DNA hypomethylation. Sci Rep 2023; 13:6874. [PMID: 37106015 PMCID: PMC10140063 DOI: 10.1038/s41598-023-33932-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 04/21/2023] [Indexed: 04/29/2023] Open
Abstract
DNA methylation is important for establishing and maintaining cell identity and for genomic stability. This is achieved by regulating the accessibility of regulatory and transcriptional elements and the compaction of subtelomeric, centromeric, and other inactive genomic regions. Carcinogenesis is accompanied by a global loss in DNA methylation, which facilitates the transformation of cells. Cancer hypomethylation may also cause genomic instability, for example through interference with the protective function of telomeres and centromeres. However, understanding the role(s) of hypomethylation in tumor evolution is incomplete because the precise mutational consequences of global hypomethylation have thus far not been systematically assessed. Here we made genome-wide inventories of all possible genetic variation that accumulates in single cells upon the long-term global hypomethylation by CRISPR interference-mediated conditional knockdown of DNMT1. Depletion of DNMT1 resulted in a genomewide reduction in DNA methylation. The degree of DNA methylation loss was similar to that observed in many cancer types. Hypomethylated cells showed reduced proliferation rates, increased transcription of genes, reactivation of the inactive X-chromosome and abnormal nuclear morphologies. Prolonged hypomethylation was accompanied by increased chromosomal instability. However, there was no increase in mutational burden, enrichment for certain mutational signatures or accumulation of structural variation to the genome. In conclusion, the primary consequence of hypomethylation is genomic instability, which in cancer leads to increased tumor heterogeneity and thereby fuels cancer evolution.
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Affiliation(s)
- Nicolle Besselink
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Janneke Keijer
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Carlo Vermeulen
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Sander Boymans
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jeroen de Ridder
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Arne van Hoeck
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Edwin Cuppen
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Hartwig Medical Foundation, Amsterdam, The Netherlands
| | - Ewart Kuijk
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
- Division of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
- Regenerative Medicine Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
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23
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El-Sayed A, Aleya L, Kamel M. Epigenetics and the role of nutraceuticals in health and disease. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:28480-28505. [PMID: 36694069 DOI: 10.1007/s11356-023-25236-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 01/05/2023] [Indexed: 06/17/2023]
Abstract
In the post-genomic era, the data provided by complete genome sequencing could not answer several fundamental questions about the causes of many noninfectious diseases, diagnostic biomarkers, and novel therapeutic approaches. The rapidly expanding understanding of epigenetic mechanisms, as well as widespread acceptance of their hypothesized role in disease induction, facilitated the development of a number of novel diagnostic markers and therapeutic concepts. Epigenetic aberrations are reversible in nature, which enables the treatment of serious incurable diseases. Therefore, the interest in epigenetic modulatory effects has increased over the last decade, so about 60,000 publications discussing the expression of epigenetics could be detected in the PubMed database. Out of these, 58,442 were published alone in the last 10 years, including 17,672 reviews (69 historical articles), 314 clinical trials, 202 case reports, 197 meta-analyses, 156 letters to the editor, 108 randomized controlled trials, 87 observation studies, 40 book chapters, 22 published lectures, and 2 clinical trial protocols. The remaining publications are either miscellaneous or a mixture of the previously mentioned items. According to the species and gender, the publications included 44,589 human studies (17,106 females, 14,509 males, and the gender is not mentioned in the remaining papers) and 30,253 animal studies. In the present work, the role of epigenetic modulations in health and disease and the influencing factors in epigenetics are discussed.
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Affiliation(s)
- Amr El-Sayed
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
| | - Lotfi Aleya
- Chrono-Environnement Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, 25030, Besançon Cedex, France
| | - Mohamed Kamel
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt.
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24
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Galati S, DalCorso G, Furini A, Fragni R, Maccari C, Mozzoni P, Giannelli G, Buschini A, Visioli G. DNA methylation is enhanced during Cd hyperaccumulation in Noccaea caerulescens ecotype Ganges. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:26178-26190. [PMID: 36352075 PMCID: PMC9995422 DOI: 10.1007/s11356-022-23983-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/30/2022] [Indexed: 06/16/2023]
Abstract
In this study, we assess the DNA damage occurring in response to cadmium (Cd) in the Cd hyperaccumulator Noccaea caerulescens Ganges (GA) vs the non-accumulator and close-relative species Arabidopsis thaliana. At this purpose, the alkaline comet assay was utilized to evaluate the Cd-induced variations in nucleoids and the methy-sens comet assay, and semiquantitative real-time (qRT)-PCR were also performed to associate nucleus variations to possible DNA modifications. Cadmium induced high DNA damages in nuclei of A. thaliana while only a small increase in DNA migration was observed in N. caerulescens GA. In addition, in N. caerulescens GA, CpG DNA methylation increase upon Cd when compared to control condition, along with an increase in the expression of MET1 gene, coding for the DNA-methyltransferase. N. caerulescens GA does not show any oxidative stress under Cd treatment, while A. thaliana Cd-treated plants showed an upregulation of transcripts of the respiratory burst oxidase, accumulation of reactive oxygen species, and enhanced superoxide dismutase activity. These data suggest that epigenetic modifications occur in the N. caerulescens GA exposed to Cd to preserve genome integrity, contributing to Cd tolerance.
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Affiliation(s)
- Serena Galati
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
| | | | - Antonella Furini
- Department of Biotechnology, University of Verona, Verona, Italy
| | - Rosaria Fragni
- SSICA, Experimental Station for the Food Preserving Industry, Parma, Italy
| | - Chiara Maccari
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Paola Mozzoni
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Centre for Research in Toxicology (CERT), University of Parma, Parma, Italy
| | - Gianluigi Giannelli
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
| | - Annamaria Buschini
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
| | - Giovanna Visioli
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy.
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25
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Ko B, Hanna M, Yu M, Grady WM. Epigenetic Alterations in Colorectal Cancer. EPIGENETICS AND HUMAN HEALTH 2023:331-361. [DOI: 10.1007/978-3-031-42365-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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26
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Weekman EM, Winder Z, Rogers CB, Abner EL, Sudduth TL, Patel E, Dugan AJ, Fister SX, Wasek B, Nelson PT, Jicha GA, Bottiglieri T, Fardo DW, Wilcock DM. Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue. ALZHEIMER'S & DEMENTIA (NEW YORK, N. Y.) 2022; 8:e12368. [PMID: 36514441 PMCID: PMC9732462 DOI: 10.1002/trc2.12368] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 11/09/2022] [Accepted: 11/11/2022] [Indexed: 12/14/2022]
Abstract
Introduction Vascular contributions to cognitive impairment and dementia (VCID) are a leading cause of dementia. An underappreciated, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), defined by elevated levels of plasma homocysteine, most often due to impaired B vitamin absorption in aged persons. Studies aimed at identifying neuropathologic features and gene expression profiles associated with HHcy have been lacking. Methods A subset of research volunteers from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort came to autopsy and had ante mortem plasma homocysteine levels available. Brain tissue and blood plasma drawn closest to death were used to measure homocysteine and related metabolites in the current pilot study. Genetic expression profiles of inflammatory markers were evaluated using the Human Neuroinflammation NanoString panel. Further analyses included an evaluation of plasma homocysteine effects on amyloid beta, tau, ionized calcium-binding adaptor molecule 1, and glial fibrillary acidic protein immunohistochemistry in the frontal and occipital cortices. Analytes and other study outcomes were evaluated in relation to ante mortem HHcy status: We identified 13 persons with normal ante mortem plasma homocysteine levels (<14 µmol/L) and 18 who had high plasma homocysteine levels (≥14 µmol/L). Results Participants with HHcy demonstrated increased levels of several plasma homocysteine cycle metabolites such as total cysteine, S-adenosyl-homocysteine, cystathionine, and choline. Inflammatory gene expression profiles showed a general downregulation in the setting of elevated plasma homocysteine. HHcy was associated with more and longer microglial processes, but smaller and fewer astrocytes, especially in participants of older age at death. HHcy in older participants was also associated with occipital cortex microhemorrhages and increased severity of atherosclerosis throughout the cerebral vasculature. Conclusions Increased plasma homocysteine and older age were associated with the downregulation of inflammatory gene expression markers in association with significant glial and vascular pathology changes. Impaired immune function is a plausible mechanism by which HHcy increases cerebrovascular damage leading to impaired cognitive function.
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Affiliation(s)
- Erica M. Weekman
- Sanders‐Brown Center on AgingUniversity of KentuckyLexingtonKentuckyUSA
| | - Zach Winder
- Sanders‐Brown Center on AgingUniversity of KentuckyLexingtonKentuckyUSA
| | - Colin B. Rogers
- Sanders‐Brown Center on AgingUniversity of KentuckyLexingtonKentuckyUSA
| | - Erin L. Abner
- Sanders‐Brown Center on AgingUniversity of KentuckyLexingtonKentuckyUSA
| | | | - Ela Patel
- Sanders‐Brown Center on AgingUniversity of KentuckyLexingtonKentuckyUSA
| | - Adam J. Dugan
- Sanders‐Brown Center on AgingUniversity of KentuckyLexingtonKentuckyUSA
| | - Shuling X. Fister
- Sanders‐Brown Center on AgingUniversity of KentuckyLexingtonKentuckyUSA
| | - Brandi Wasek
- Baylor Scott and White Research InstituteCenter of MetabolomicsInstitute of Metabolic DiseaseDallasTexasUSA
| | - Peter T. Nelson
- Sanders‐Brown Center on AgingUniversity of KentuckyLexingtonKentuckyUSA
| | - Gregory A. Jicha
- Sanders‐Brown Center on AgingUniversity of KentuckyLexingtonKentuckyUSA
| | - Teodoro Bottiglieri
- Baylor Scott and White Research InstituteCenter of MetabolomicsInstitute of Metabolic DiseaseDallasTexasUSA
| | - David W. Fardo
- Sanders‐Brown Center on AgingUniversity of KentuckyLexingtonKentuckyUSA
| | - Donna M. Wilcock
- Sanders‐Brown Center on AgingUniversity of KentuckyLexingtonKentuckyUSA
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27
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Bisht D, Arora A, Sachan M. Role of DNA De-methylation intermediate '5-hydroxymethylcytosine' in ovarian cancer management: A comprehensive review. Biomed Pharmacother 2022; 155:113674. [PMID: 36099791 DOI: 10.1016/j.biopha.2022.113674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/31/2022] [Accepted: 09/05/2022] [Indexed: 11/16/2022] Open
Abstract
Ovarian cancer remains the most eminent silent killer, with high morbidity and mortality among all gynaecological cancers. The advanced-stage patient's diagnosis has a low survival rate caused by its asymptomatic progression and diverse histopathological sub-types, wherefore in poor prognosis and highly recurring malignancy with multidrug resistance towards chemotherapy. Epigenetic biomarkers open promising avenues of intriguing research to combat OC malignancy, furthermore a tool for its early diagnosis. 5-hydroxymethycytosine (5-hmC), alias the sixth base of the genome, is an intermediate formed during the recently established DNA demethylation process and catalysed via ten-eleven translocation (TET) family of enzymes. It plays a significant role in regulating gene expression and has sparked interest in various cancer types. This review summarizes the role of active DNA demethylation process, its enzymes and intermediate 5-hmC in epigenetic landscape of ovarian cancer as a potent biomarker for clinical translation in identification of therapeutic targets, diagnostic and prognostic evaluation.
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Affiliation(s)
- Deepa Bisht
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, Uttar Pradesh, India
| | - Arisha Arora
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, 781039 Assam, India
| | - Manisha Sachan
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, Uttar Pradesh, India.
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28
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Awal MA, Nur SM, Al Khalaf AK, Rehan M, Ahmad A, Hosawi SBI, Choudhry H, Khan MI. Structural-Guided Identification of Small Molecule Inhibitor of UHRF1 Methyltransferase Activity. Front Genet 2022; 13:928884. [PMID: 35991572 PMCID: PMC9382028 DOI: 10.3389/fgene.2022.928884] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/17/2022] [Indexed: 11/13/2022] Open
Abstract
Ubiquitin-like containing plant homeodomain Ring Finger 1 (UHRF1) protein is recognized as a cell-cycle-regulated multidomain protein. UHRF1 importantly manifests the maintenance of DNA methylation mediated by the interaction between its SRA (SET and RING associated) domain and DNA methyltransferase-1 (DNMT1)-like epigenetic modulators. However, overexpression of UHRF1 epigenetically responds to the aberrant global methylation and promotes tumorigenesis. To date, no potential molecular inhibitor has been studied against the SRA domain. Therefore, this study focused on identifying the active natural drug-like candidates against the SRA domain. A comprehensive set of in silico approaches including molecular docking, molecular dynamics (MD) simulation, and toxicity analysis was performed to identify potential candidates. A dataset of 709 natural compounds was screened through molecular docking where chicoric acid and nystose have been found showing higher binding affinities to the SRA domain. The MD simulations also showed the protein ligand interaction stability of and in silico toxicity analysis has also showed chicoric acid as a safe and nontoxic drug. In addition, chicoric acid possessed a longer interaction time and higher LD50 of 5000 mg/kg. Moreover, the global methylation level (%5 mC) has been assessed after chicoric acid treatment was in the colorectal cancer cell line (HCT116) at different doses. The result showed that 7.5 µM chicoric acid treatment reduced methylation levels significantly. Thus, the study found chicoric acid can become a possible epidrug-like inhibitor against the SRA domain of UHRF1 protein.
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Affiliation(s)
- Md Abdul Awal
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Suza Mohammad Nur
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ali Khalaf Al Khalaf
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohd Rehan
- King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Aamir Ahmad
- Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Salman Bakr I. Hosawi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hani Choudhry
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Centre of Artificial Intelligence for Precision Medicines, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammad Imran Khan
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Centre of Artificial Intelligence for Precision Medicines, King Abdulaziz University, Jeddah, Saudi Arabia
- *Correspondence: Mohammad Imran Khan,
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29
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Watcharanurak P, Mutirangura A. Human RNA-directed DNA methylation methylates high-mobility group box 1 protein-produced DNA gaps. Epigenomics 2022; 14:741-756. [PMID: 35762252 DOI: 10.2217/epi-2022-0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Background: DNA sequences around HMGB1-produced DNA gaps are hypermethylates. DNA methylation of interspersed repetitive sequences (IRS) such as Alu elements can be established through AGO4-mediating, RNA-directed DNA methylation (RdDM). HMGB1 depletion, DNA gap reduction and global hypomethylation promote genomic instability. Methods: HMGB1, SIRT1, AGO4 and DNA gap colocalizations were evaluated. Then, Alu methylation was analyzed in HMGB1-deficient or HMGB1-overexpressing cells and Alu siRNA-transfected HMGB1-deficient cells. Results: HMGB1, SIRT1, AGO4 and DNA gap are colocalized in the nucleus. Moreover, HMGB1 or Alu siRNA increased Alu methylation, whereas Alu siRNA could not methylate HMGB1-deficient cells. Conclusion: AGO4 play a role in methylating DNA sequence around HMGB1-produced DNA gaps and localize DNA gap in IRS, and loss of intranuclear HMGB1 causes global hypomethylation.
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Affiliation(s)
- Papitchaya Watcharanurak
- Interdisciplinary Program of Biomedical Sciences, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand.,Department of Anatomy, Center of Excellence in Molecular Genetics of Cancer & Human Disease, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Apiwat Mutirangura
- Department of Anatomy, Center of Excellence in Molecular Genetics of Cancer & Human Disease, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
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CpG Methylation Altered the Stability and Structure of the i-Motifs Located in the CpG Islands. Int J Mol Sci 2022; 23:ijms23126467. [PMID: 35742916 PMCID: PMC9223787 DOI: 10.3390/ijms23126467] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/04/2022] [Accepted: 06/07/2022] [Indexed: 11/25/2022] Open
Abstract
Cytosine methylation within the 5′-C-phosphate-G-3′ sequence of nucleotides (called CpG methylation) is a well-known epigenetic modification of genomic DNA that plays an important role in gene expression and development. CpG methylation is likely to be altered in the CpG islands. CpG islands are rich in cytosine, forming a structure called the i-motif via cytosine-cytosine hydrogen bonding. However, little is known about the effect of CpG methylation on the i-motif. In this study, The CpG methylation-induced structural changes on the i-motif was examined by thermal stability, circular dichroism (CD) spectroscopy, and native-polyacrylamide gel electrophoresis (Native-PAGE) evaluation of five i-motif-forming DNAs from four cancer-related genes (VEGF, C-KIT, BCL2, and HRAS). This research shows that CpG methylation increased the transitional pH of several i-motif-forming DNAs and their thermal stability. When examining the effect of CpG methylation on the i-motif in the presence of opposite G4-forming DNAs, CpG methylation influenced the proportion of G4 and i-motif formation. This study showed that CpG methylation altered the stability and structure of the i-motif in CpG islands.
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31
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Switzer CH, Cho HJ, Eykyn TR, Lavender P, Eaton P. NOS2 and S-nitrosothiol signaling induces DNA hypomethylation and LINE-1 retrotransposon expression. Proc Natl Acad Sci U S A 2022; 119:e2200022119. [PMID: 35584114 PMCID: PMC9173756 DOI: 10.1073/pnas.2200022119] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 03/29/2022] [Indexed: 12/31/2022] Open
Abstract
Inducible nitric oxide synthase (NOS2) produces high local concentrations of nitric oxide (NO), and its expression is associated with inflammation, cellular stress signals, and cellular transformation. Additionally, NOS2 expression results in aggressive cancer cell phenotypes and is correlated with poor outcomes in patients with breast cancer. DNA hypomethylation, especially of noncoding repeat elements, is an early event in carcinogenesis and is a common feature of cancer cells. In addition to altered gene expression, DNA hypomethylation results in genomic instability via retrotransposon activation. Here, we show that NOS2 expression and associated NO signaling results in substantial DNA hypomethylation in human cell lines by inducing the degradation of DNA (cytosine-5)–methyltransferase 1 (DNMT1) protein. Similarly, NOS2 expression levels were correlated with decreased DNA methylation in human breast tumors. NOS2 expression and NO signaling also resulted in long interspersed noncoding element 1 (LINE-1) retrotransposon hypomethylation, expression, and DNA damage. DNMT1 degradation was mediated by an NO/p38-MAPK/lysine acetyltransferase 5–dependent mechanism. Furthermore, we show that this mechanism is required for NO-mediated epithelial transformation. Therefore, we conclude that NOS2 and NO signaling results in DNA damage and malignant cellular transformation via an epigenetic mechanism.
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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, EC1M 6BQ, United Kingdom
| | - Hyun-Ju Cho
- William Harvey Research Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, United Kingdom
| | - Thomas R. Eykyn
- School of Biomedical Engineering & Imaging Sciences, King’s College London, St. Thomas’ Hospital, London, SE1 7EH, United Kingdom
| | - Paul Lavender
- AsthmaUK Centre in Allergic Mechanisms of Asthma, School of Immunology and Microbial Science, King’s College London, Guy’s Hospital, London, SE1 9RT, United Kingdom
| | - Philip Eaton
- William Harvey Research Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, United Kingdom
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32
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Multi-scale Chimerism: An experimental window on the algorithms of anatomical control. Cells Dev 2022; 169:203764. [PMID: 34974205 DOI: 10.1016/j.cdev.2021.203764] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 12/12/2021] [Accepted: 12/24/2021] [Indexed: 12/22/2022]
Abstract
Despite the immense progress in genetics and cell biology, major knowledge gaps remain with respect to prediction and control of the global morphologies that will result from the cooperation of cells with known genomes. The understanding of cooperativity, competition, and synergy across diverse biological scales has been obscured by a focus on standard model systems that exhibit invariant species-specific anatomies. Morphogenesis of chimeric biological material is an especially instructive window on the control of biological growth and form because it emphasizes the need for prediction without reliance on familiar, standard outcomes. Here, we review an important and fascinating body of data from experiments utilizing DNA transfer, cell transplantation, organ grafting, and parabiosis. We suggest that these are all instances (at different levels of organization) of one general phenomenon: chimerism. Multi-scale chimeras are a powerful conceptual and experimental tool with which to probe the mapping between properties of components and large-scale anatomy: the laws of morphogenesis. The existing data and future advances in this field will impact not only the understanding of cooperation and the evolution of body forms, but also the design of strategies for system-level outcomes in regenerative medicine and swarm robotics.
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33
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The Role of Epigenetic Modifications in Human Cancers and the Use of Natural Compounds as Epidrugs: Mechanistic Pathways and Pharmacodynamic Actions. Biomolecules 2022; 12:biom12030367. [PMID: 35327559 PMCID: PMC8945214 DOI: 10.3390/biom12030367] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/16/2022] [Accepted: 01/18/2022] [Indexed: 12/03/2022] Open
Abstract
Cancer is a complex disease resulting from the genetic and epigenetic disruption of normal cells. The mechanistic understanding of the pathways involved in tumor transformation has implicated a priori predominance of epigenetic perturbations and a posteriori genetic instability. In this work, we aimed to explain the mechanistic involvement of epigenetic pathways in the cancer process, as well as the abilities of natural bioactive compounds isolated from medicinal plants (flavonoids, phenolic acids, stilbenes, and ketones) to specifically target the epigenome of tumor cells. The molecular events leading to transformation, angiogenesis, and dissemination are often complex, stochastic, and take turns. On the other hand, the decisive advances in genomics, epigenomics, transcriptomics, and proteomics have allowed, in recent years, for the mechanistic decryption of the molecular pathways of the cancerization process. This could explain the possibility of specifically targeting this or that mechanism leading to cancerization. With the plasticity and flexibility of epigenetic modifications, some studies have started the pharmacological screening of natural substances against different epigenetic pathways (DNA methylation, histone acetylation, histone methylation, and chromatin remodeling) to restore the cellular memory lost during tumor transformation. These substances can inhibit DNMTs, modify chromatin remodeling, and adjust histone modifications in favor of pre-established cell identity by the differentiation program. Epidrugs are molecules that target the epigenome program and can therefore restore cell memory in cancerous diseases. Natural products isolated from medicinal plants such as flavonoids and phenolic acids have shown their ability to exhibit several actions on epigenetic modifiers, such as the inhibition of DNMT, HMT, and HAT. The mechanisms of these substances are specific and pleiotropic and can sometimes be stochastic, and their use as anticancer epidrugs is currently a remarkable avenue in the fight against human cancers.
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Datta S, Patel M, Kashyap S, Patel D, Singh U. Chimeric chromosome landscapes of human somatic cell cultures show dependence on stress and regulation of genomic repeats by CGGBP1. Oncotarget 2022; 13:136-155. [PMID: 35070079 PMCID: PMC8765472 DOI: 10.18632/oncotarget.28174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 12/20/2021] [Indexed: 11/25/2022] Open
Abstract
Genomes of somatic cells in culture are prone to spontaneous mutations due to errors in replication and DNA repair. Some of these errors, such as chromosomal fusions, are not rectifiable and subject to selection or elimination in growing cultures. Somatic cell cultures are thus expected to generate background levels of potentially stable chromosomal chimeras. A description of the landscape of such spontaneously generated chromosomal chimeras in cultured cells will help understand the factors affecting somatic mosaicism. Here we show that short homology-associated non-homologous chromosomal chimeras occur in normal human fibroblasts and HEK293T cells at genomic repeats. The occurrence of chromosomal chimeras is enhanced by heat stress and depletion of a repeat regulatory protein CGGBP1. We also present evidence of homologous chromosomal chimeras between allelic copies in repeat-rich DNA obtained by methylcytosine immunoprecipitation. The formation of homologous chromosomal chimeras at Alu and L1 repeats increases upon depletion of CGGBP1. Our data are derived from de novo sequencing from three different cell lines under different experimental conditions and our chromosomal chimera detection pipeline is applicable to long as well as short read sequencing platforms. These findings present significant information about the generation, sensitivity and regulation of somatic mosaicism in human cell cultures.
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Affiliation(s)
- Subhamoy Datta
- HoMeCell Lab, Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat 382355, India
| | - Manthan Patel
- HoMeCell Lab, Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat 382355, India
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, UK
| | - Sukesh Kashyap
- HoMeCell Lab, Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat 382355, India
| | - Divyesh Patel
- HoMeCell Lab, Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat 382355, India
- Current address: Research Programs Unit, Applied Tumor Genomics Program, Faculty of Medicine, University of Helsinki, Biomedicum, Helsinki 00290, Finland
| | - Umashankar Singh
- HoMeCell Lab, Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat 382355, India
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Yildiz CB, Zimmer-Bensch G. Role of DNMTs in the Brain. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1389:363-394. [DOI: 10.1007/978-3-031-11454-0_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Adampourezare M, Saadati A, Hasanzadeh M, Dehghan G, Feizi MAH. Reliable recognition of DNA methylation using bioanalysis of hybridization on the surface of Ag/GQD nanocomposite stabilized on poly (β-cyclodextrin): A new platform for DNA damage studies using genosensor technology. J Mol Recognit 2021; 35:e2945. [PMID: 34904757 DOI: 10.1002/jmr.2945] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 11/26/2021] [Accepted: 11/27/2021] [Indexed: 12/27/2022]
Abstract
Due to the role of DNA methylation in causing cancer in the present study, an innovative and inexpensive method was designed for the sensitive detection of DNA methylation. The silver-graphene quantum dots (Ag/GQDs) nano ink with high electrical conductivity was used as a substrate for genosensor fabrication toward identification of DNA hybridization. Also, poly (β-cyclodextrin) (p[β-CD]) has been used as a biointerface for the stabilization of Ag/GQD nano ink. The thiolated pDNA strand (5'-SH-TCCGCTTCCCGACCCGCACTCCGC-3') (as bioreceptor element) was fixed on the substrate and hybridized with methylated (5'-GC(M)GGAGTGC(M)GGGTC(M)GGGAAGC(M)GGA-3') and unmethylated (5'-GCGGAGTGCGGGTCGGGAAGCGGA-3') cDNAs, as target sequences were studied using electroanalysis methods. Under optimal conditions and using electrochemical techniques, the linear range was 1 am to 1 pm with LLOQ of 1aM. Finally, the designed DNA genosensor was used for detection of DNA methylation in human plasma samples and can be used to detect methylation in patient samples. It is expected that the designed DNA-based biodevice will be used to early stage diagnosis of cancer using monitoring of DNA methylation. Also, this type of genosensor can be used for epigenetic studies in the near future.
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Affiliation(s)
- Mina Adampourezare
- Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran.,Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arezoo Saadati
- Food and Drug Safety Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hasanzadeh
- Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gholamreza Dehghan
- Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
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Mensah IK, Norvil AB, AlAbdi L, McGovern S, Petell CJ, He M, Gowher H. Misregulation of the expression and activity of DNA methyltransferases in cancer. NAR Cancer 2021; 3:zcab045. [PMID: 34870206 PMCID: PMC8634572 DOI: 10.1093/narcan/zcab045] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/29/2021] [Accepted: 11/10/2021] [Indexed: 12/15/2022] Open
Abstract
In mammals, DNA methyltransferases DNMT1 and DNMT3's (A, B and L) deposit and maintain DNA methylation in dividing and nondividing cells. Although these enzymes have an unremarkable DNA sequence specificity (CpG), their regional specificity is regulated by interactions with various protein factors, chromatin modifiers, and post-translational modifications of histones. Changes in the DNMT expression or interacting partners affect DNA methylation patterns. Consequently, the acquired gene expression may increase the proliferative potential of cells, often concomitant with loss of cell identity as found in cancer. Aberrant DNA methylation, including hypermethylation and hypomethylation at various genomic regions, therefore, is a hallmark of most cancers. Additionally, somatic mutations in DNMTs that affect catalytic activity were mapped in Acute Myeloid Leukemia cancer cells. Despite being very effective in some cancers, the clinically approved DNMT inhibitors lack specificity, which could result in a wide range of deleterious effects. Elucidating distinct molecular mechanisms of DNMTs will facilitate the discovery of alternative cancer therapeutic targets. This review is focused on: (i) the structure and characteristics of DNMTs, (ii) the prevalence of mutations and abnormal expression of DNMTs in cancer, (iii) factors that mediate their abnormal expression and (iv) the effect of anomalous DNMT-complexes in cancer.
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Affiliation(s)
- Isaiah K Mensah
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | | | - Lama AlAbdi
- Department of Zoology, Collage of Science, King Saud University, Riyadh, Saudi Arabia
| | - Sarah McGovern
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | | | - Ming He
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Humaira Gowher
- Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
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Desaulniers D, Vasseur P, Jacobs A, Aguila MC, Ertych N, Jacobs MN. Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications. Int J Mol Sci 2021; 22:10969. [PMID: 34681626 PMCID: PMC8535778 DOI: 10.3390/ijms222010969] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/30/2021] [Accepted: 10/04/2021] [Indexed: 12/15/2022] Open
Abstract
Epigenetics involves a series of mechanisms that entail histone and DNA covalent modifications and non-coding RNAs, and that collectively contribute to programing cell functions and differentiation. Epigenetic anomalies and DNA mutations are co-drivers of cellular dysfunctions, including carcinogenesis. Alterations of the epigenetic system occur in cancers whether the initial carcinogenic events are from genotoxic (GTxC) or non-genotoxic (NGTxC) carcinogens. NGTxC are not inherently DNA reactive, they do not have a unifying mode of action and as yet there are no regulatory test guidelines addressing mechanisms of NGTxC. To fil this gap, the Test Guideline Programme of the Organisation for Economic Cooperation and Development is developing a framework for an integrated approach for the testing and assessment (IATA) of NGTxC and is considering assays that address key events of cancer hallmarks. Here, with the intent of better understanding the applicability of epigenetic assays in chemical carcinogenicity assessment, we focus on DNA methylation and histone modifications and review: (1) epigenetic mechanisms contributing to carcinogenesis, (2) epigenetic mechanisms altered following exposure to arsenic, nickel, or phenobarbital in order to identify common carcinogen-specific mechanisms, (3) characteristics of a series of epigenetic assay types, and (4) epigenetic assay validation needs in the context of chemical hazard assessment. As a key component of numerous NGTxC mechanisms of action, epigenetic assays included in IATA assay combinations can contribute to improved chemical carcinogen identification for the better protection of public health.
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Affiliation(s)
- Daniel Desaulniers
- Environmental Health Sciences and Research Bureau, Hazard Identification Division, Health Canada, AL:2203B, Ottawa, ON K1A 0K9, Canada
| | - Paule Vasseur
- CNRS, LIEC, Université de Lorraine, 57070 Metz, France;
| | - Abigail Jacobs
- Independent at the Time of Publication, Previously US Food and Drug Administration, Rockville, MD 20852, USA;
| | - M. Cecilia Aguila
- Toxicology Team, Division of Human Food Safety, Center for Veterinary Medicine, US Food and Drug Administration, Department of Health and Human Services, Rockville, MD 20852, USA;
| | - Norman Ertych
- German Centre for the Protection of Laboratory Animals (Bf3R), German Federal Institute for Risk Assessment, Diedersdorfer Weg 1, 12277 Berlin, Germany;
| | - Miriam N. Jacobs
- Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton OX11 0RQ, UK;
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Noonepalle SKR, Karabon L, Chiappinelli KB, Villagra A. Editorial: Genetic and Epigenetic Control of Immune Responses. Front Immunol 2021; 12:775101. [PMID: 34675944 PMCID: PMC8523980 DOI: 10.3389/fimmu.2021.775101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 09/16/2021] [Indexed: 12/15/2022] Open
Affiliation(s)
- Satish kumar R. Noonepalle
- Department of Biochemistry and Molecular Medicine, GW Cancer Center, School of Medicine and Health Sciences, George Washington University, Washington DC, United States
| | - Lidia Karabon
- Department of Experimental Therapy, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Katherine B. Chiappinelli
- Department of Microbiology, Immunology, and Tropical Medicine, GW Cancer Center, School of Medicine and Health Sciences, George Washington University, Washington DC, United States
| | - Alejandro Villagra
- Department of Biochemistry and Molecular Medicine, GW Cancer Center, School of Medicine and Health Sciences, George Washington University, Washington DC, United States
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An Epigenetic Perspective on Intra-Tumour Heterogeneity: Novel Insights and New Challenges from Multiple Fields. Cancers (Basel) 2021; 13:cancers13194969. [PMID: 34638453 PMCID: PMC8508087 DOI: 10.3390/cancers13194969] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/29/2021] [Accepted: 10/01/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Although research on cancer biology in recent decades has unveiled the main genetic perturbations driving the onset of tumorigenesis, we are still far from properly treating this disease without the occurrence of drug resistance and metastatic burden. This achievement is hampered by the onset of intra-tumour heterogeneity (ITH), which increases cancer cell fitness and plasticity, thereby fostering cell adaptation to foreign environments and stimuli. In this review, we discuss the contribution of the epigenetic factors in sustaining ITH and their interplay with the tumour microenvironment. We also highlight the recent technological advancements that are contributing to defining the epigenetic mechanisms governing tumour heterogeneity at the single-cell level. Abstract Cancer is a group of heterogeneous diseases that results from the occurrence of genetic alterations combined with epigenetic changes and environmental stimuli that increase cancer cell plasticity. Indeed, multiple cancer cell populations coexist within the same tumour, favouring cancer progression and metastatic dissemination as well as drug resistance, thereby representing a major obstacle for treatment. Epigenetic changes contribute to the onset of intra-tumour heterogeneity (ITH) as they facilitate cell adaptation to perturbation of the tumour microenvironment. Despite being its central role, the intrinsic multi-layered and reversible epigenetic pattern limits the possibility to uniquely determine its contribution to ITH. In this review, we first describe the major epigenetic mechanisms involved in tumourigenesis and then discuss how single-cell-based approaches contribute to dissecting the key role of epigenetic changes in tumour heterogeneity. Furthermore, we highlight the importance of dissecting the interplay between genetics, epigenetics, and tumour microenvironments to decipher the molecular mechanisms governing tumour progression and drug resistance.
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Recalde M, Gárate-Rascón M, Elizalde M, Azkona M, Latasa MU, Bárcena-Varela M, Sangro B, Fernández-Barrena MG, Ávila MA, Arechederra M, Berasain C. The splicing regulator SLU7 is required to preserve DNMT1 protein stability and DNA methylation. Nucleic Acids Res 2021; 49:8592-8609. [PMID: 34331453 PMCID: PMC8421144 DOI: 10.1093/nar/gkab649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 07/01/2021] [Accepted: 07/21/2021] [Indexed: 01/13/2023] Open
Abstract
Gene expression is finely and dynamically controlled through the tightly coordinated and interconnected activity of epigenetic modulators, transcription and splicing factors and post-translational modifiers. We have recently identified the splicing factor SLU7 as essential for maintaining liver cell identity and genome integrity and for securing cell division both trough transcriptional and splicing mechanisms. Now we uncover a new function of SLU7 controlling gene expression at the epigenetic level. We show that SLU7 is required to secure DNMT1 protein stability and a correct DNA methylation. We demonstrate that SLU7 is part in the chromatome of the protein complex implicated in DNA methylation maintenance interacting with and controlling the integrity of DNMT1, its adaptor protein UHRF1 and the histone methyl-transferase G9a at the chromatin level. Mechanistically, we found that SLU7 assures DNMT1 stability preventing its acetylation and degradation by facilitating its interaction with HDAC1 and the desubiquitinase USP7. Importantly, we demonstrate that this DNMT1 dependency on SLU7 occurs in a large panel of proliferating cell lines of different origins and in in vivo models of liver proliferation. Overall, our results uncover a novel and non-redundant role of SLU7 in DNA methylation and present SLU7 as a holistic regulator of gene expression.
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Affiliation(s)
- Miriam Recalde
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain
| | - María Gárate-Rascón
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain
| | - María Elizalde
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain
| | - María Azkona
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain
| | - M Ujue Latasa
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain
| | - Marina Bárcena-Varela
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain
| | - Bruno Sangro
- IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid 28029, Spain.,Hepatology Unit, Navarra University Clinic, Pamplona 31008, Spain
| | - Maite G Fernández-Barrena
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid 28029, Spain
| | - Matías A Ávila
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid 28029, Spain
| | - María Arechederra
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain
| | - Carmen Berasain
- Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid 28029, Spain
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Y disruption, autosomal hypomethylation and poor male lung cancer survival. Sci Rep 2021; 11:12453. [PMID: 34127738 PMCID: PMC8203787 DOI: 10.1038/s41598-021-91907-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 05/26/2021] [Indexed: 01/27/2023] Open
Abstract
Lung cancer is the most frequent cause of cancer death worldwide. It affects more men than women, and men generally have worse survival outcomes. We compared gene co-expression networks in affected and unaffected lung tissue from 126 consecutive patients with Stage IA-IV lung cancer undergoing surgery with curative intent. We observed marked degradation of a sex-associated transcription network in tumour tissue. This disturbance, detected in 27.7% of male tumours in the discovery dataset and 27.3% of male tumours in a further 123-sample replication dataset, was coincident with partial losses of the Y chromosome and extensive autosomal DNA hypomethylation. Central to this network was the epigenetic modifier and regulator of sexually dimorphic gene expression, KDM5D. After accounting for prognostic and epidemiological covariates including stage and histology, male patients with tumour KDM5D deficiency showed a significantly increased risk of death (Hazard Ratio [HR] 3.80, 95% CI 1.40-10.3, P = 0.009). KDM5D deficiency was confirmed as a negative prognostic indicator in a further 1100 male lung tumours (HR 1.67, 95% CI 1.4-2.0, P = 1.2 × 10-10). Our findings identify tumour deficiency of KDM5D as a prognostic marker and credible mechanism underlying sex disparity in lung cancer.
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Lorzadeh A, Romero-Wolf M, Goel A, Jadhav U. Epigenetic Regulation of Intestinal Stem Cells and Disease: A Balancing Act of DNA and Histone Methylation. Gastroenterology 2021; 160:2267-2282. [PMID: 33775639 PMCID: PMC8169626 DOI: 10.1053/j.gastro.2021.03.036] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 03/10/2021] [Accepted: 03/23/2021] [Indexed: 02/08/2023]
Abstract
Genetic mutations or regulatory failures underlie cellular malfunction in many diseases, including colorectal cancer and inflammatory bowel diseases. However, mutational defects alone fail to explain the complexity of such disorders. Epigenetic regulation-control of gene action through chemical and structural changes of chromatin-provides a platform to integrate multiple extracellular inputs and prepares the cellular genome for appropriate gene expression responses. Coregulation by polycomb repressive complex 2-mediated trimethylation of lysine 27 on histone 3 and DNA methylation has emerged as one of the most influential epigenetic controls in colorectal cancer and many other diseases, but molecular details remain inadequate. Here we review the molecular interplay of these epigenetic features in relation to gastrointestinal development, homeostasis, and disease biology. We discuss other epigenetic mechanisms pertinent to the balance of trimethylation of lysine 27 on histone 3 and DNA methylation and their actions in gastrointestinal cancers. We also review the current molecular understanding of chromatin control in the pathogenesis of inflammatory bowel diseases.
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Affiliation(s)
- Alireza Lorzadeh
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Maile Romero-Wolf
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Unmesh Jadhav
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
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El-Sayed A, Aleya L, Kamel M. The link among microbiota, epigenetics, and disease development. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:28926-28964. [PMID: 33860421 DOI: 10.1007/s11356-021-13862-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 04/06/2021] [Indexed: 06/12/2023]
Abstract
The microbiome is a community of various microorganisms that inhabit or live on the skin of humans/animals, sharing the body space with their hosts. It is a sort of complex ecosystem of trillions of commensals, symbiotic, and pathogenic microorganisms, including trillions of bacteria, archaea, protozoa, fungi, and viruses. The microbiota plays a role in the health and disease status of the host. Their number, species dominance, and viability are dynamic. Their long-term disturbance is usually accompanied by serious diseases such as metabolic disorders, cardiovascular diseases, or even cancer. While epigenetics is a term that refers to different stimuli that induce modifications in gene expression patterns without structural changes in the inherited DNA sequence, these changes can be reversible or even persist for several generations. Epigenetics can be described as cell memory that stores experience against internal and external factors. Results from multiple institutions have contributed to the role and close interaction of both microbiota and epigenetics in disease induction. Understanding the mechanisms of both players enables a better understanding of disease induction and development and also opens the horizon to revolutionary therapeutic approaches. The present review illustrates the roles of diet, microbiome, and epigenetics in the induction of several chronic diseases. In addition, it discusses the application of epigenetic data to develop diagnostic biomarkers and therapeutics and evaluate their safety for patients. Understanding the interaction among all these elements enables the development of innovative preventive/therapeutic approaches for disease control.
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Affiliation(s)
- Amr El-Sayed
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Lotfi Aleya
- Chrono-Environnement Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, F-25030, Besançon Cedex, France
| | - Mohamed Kamel
- Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
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Dejima H, Hu X, Chen R, Zhang J, Fujimoto J, Parra ER, Haymaker C, Hubert SM, Duose D, Solis LM, Su D, Fukuoka J, Tabata K, Pham HHN, Mcgranahan N, Zhang B, Ye J, Ying L, Little L, Gumbs C, Chow CW, Estecio MR, Godoy MCB, Antonoff MB, Sepesi B, Pass HI, Behrens C, Zhang J, Vaporciyan AA, Heymach JV, Scheet P, Lee JJ, Wu J, Futreal PA, Reuben A, Kadara H, Wistuba II, Zhang J. Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features. Nat Commun 2021; 12:2722. [PMID: 33976164 PMCID: PMC8113327 DOI: 10.1038/s41467-021-22890-x] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 03/31/2021] [Indexed: 12/13/2022] Open
Abstract
The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC.
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Affiliation(s)
- Hitoshi Dejima
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xin Hu
- Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Runzhe Chen
- Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jiexin Zhang
- Department of Bioinformatics & Computational Biology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Junya Fujimoto
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Edwin R Parra
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Cara Haymaker
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shawna M Hubert
- Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dzifa Duose
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Luisa M Solis
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dan Su
- Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China.,Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Junya Fukuoka
- Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kazuhiro Tabata
- Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Hoa H N Pham
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Nicholas Mcgranahan
- Cancer Research United Kingdom-University College London Lung Cancer Centre of Excellence, London, UK
| | - Baili Zhang
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jie Ye
- Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lisha Ying
- Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China.,Zhejiang Cancer Research Institute, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Latasha Little
- Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Curtis Gumbs
- Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chi-Wan Chow
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Marcos Roberto Estecio
- Department of Epigenetics and Molecular Carcinogenesis, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Center of Cancer Epigenetics, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Myrna C B Godoy
- Department of Thoracic Imaging, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mara B Antonoff
- Department of Thoracic and Cardiovascular Surgery, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Boris Sepesi
- Department of Thoracic and Cardiovascular Surgery, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Harvey I Pass
- Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, NY, USA
| | - Carmen Behrens
- Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jianhua Zhang
- Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ara A Vaporciyan
- Department of Thoracic and Cardiovascular Surgery, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John V Heymach
- Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Paul Scheet
- Department of Epidemiology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - J Jack Lee
- Department of Biostatistics, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jia Wu
- Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - P Andrew Futreal
- Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Alexandre Reuben
- Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Humam Kadara
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Jianjun Zhang
- Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX, USA. .,Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Moderate DNA hypomethylation suppresses intestinal tumorigenesis by promoting caspase-3 expression and apoptosis. Oncogenesis 2021; 10:38. [PMID: 33947834 PMCID: PMC8096944 DOI: 10.1038/s41389-021-00328-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 03/18/2021] [Accepted: 04/09/2021] [Indexed: 12/14/2022] Open
Abstract
Global DNA hypomethylation is a most common epigenetic alteration in human neoplasia. However, accumulative evidence shows that global DNA hypomethylation impacts tumorigenesis in a tissue-specific manner, promoting tumorigenesis in some but suppressing tumorigenesis in others including colorectal cancer. The underlying mechanisms, especially how DNA hypomethylation suppresses tumorigenesis, remain largely unknown. Here, we investigate how DNA hypomethylation affects intestinal tumorigenesis by using an Uhrf1 tandem tudor domain knockin mutant mouse model (Uhrf1ki/ki) that exhibits a moderate ~10% reduction of global DNA methylation. We found that both chemical-induced colorectal carcinogenesis and Apc loss of heterozygosity (LOH)-induced intestinal tumorigenesis are substantially suppressed in the Uhrf1 mutant mice. Furthermore, unlike Dnmt1 hypomorphic mice in which DNA hypomethylation suppresses the incidence of macroscopic intestinal tumors but promotes the formation of microadenoma in ApcMin/+ background, Uhrf1ki/ki/ApcMin/+ mice have markedly reduced incidence of both microadenoma and macroadenoma. DNA hypomethylation does not appear to affect Apc LOH, activation of the Wnt or Hippo pathway, or tumor cell proliferation, but acts cooperatively with activated Wnt pathway to enhance the caspase-3 gene expression, activation, and apoptosis. Furthermore, increased caspase-3 expression correlates with DNA hypomethylation within the caspase-3 enhancer regions. Taken together, we present a new mouse model for investigating the role of and the molecular mechanisms by which DNA hypomethylation suppresses intestinal tumorigenesis. Our finding that a moderate DNA hypomethylation is sufficient to suppress intestinal tumorigenesis by promoting caspase-3 expression and apoptosis sheds new light on DNA-methylation inhibitor-based colorectal cancer therapeutics.
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Feng B, Hess J. Immune-Related Mutational Landscape and Gene Signatures: Prognostic Value and Therapeutic Impact for Head and Neck Cancer. Cancers (Basel) 2021; 13:cancers13051162. [PMID: 33800421 PMCID: PMC7962834 DOI: 10.3390/cancers13051162] [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: 01/11/2021] [Revised: 02/28/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Immunotherapy has emerged as a standard-of-care for most human malignancies, including head and neck cancer, but only a limited number of patients exhibit a durable clinical benefit. An urgent medical need is the establishment of accurate response predictors, which is handicapped by the growing body of molecular, cellular and clinical variables that modify the complex nature of an effective anti-tumor immune response. This review summarizes more recent efforts to elucidate immune-related mutational landscapes and gene expression signatures by integrative analysis of multi-omics data, and highlights their potential therapeutic impact for head and neck cancer. A better knowledge of the underlying principles and relevant interactions could pave the way for rational therapeutic combinations to improve the efficacy of immunotherapy, in particular for those cancer patients at a higher risk for treatment failure. Abstract Immunotherapy by immune checkpoint inhibition has become a main pillar in the armamentarium to treat head and neck cancer and is based on the premise that the host immune system can be reactivated to successfully eliminate cancer cells. However, the response rate remains low and only a small subset of head and neck cancer patients achieves a durable clinical benefit. The availability of multi-omics data and emerging computational technologies facilitate not only a deeper understanding of the cellular composition in the tumor immune microenvironment but also enables the study of molecular principles in the complex regulation of immune surveillance versus tolerance. These knowledges will pave the way to apply immunotherapy more precisely and effectively. This review aims to provide a holistic view on how the immune landscape dictates the tumor fate and vice versa, and how integrative analysis of multi-omics data contribute to our current knowledge on the accuracy of predictive biomarkers and on a broad range of factors influencing the response to immunotherapy in head and neck cancer.
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Affiliation(s)
- Bohai Feng
- Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany;
- Department of Otorhinolaryngology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Jochen Hess
- Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany;
- Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Correspondence:
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Binz RL, Sadhukhan R, Miousse IR, Garg S, Koturbash I, Zhou D, Hauer-Jensen M, Pathak R. Dietary Methionine Deficiency Enhances Genetic Instability in Murine Immune Cells. Int J Mol Sci 2021; 22:ijms22052378. [PMID: 33673497 PMCID: PMC7956689 DOI: 10.3390/ijms22052378] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 02/23/2021] [Accepted: 02/26/2021] [Indexed: 11/20/2022] Open
Abstract
Both cell and animal studies have shown that complete or partial deficiency of methionine inhibits tumor growth. Consequently, the potential implementation of this nutritional intervention has recently been of great interest for the treatment of cancer patients. Unfortunately, diet alteration can also affect healthy immune cells such as monocytes/macrophages and their precursor cells in bone marrow. As around half of cancer patients are treated with radiotherapy, the potential deleterious effect of dietary methionine deficiency on immune cells prior to and/or following irradiation needs to be evaluated. Therefore, we examined whether modulation of methionine content alters genetic stability in the murine RAW 264.7 monocyte/macrophage cell line in vitro by chromosomal analysis after 1-month culture in a methionine-deficient or supplemented medium. We also analyzed chromosomal aberrations in the bone marrow cells of CBA/J mice fed with methionine-deficient or supplemented diet for 2 months. While all RAW 264.7 cells revealed a complex translocation involving three chromosomes, three different clones based on the banding pattern of chromosome 9 were identified. Methionine deficiency altered the ratio of the three clones and increased chromosomal aberrations and DNA damage in RAW 264.7. Methionine deficiency also increased radiation-induced chromosomal aberration and DNA damage in RAW 264.7 cells. Furthermore, mice maintained on a methionine-deficient diet showed more chromosomal aberrations in bone marrow cells than those given methionine-adequate or supplemented diets. These findings suggest that caution is warranted for clinical implementation of methionine-deficient diet concurrent with conventional cancer therapy.
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Affiliation(s)
- Regina L. Binz
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (R.L.B.); (R.S.); (S.G.); (M.H.-J.)
| | - Ratan Sadhukhan
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (R.L.B.); (R.S.); (S.G.); (M.H.-J.)
| | - Isabelle R. Miousse
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Sarita Garg
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (R.L.B.); (R.S.); (S.G.); (M.H.-J.)
| | - Igor Koturbash
- Department of Environmental and Occupational Health, College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
- Center for Dietary Supplements Research, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Daohong Zhou
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA;
| | - Martin Hauer-Jensen
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (R.L.B.); (R.S.); (S.G.); (M.H.-J.)
| | - Rupak Pathak
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (R.L.B.); (R.S.); (S.G.); (M.H.-J.)
- Correspondence: ; Tel.: +1-501-603-1472
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49
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Rusetska N, Kober P, Król SK, Boresowicz J, Maksymowicz M, Kunicki J, Bonicki W, Bujko M. Invasive and Noninvasive Nonfunctioning Gonadotroph Pituitary Tumors Differ in DNA Methylation Level of LINE-1 Repetitive Elements. J Clin Med 2021; 10:560. [PMID: 33546126 PMCID: PMC7913198 DOI: 10.3390/jcm10040560] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 12/11/2022] Open
Abstract
PURPOSE Epigenetic dysregulation plays a role in pituitary tumor pathogenesis. Some differences in DNA methylation were observed between invasive and noninvasive nonfunctioning gonadotroph tumors. This study sought to determine the role of DNA methylation changes in repetitive LINE-1 elements in nonfunctioning gonadotroph pituitary tumors. METHODS We investigated LINE-1 methylation levels in 80 tumors and normal pituitary glands with bisulfite-pyrosequencing. Expression of two LINE-1 open reading frames (L1-ORF1 and L1-ORF2) was analyzed with qRT-PCR in tumor samples and mouse gonadotroph pituitary cells treated with DNA methyltransferase inhibitor. Immunohistochemical staining against L1-ORF1p was also performed in normal pituitary glands and tumors. RESULTS Hypomethylation of LINE-1 was observed in pituitary tumors. Tumors characterized by invasive growth revealed lower LINE-1 methylation level than noninvasive ones. LINE-1 methylation correlated with overall DNA methylation assessed with HM450K arrays and negatively correlated with L1-ORF1 and L1-ORF2 expression. Treatment of αT3-1 gonadotroph cells with 5-Azacytidine clearly increased the level of L1-ORF1 and L1-ORF2 mRNA; however, its effect on LβT2 cells was less pronounced. Immunoreactivity against L1-ORF1p was higher in tumors than normal tissue. No difference in L1-ORF1p expression was observed in invasive and noninvasive tumors. CONCLUSION Hypomethylation of LINE-1 is related to invasive growth and influences transcriptional activity of transposable elements.
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Affiliation(s)
- Natalia Rusetska
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (N.R.); (P.K.); (S.K.K.); (J.B.)
| | - Paulina Kober
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (N.R.); (P.K.); (S.K.K.); (J.B.)
| | - Sylwia Katarzyna Król
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (N.R.); (P.K.); (S.K.K.); (J.B.)
| | - Joanna Boresowicz
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (N.R.); (P.K.); (S.K.K.); (J.B.)
| | - Maria Maksymowicz
- Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland;
| | - Jacek Kunicki
- Department of Neurosurgery, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (J.K.); (W.B.)
| | - Wiesław Bonicki
- Department of Neurosurgery, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (J.K.); (W.B.)
| | - Mateusz Bujko
- Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; (N.R.); (P.K.); (S.K.K.); (J.B.)
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50
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Alves N, Neuparth T, Barros S, Santos MM. The anti-lipidemic drug simvastatin modifies epigenetic biomarkers in the amphipod Gammarus locusta. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 209:111849. [PMID: 33387775 DOI: 10.1016/j.ecoenv.2020.111849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 12/17/2020] [Accepted: 12/19/2020] [Indexed: 06/12/2023]
Abstract
The adverse effects of certain environmental chemicals have been recently associated with the modulation of the epigenome. Although changes in the epigenetic signature have yet to be integrated into hazard and risk assessment, they are interesting candidates to link environmental exposures and altered phenotypes, since these changes may be passed across multiple non-exposed generations. Here, we addressed the effects of simvastatin (SIM), one of the most prescribed pharmaceuticals in the world, on epigenetic regulation using the amphipod Gammarus locusta as a proxy, to support its integration into hazard and environmental risk assessment. SIM is a known modulator of the epigenome in mammalian cell lines and has been reported to impact G. locusta ecological endpoints at environmentally relevant levels. G. locusta juveniles were exposed to three SIM environmentally relevant concentrations (0.32, 1.6 and 8 µg L-1) for 15 days. Gene transcription levels of selected epigenetic regulators, i.e., dnmt1, dmap1, usp7, kat5 and uhrf1 were assessed, along with the quantification of DNA methylation levels and evaluation of key ecological endpoints: survival and growth. Exposure to 0.32 and 8 µg L-1 SIM induced significant downregulation of DNA methyltransferase 1 (dnmt1), concomitant with global DNA hypomethylation and growth impacts. Overall, this work is the first to validate the basal expression of key epigenetic regulators in a keystone marine crustacean, supporting the integration of epigenetic biomarkers into hazard assessment frameworks.
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Affiliation(s)
- Nélson Alves
- CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos S/N, 4450-208 Matosinhos, Portugal; FCUP - Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre nº 1021/1055, 4169-007 Porto, Portugal
| | - Teresa Neuparth
- CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos S/N, 4450-208 Matosinhos, Portugal.
| | - Susana Barros
- CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos S/N, 4450-208 Matosinhos, Portugal
| | - Miguel M Santos
- CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos S/N, 4450-208 Matosinhos, Portugal; FCUP - Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre nº 1021/1055, 4169-007 Porto, Portugal.
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