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Chakraborty P, Mukherjee C. The interplay of metabolic and epigenetic players in disease development. Biochem Biophys Res Commun 2024; 734:150621. [PMID: 39217811 DOI: 10.1016/j.bbrc.2024.150621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 08/14/2024] [Accepted: 08/28/2024] [Indexed: 09/04/2024]
Abstract
Epigenetic modifications and their alterations can cause variation in gene expression patterns which can ultimately affect a healthy individual. Until a few years ago, it was thought that the epigenome affects the transcriptome which can regulate the proteome and the metabolome. Recent studies have shown that the metabolome independently also plays a major role in regulating the epigenome bypassing the need for transcriptomic control. Alternatively, an imbalanced metabolome, stemming from transcriptome abnormalities, can further impact the transcriptome, creating a self-perpetuating cycle of interconnected occurrences. As a result, external factors such as nutrient intake and diet can have a direct impact on the metabolic pools and its reprogramming can change the levels and activity of epigenetic modifiers. Thus, the epigenetic landscape steers toward a diseased condition. In this review, we have discussed how different metabolites and dietary patterns can bring about changes in different arms of the epigenetic machinery such as methylation, acetylation as well as RNA mediated epigenetic mechanisms. We checked for limiting metabolites such as αKG, acetyl-CoA, ATP, NAD+, and FAD, whose abundance levels can lead to common diseases such as cancer, neurodegeneration etc. This gives a clearer picture of how an integrated approach including both epigenetics and metabolomics can be used for therapeutic purposes.
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Affiliation(s)
- Pallavi Chakraborty
- RNABio Lab, Institute of Health Sciences, Presidency University, Kolkata, West Bengal, India; Shiv Nadar Institute of Eminence, Greater Noida, Uttar Pradesh, India
| | - Chandrama Mukherjee
- RNABio Lab, Institute of Health Sciences, Presidency University, Kolkata, West Bengal, India.
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2
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Wu T, Cai W, Chen X. Epigenetic regulation of neurotransmitter signaling in neurological disorders. Neurobiol Dis 2023; 184:106232. [PMID: 37479091 DOI: 10.1016/j.nbd.2023.106232] [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: 06/07/2023] [Revised: 07/09/2023] [Accepted: 07/16/2023] [Indexed: 07/23/2023] Open
Abstract
Neurotransmission signaling is a highly conserved system attributed to various regulatory events. The excitatory and inhibitory neurotransmitter systems have been extensively studied, and their role in neuronal cell proliferation, synaptogenesis and dendrite formation in the adult brain is well established. Recent research has shown that epigenetic regulation plays a crucial role in mediating the expression of key genes associated with neurotransmitter pathways, including neurotransmitter receptor and transporter genes. The dysregulation of these genes has been linked to a range of neurological disorders such as attention-deficit/hyperactivity disorder, Parkinson's disease and schizophrenia. This article focuses on epigenetic regulatory mechanisms that control the expression of genes associated with four major chemical carriers in the brain: dopamine (DA), Gamma-aminobutyric acid (GABA), glutamate and serotonin. Additionally, we explore how aberrant epigenetic regulation of these genes can contribute to the pathogenesis of relevant neurological disorders. By targeting the epigenetic mechanisms that control neurotransmitter gene expression, there is a promising opportunity to advance the development of more effective treatments for neurological disorders with the potential to significantly improve the quality of life of individuals impacted by these conditions.
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Affiliation(s)
- Tingyan Wu
- Institute of Neurology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China
| | - Weili Cai
- School of Medical Technology, Jiangsu College of Nursing, Huai'an 22305, China.
| | - Xi Chen
- Institute of Neurology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China.
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3
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Lehman NL. Early ependymal tumor with MN1-BEND2 fusion: a mostly cerebral tumor of female children with a good prognosis that is distinct from classical astroblastoma. J Neurooncol 2023; 161:425-439. [PMID: 36604386 PMCID: PMC9992034 DOI: 10.1007/s11060-022-04222-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 12/19/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE Review of the clinicopathologic and genetic features of early ependymal tumor with MN1-BEND2 fusion (EET MN1-BEND2), classical astroblastomas, and recently described related pediatric CNS tumors. I also briefly review general mechanisms of gene expression silencing by DNA methylation and chromatin remodeling, and genomic DNA methylation profiling as a powerful new tool for CNS tumor classification. METHODS Literature review and illustration of tumor histopathologic features and prenatal gene expression timelines. RESULTS Astroblastoma, originally descried by Bailey and Cushing in 1926, has been an enigmatic tumor. Whether they are of ependymal or astrocytic derivation was argued for decades. Recent genetic evidence supports existence of both ependymal and astrocytic astroblastoma-like tumors. Studies have shown that tumors exhibiting astroblastoma-like histology can be classified into discrete entities based on their genomic DNA methylation profiles, gene expression, and in some cases, the presence of unique gene fusions. One such tumor, EET MN1-BEND2 occurs mostly in female children, and has an overall very good prognosis with surgical management. It contains a gene fusion comprised of portions of the MN1 gene at chromosomal location 22q12.1 and the BEND2 gene at Xp22.13. Other emerging pediatric CNS tumor entities demonstrating ependymal or astroblastoma-like histological features also harbor gene fusions involving chromosome X, 11q22 and 22q12 breakpoint regions. CONCLUSIONS Genomic DNA profiling has facilitated discovery of several new CNS tumor entities, however, traditional methods, such as immunohistochemistry, DNA or RNA sequencing, and cytogenetic studies, including fluorescence in situ hybridization, remain necessary for their accurate biological classification and diagnosis.
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Affiliation(s)
- Norman L Lehman
- Departments of Pathology and Laboratory Medicine, Biochemistry and Molecular Genetics, and the Brown Cancer Center, University of Louisville, 505 S Hancock St, Louisville, KY, 40202, USA.
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Liu P, Liang J, Jiang F, Cai W, Shen F, Liang J, Zhang J, Sun Z, Sui N. Gnas Promoter Hypermethylation in the Basolateral Amygdala Regulates Reconsolidation of Morphine Reward Memory in Rats. Genes (Basel) 2022; 13:genes13030553. [PMID: 35328106 PMCID: PMC8950747 DOI: 10.3390/genes13030553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/17/2022] [Accepted: 03/18/2022] [Indexed: 12/12/2022] Open
Abstract
Impairing reconsolidation may disrupt drug memories to prevent relapse, meanwhile long-term transcription regulations in the brain regions contribute to the occurrence of emotional memories. The basolateral amygdala (BLA) is involved in the drug-cue association, while the nucleus accumbens (NAc) responds to the drug reward. Here, we assessed whether DNA methyltransferases (Dnmts) in these two brain regions function identically in the reconsolidation of morphine reward memory. We show that Dnmts inhibition in the BLA but not in the NAc after memory retrieval impaired reconsolidation of a morphine reward memory. Moreover, the mRNA levels of Dnmt3a and Dnmt3b, rather than Dnmt1, in the BLA were continuously upregulated after retrieval. We further identified the differentially methylated regions (DMRs) in genes in the BLA after retrieval, and focused on the DMRs located in gene promoter regions. Among them were three genes (Gnas, Sox10, and Pik3r1) involved in memory modulation. Furthermore, Gnas promoter hypermethylation was confirmed to be inversely correlated with the downregulation of Gnas mRNA levels. The findings indicate that the specific transcription regulation mechanism in the BLA and NAc on reconsolidation of opiate-associated memories can be dissociable, and DNA hypermethylation of Gnas in the BLA is necessary for the reconsolidation of morphine reward memories.
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Affiliation(s)
- Peng Liu
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing 100101, China; (P.L.); (F.J.); (F.S.); (J.L.); (N.S.)
- Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China
| | - Jialong Liang
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China; (J.L.); (W.C.)
| | - Fengze Jiang
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing 100101, China; (P.L.); (F.J.); (F.S.); (J.L.); (N.S.)
- Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China
| | - Wanshi Cai
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China; (J.L.); (W.C.)
| | - Fang Shen
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing 100101, China; (P.L.); (F.J.); (F.S.); (J.L.); (N.S.)
- Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China
| | - Jing Liang
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing 100101, China; (P.L.); (F.J.); (F.S.); (J.L.); (N.S.)
- Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China
| | - Jianjun Zhang
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing 100101, China; (P.L.); (F.J.); (F.S.); (J.L.); (N.S.)
- Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China
- Correspondence: (J.Z.); (Z.S.)
| | - Zhongsheng Sun
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China; (J.L.); (W.C.)
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China
- Correspondence: (J.Z.); (Z.S.)
| | - Nan Sui
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing 100101, China; (P.L.); (F.J.); (F.S.); (J.L.); (N.S.)
- Department of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China
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5
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Blackwood CA, Cadet JL. Epigenetic and Genetic Factors Associated With Opioid Use Disorder: Are These Relevant to African American Populations. Front Pharmacol 2021; 12:798362. [PMID: 35002733 PMCID: PMC8727544 DOI: 10.3389/fphar.2021.798362] [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: 10/20/2021] [Accepted: 12/07/2021] [Indexed: 01/02/2023] Open
Abstract
In the United States, the number of people suffering from opioid use disorder has skyrocketed in all populations. Nevertheless, observations of racial disparities amongst opioid overdose deaths have recently been described. Opioid use disorder is characterized by compulsive drug consumption followed by periods of withdrawal and recurrent relapses while patients are participating in treatment programs. Similar to other rewarding substances, exposure to opioid drugs is accompanied by epigenetic changes in the brain. In addition, genetic factors that are understudied in some racial groups may also impact the clinical manifestations of opioid use disorder. These studies are important because genetic factors and epigenetic alterations may also influence responses to pharmacological therapeutic approaches. Thus, this mini-review seeks to briefly summarize what is known about the genetic bases of opioid use disorder in African Americans.
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Affiliation(s)
- Christopher A. Blackwood
- Molecular Neuropsychiatry Research Branch, NIH/NIDA Intramural Research Program, Baltimore, MD, United States
| | - Jean Lud Cadet
- Molecular Neuropsychiatry Research Branch, NIH/NIDA Intramural Research Program, Baltimore, MD, United States
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6
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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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7
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Loaeza-Loaeza J, Beltran AS, Hernández-Sotelo D. DNMTs and Impact of CpG Content, Transcription Factors, Consensus Motifs, lncRNAs, and Histone Marks on DNA Methylation. Genes (Basel) 2020; 11:genes11111336. [PMID: 33198240 PMCID: PMC7696963 DOI: 10.3390/genes11111336] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/06/2020] [Accepted: 11/10/2020] [Indexed: 12/15/2022] Open
Abstract
DNA methyltransferases (DNMTs) play an essential role in DNA methylation and transcriptional regulation in the genome. DNMTs, along with other poorly studied elements, modulate the dynamic DNA methylation patterns of embryonic and adult cells. We summarize the current knowledge on the molecular mechanism of DNMTs’ functional targeting to maintain genome-wide DNA methylation patterns. We focus on DNMTs’ intrinsic characteristics, transcriptional regulation, and post-transcriptional modifications. Furthermore, we focus special attention on the DNMTs’ specificity for target sites, including key cis-regulatory factors such as CpG content, common motifs, transcription factors (TF) binding sites, lncRNAs, and histone marks to regulate DNA methylation. We also review how complexes of DNMTs/TFs or DNMTs/lncRNAs are involved in DNA methylation in specific genome regions. Understanding these processes is essential because the spatiotemporal regulation of DNA methylation modulates gene expression in health and disease.
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Affiliation(s)
- Jaqueline Loaeza-Loaeza
- Laboratorio de Epigenética del Cáncer, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, NC 39087 Chilpancingo, Mexico;
| | - Adriana S. Beltran
- Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA;
| | - Daniel Hernández-Sotelo
- Laboratorio de Epigenética del Cáncer, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, NC 39087 Chilpancingo, Mexico;
- Correspondence:
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8
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Martynyuk AE, Ju LS, Morey TE, Zhang JQ. Neuroendocrine, epigenetic, and intergenerational effects of general anesthetics. World J Psychiatry 2020; 10:81-94. [PMID: 32477904 PMCID: PMC7243620 DOI: 10.5498/wjp.v10.i5.81] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/18/2020] [Accepted: 03/26/2020] [Indexed: 02/05/2023] Open
Abstract
The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs.
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Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology and the McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Jia-Qiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, Henan Province, China
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9
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Dzobo K. Epigenomics-Guided Drug Development: Recent Advances in Solving the Cancer Treatment "jigsaw puzzle". OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2020; 23:70-85. [PMID: 30767728 DOI: 10.1089/omi.2018.0206] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The human epigenome plays a key role in determining cellular identity and eventually function. Drug discovery undertakings have focused mainly on the role of genomics in carcinogenesis, with the focus turning to the epigenome recently. Drugs targeting DNA and histone modifications are under development with some such as 5-azacytidine, decitabine, vorinostat, and panobinostat already approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This expert review offers a critical analysis of the epigenomics-guided drug discovery and development and the opportunities and challenges for the next decade. Importantly, the coupling of epigenetic editing techniques, such as clustered regularly interspersed short palindromic repeat (CRISPR)-CRISPR-associated protein-9 (Cas9) and APOBEC-coupled epigenetic sequencing (ACE-seq) with epigenetic drug screens, will allow the identification of small-molecule inhibitors or drugs able to reverse epigenetic changes responsible for many diseases. In addition, concrete and sustainable innovation in cancer treatment ought to integrate epigenome targeting drugs with classic therapies such as chemotherapy and immunotherapy.
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Affiliation(s)
- Kevin Dzobo
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.,2 Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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10
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Tarashi S, Badi SA, Moshiri A, Ebrahimzadeh N, Fateh A, Vaziri F, Aazami H, Siadat SD, Fuso A. The inter-talk between Mycobacterium tuberculosis and the epigenetic mechanisms. Epigenomics 2020; 12:455-469. [PMID: 32267165 DOI: 10.2217/epi-2019-0187] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 01/24/2020] [Indexed: 12/23/2022] Open
Abstract
Epigenetics regulate gene function without any alteration in the DNA sequence. The epigenetics represent one of the most important regulators in different cellular processes and have initially been developed in microorganisms as a protective strategy. The evaluation of the epigenetic mechanisms is also important in achieving an efficient control strategy in tuberculosis (TB). TB is one of the most significant epidemiological concerns in human history. Despite several in vivo and in vitro studies that have evaluated different epigenetic modifications in TB, many aspects of the association between epigenetics and TB are not fully understood. The current paper is aimed at reviewing our knowledge on histone modifications and DNA methylation modifications, as well as miRNAs regulation in TB.
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Affiliation(s)
- Samira Tarashi
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
- Mycobacteriology & Pulmonary Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Sara Ahmadi Badi
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
- Mycobacteriology & Pulmonary Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Arfa Moshiri
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
- Gastroenterology & Liver Diseases Research Center, Research Institute for Gastroenterology & Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Laboratory of Molecular Medicine, IRCCS Institute Giannina Gaslini, Genova, Italy
| | - Nayereh Ebrahimzadeh
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
- Mycobacteriology & Pulmonary Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Abolfazl Fateh
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
- Mycobacteriology & Pulmonary Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Farzam Vaziri
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
- Mycobacteriology & Pulmonary Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Hossein Aazami
- Endocrinology & Metabolism Research Center, Endocrinology & Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Davar Siadat
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
- Mycobacteriology & Pulmonary Research Department, Pasteur Institute of Iran, Tehran, Iran
- Endocrinologyand Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Andrea Fuso
- Department of Experimental Medicine, Sapienza University of Rome, Italy
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11
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Zhang J, Jiang F, Zheng W, Duan Y, Jin S, Shen F, Liang J, Li M, Sui N. DNMT3a in the hippocampal CA1 is crucial in the acquisition of morphine self-administration in rats. Addict Biol 2020; 25:e12730. [PMID: 30950138 DOI: 10.1111/adb.12730] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 01/11/2019] [Accepted: 01/24/2019] [Indexed: 12/17/2022]
Abstract
Drug-reinforced excessive operant responding is one fundamental feature of long-lasting addiction-like behaviors and relapse in animals. However, the transcriptional regulatory mechanisms responsible for the persistent drug-specific (not natural rewards) operant behavior are not entirely clear. In this study, we demonstrate a key role for one of the de novo DNA methyltransferase, DNMT3a, in the acquisition of morphine self-administration (SA) in rats. The expression of DNMT3a in the hippocampal CA1 region but not in the nucleus accumbens shell was significantly up-regulated after 1- and 7-day morphine SA (0.3 mg/kg/infusion) but not after the yoked morphine injection. On the other hand, saccharin SA did not affect the expression of DNMT3a or DNMT3b. DNMT inhibitor 5-aza-2-deoxycytidine (5-aza) microinjected into the hippocampal CA1 significantly attenuated the acquisition of morphine SA. Knockdown of DNMT3a also impaired the ability to acquire the morphine SA. Overall, these findings suggest that DNMT3a in the hippocampus plays an important role in the acquisition of morphine SA and may be a valid target to prevent the development of morphine addiction.
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Affiliation(s)
- Jian‐Jun Zhang
- CAS Key Laboratory of Mental HealthInstitute of Psychology Beijing China
- Department of PsychologyUniversity of Chinese Academy of Sciences Beijing China
| | - Feng‐Ze Jiang
- CAS Key Laboratory of Mental HealthInstitute of Psychology Beijing China
- Department of PsychologyUniversity of Chinese Academy of Sciences Beijing China
| | - Wei Zheng
- CAS Key Laboratory of Mental HealthInstitute of Psychology Beijing China
- Department of PsychologyUniversity of Chinese Academy of Sciences Beijing China
| | - Ying Duan
- CAS Key Laboratory of Mental HealthInstitute of Psychology Beijing China
- Department of PsychologyUniversity of Chinese Academy of Sciences Beijing China
| | - Shu‐Bo Jin
- CAS Key Laboratory of Mental HealthInstitute of Psychology Beijing China
- Department of PsychologyUniversity of Chinese Academy of Sciences Beijing China
| | - Fang Shen
- CAS Key Laboratory of Mental HealthInstitute of Psychology Beijing China
- Department of PsychologyUniversity of Chinese Academy of Sciences Beijing China
| | - Jing Liang
- CAS Key Laboratory of Mental HealthInstitute of Psychology Beijing China
- Department of PsychologyUniversity of Chinese Academy of Sciences Beijing China
| | - Ming Li
- Department of PsychologyUniversity of Nebraska–Lincoln Lincoln Nebraska USA
| | - Nan Sui
- CAS Key Laboratory of Mental HealthInstitute of Psychology Beijing China
- Department of PsychologyUniversity of Chinese Academy of Sciences Beijing China
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DNA Modification Readers and Writers and Their Interplay. J Mol Biol 2019:S0022-2836(19)30718-1. [PMID: 31866298 DOI: 10.1016/j.jmb.2019.12.018] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 11/28/2019] [Accepted: 12/05/2019] [Indexed: 12/15/2022]
Abstract
Genomic DNA is modified in a postreplicative manner and several modifications, the enzymes responsible for their deposition as well as proteins that read these modifications, have been described. Here, we focus on the impact of DNA modifications on the DNA helix and review the writers and readers of cytosine modifications and how they interplay to shape genome composition, stability, and function.
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13
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Yi Y, Xie H, Xiao X, Wang B, Du R, Liu Y, Li Z, Wang J, Sun L, Deng Z, Li J. Ultraviolet A irradiation induces senescence in human dermal fibroblasts by down-regulating DNMT1 via ZEB1. Aging (Albany NY) 2019; 10:212-228. [PMID: 29466247 PMCID: PMC5842848 DOI: 10.18632/aging.101383] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 02/09/2018] [Indexed: 12/20/2022]
Abstract
In this study, we report the role of DNA methyltransferase 1 (DNMT1) in ultraviolet A (UVA)-induced senescence in human dermal fibroblasts (HDFs). We show that DNMT1 expression was significantly reduced during UVA-induced senescence, and this senescence could be alleviated or aggravated by the up- or down-regulation of DNMT1, respectively. Expression of the transcription factor zinc finger E-box binding homeobox 1(ZEB1) also decreased after UVA irradiation, following a UVA-induced increase of intracellular reactive oxygen species (ROS). We show that ZEB1 binds to the DMNT1 promoter and regulates its transcription, which, in turn, affects cellular senescence. These changes in DMNT1 and ZEB1 expression following UVA exposure were confirmed in matched skin specimens that had or had not been sun-exposed. On analyzing the promoter methylation of 24 senescence associated genes in these matched skin specimens, we discovered that p53 promoter methylation was significantly reduced in sun-exposed skin. In vitro experiments confirmed that UVA irradiation reduced p53 promoter methylation, and DNMT1 up-regulation could reverse this effect. Collectively, down-regulation of ZEB1 caused by UVA induced ROS could transcriptionally inhibit DNMT1, leading to low methylation level of senescence related proteins p53 and increase its expression, eventually result in cellar senescence.
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Affiliation(s)
- Yuxin Yi
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
| | - Hongfu Xie
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiao Xiao
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Ben Wang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Rui Du
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Yingzi Liu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Zibo Li
- The State Key Laboratory of Medical Genetics & School of Life Sciences, Central South University, Changsha, China
| | - Jun Wang
- The State Key Laboratory of Medical Genetics & School of Life Sciences, Central South University, Changsha, China
| | - Lunquan Sun
- Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Zhili Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, China.,Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Ji Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, China.,Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
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14
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Luo Y, Xie C, Brocker CN, Fan J, Wu X, Feng L, Wang Q, Zhao J, Lu D, Tandon M, Cam M, Krausz KW, Liu W, Gonzalez FJ. Intestinal PPARα Protects Against Colon Carcinogenesis via Regulation of Methyltransferases DNMT1 and PRMT6. Gastroenterology 2019; 157:744-759.e4. [PMID: 31154022 PMCID: PMC7388731 DOI: 10.1053/j.gastro.2019.05.057] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 05/08/2019] [Accepted: 05/17/2019] [Indexed: 12/30/2022]
Abstract
BACKGROUND & AIMS Many genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that regulates systemic lipid homeostasis. We explored the role of intestinal PPARα in colon carcinogenesis. METHODS Colon cancer was induced in mice with intestine-specific disruption of Ppara (PparaΔIE), Pparafl/fl (control), and mice with disruption of Ppara that express human PPARA (human PPARA transgenic mice), by administration of azoxymethane with or without dextran sulfate sodium (DSS). Colons were collected from mice and analyzed by immunoblots, quantitative polymerase chain reaction, and histopathology. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses were performed on urine and colons. We used molecular biology and biochemical approaches to study mechanisms in mouse colons, primary intestinal epithelial cells, and colon cancer cell lines. Gene expression data and clinical features of patients with colorectal tumors were obtained from Oncomine, and human colorectal-tumor specimens and adjacent normal tissues were collected and analyzed by immunohistochemistry. RESULTS Levels of Ppara messenger RNA were reduced in colon tumors from mice. PparaΔIE mice developed more and larger colon tumors than control mice following administration of azoxymethane, with or without DSS. Metabolomic analyses revealed increases in methylation-related metabolites in urine and colons from PparaΔIE mice, compared with control mice, following administration of azoxymethane, with or without DSS. Levels of DNA methyltransferase 1 (DNMT1) and protein arginine methyltransferase 6 (PRMT6) were increased in colon tumors from PparaΔIE mice, compared with colon tumors from control mice. Depletion of PPARα reduced the expression of retinoblastoma protein, resulting in increased expression of DNMT1 and PRMT6. DNMT1 and PRMT6 decreased expression of the tumor suppressor genes Cdkn1a (P21) and Cdkn1b (p27) via DNA methylation and histone H3R2 dimethylation-mediated repression of transcription, respectively. Fenofibrate protected human PPARA transgenic mice from azoxymethane and DSS-induced colon cancer. Human colon adenocarcinoma specimens had lower levels of PPARA and retinoblastoma protein and higher levels of DNMT1 and PRMT6 than normal colon tissues. CONCLUSIONS Loss of PPARα from the intestine promotes colon carcinogenesis by increasing DNMT1-mediated methylation of P21 and PRMT6-mediated methylation of p27 in mice. Human colorectal tumors have lower levels of PPARA messenger RNA and protein than nontumor tissues. Agents that activate PPARα might be developed for chemoprevention or treatment of colon cancer.
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Affiliation(s)
- Yuhong Luo
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Cen Xie
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Chad N. Brocker
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jie Fan
- Department of Pathology, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Xuan Wu
- Central Laboratory and Department of Laboratory Medicine, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, 200070, China,Department of Laboratory Medicine, Shanghai Skin Disease Hospital, Tongji University, Shanghai, 200072, China
| | - Lijin Feng
- Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, 200070, China
| | - Qiong Wang
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jie Zhao
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Dasheng Lu
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Mayank Tandon
- CCR Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA,Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Maggie Cam
- CCR Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Kristopher W. Krausz
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Weiwei Liu
- Central Laboratory and Department of Laboratory Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China; Department of Laboratory Medicine, Shanghai Skin Disease Hospital, Tongji University, Shanghai, China.
| | - Frank J. Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA,Correspondence Weiwei Liu. Central Laboratory and Department of Laboratory Medicine, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, 200070, China. Tel: +86-21-6630-6905; , Frank J. Gonzalez. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Tel: 1-240-760-6875;
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15
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Ji H, Zhou C, Pan R, Han L, Chen W, Xu X, Huang Y, Huang T, Zou Y, Duan S. APOE hypermethylation is significantly associated with coronary heart disease in males. Gene 2019; 689:84-89. [DOI: 10.1016/j.gene.2018.11.088] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 10/16/2018] [Accepted: 11/26/2018] [Indexed: 11/17/2022]
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16
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Candido S, Parasiliti Palumbo GA, Pennisi M, Russo G, Sgroi G, Di Salvatore V, Libra M, Pappalardo F. EpiMethEx: a tool for large-scale integrated analysis in methylation hotspots linked to genetic regulation. BMC Bioinformatics 2019; 19:385. [PMID: 30717649 PMCID: PMC7394332 DOI: 10.1186/s12859-018-2397-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 09/25/2018] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND DNA methylation is an epigenetic mechanism of genomic regulation involved in the maintenance of homeostatic balance. Dysregulation of DNA methylation status is one of the driver alterations occurring in neoplastic transformation and cancer progression. The identification of methylation hotspots associated to gene dysregulation may contribute to discover new prognostic and diagnostic biomarkers, as well as, new therapeutic targets. RESULTS We present EpiMethEx (Epigenetic Methylation and Expression), a R package to perform a large-scale integrated analysis by cyclic correlation analyses between methylation and gene expression data. For each gene, samples are segmented according to the expression levels to select genes that are differentially expressed. This stratification allows to identify CG methylation probesets modulated among gene-stratified samples. Subsequently, the methylation probesets are grouped by their relative position in gene sequence to identify wide genomic methylation events statically related to genetic modulation. CONCLUSIONS The beta-test study showed that the global methylation analysis was in agreement with scientific literature. In particular, this analysis revealed a negative association between promoter hypomethylation and overexpression in a wide number of genes. Less frequently, this overexpression was sustained by intragenic hypermethylation events.
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Affiliation(s)
- Saverio Candido
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia, 97, Catania, 95123 Italy
| | | | - Marzio Pennisi
- Department of Mathematics and Computer Science, University of Catania, Viale A. Doria, 6, Catania, 95125 Italy
| | - Giulia Russo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia, 97, Catania, 95123 Italy
| | - Giuseppe Sgroi
- Department of Mathematics and Computer Science, University of Catania, Viale A. Doria, 6, Catania, 95125 Italy
| | - Valentina Di Salvatore
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia, 97, Catania, 95123 Italy
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia, 97, Catania, 95123 Italy
| | - Francesco Pappalardo
- Department of Drug Sciences, University of Catania, Viale A. Doria, 6, Catania, 95125 Italy
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17
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Xu S, Yue Y, Zhang S, Zhou C, Cheng X, Xie X, Wang X, Lu W. STON2 negatively modulates stem-like properties in ovarian cancer cells via DNMT1/MUC1 pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:305. [PMID: 30518424 PMCID: PMC6282299 DOI: 10.1186/s13046-018-0977-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 11/23/2018] [Indexed: 12/14/2022]
Abstract
Background Cancer stem cells (CSCs) possess abilities of self-renewal and differentiation, have oncogenic potential and are regarded to be the source of cancer recurrence. However, the mechanism by which CSCs maintain their stemness remains largely unclear. Methods In this study, the cell line-derived ovarian CSCs (OCSCs), 3AO and Caov3, were enriched in serum-free medium (SFM). Differentially expressed proteins were compared between the OCSC subpopulation and parental cells using liquid chromatography (LC)-mass spectrometry (MS)/MS label-free quantitative proteomics. Sphere-forming ability assays, flow cytometry, quantitative real-time polymerase chain reaction (qPCR), western blotting, and in vivo xenograft experiments were performed to evaluate stemness. RNA-sequencing (RNA-seq) and pyrosequencing were used to reveal the mechanism by which STON2 negatively modulates the stem-like properties of ovarian cancer cells. Results Among the 74 most differentially expressed proteins, stonin 2 (STON2) was confirmed to be down-regulated in the OCSC subpopulation. We show that STON2 negatively modulates the stem-like properties of ovarian cancer cells, which are characterized by sphere formation, a CD44+CD24− ratio, and by CSC- and epithelial mesenchymal transition (EMT)-related markers. STON2 knockdown also accelerated tumorigenesis in NOD/SCID mice. Further investigation revealed a downstream target, mucin 1 (MUC1), as up-regulated upon the down regulation of STON2. A decrease in both DNA methyltransferase 1 (DNMT1) expression and methylation in the promoter region of MUC1 was associated with subsequently elevated MUC1 expression, as detected in STON2 knockdown in 3AO and Caov3 cells. Direct DNMT1 knockdown simultaneously elevated MUC1 expression. The functional significance of this STON2-DNMT1/MUC1 pathway is supported by the observation that STON2 overexpression suppresses MUC1-induced sphere formation of OCSCs. The paired expression of STON2 and MUC1 in ovarian cancer specimens was also detected revealing the prognostic value of STON2 expression to be highly dependent on MUC1 expression. Conclusions Our results imply that STON2 may negatively regulate stemness in ovarian cancer cells via DNMT1-MUC1 mediated epigenetic modification. STON2 is therefore involved in OCSC biology and may represent a therapeutic target for innovative treatments aimed at ovarian cancer eradication. Electronic supplementary material The online version of this article (10.1186/s13046-018-0977-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Shanshan Xu
- Department of Gynecologic Oncology; Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China
| | - Yongfang Yue
- Department of Gynecologic Oncology; Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China
| | - Songfa Zhang
- Department of Gynecologic Oncology; Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China
| | - Caiyun Zhou
- Department of Pathology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China
| | - Xiaodong Cheng
- Women's Reproductive Health Laboratory of Zhejiang Province; Women's Hospital; School of Medicine, Zhejiang University, Hangzhou, 310006, China
| | - Xing Xie
- Women's Reproductive Health Laboratory of Zhejiang Province; Women's Hospital; School of Medicine, Zhejiang University, Hangzhou, 310006, China
| | - Xinyu Wang
- Department of Gynecologic Oncology; Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China. .,Women's Reproductive Health Laboratory of Zhejiang Province; Women's Hospital; School of Medicine, Zhejiang University, Hangzhou, 310006, China.
| | - Weiguo Lu
- Department of Gynecologic Oncology; Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China. .,Women's Reproductive Health Laboratory of Zhejiang Province; Women's Hospital; School of Medicine, Zhejiang University, Hangzhou, 310006, China.
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18
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Ji H, Liu G, Xu X, Liu H, Xu L, Hu H, Chen Y, Hong Q, Wang Q, Shen W, Li L, Xie X, Zhou W, Duan S. Hypermethylation of the κ1 opioid receptor promoter in Chinese heroin and methamphetamine addicts. Exp Ther Med 2018; 16:2392-2398. [PMID: 30210591 PMCID: PMC6122531 DOI: 10.3892/etm.2018.6514] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 04/11/2017] [Indexed: 12/20/2022] Open
Abstract
Heroin and methamphetamine (METH) addiction continues to be a major social, economic and therapeutic problem worldwide. The opioid pathway may mediate the effects of addictive drugs. However, the potential correlation between the κ1 opioid receptor (OPRK1) and drug addiction has not yet been characterized. The aim of the present study was to investigate the potential association between methylation of the OPRK1 promoter and substance abuse. Bisulfite pyrosequencing technology was used to determine the levels of OPRK1 promoter methylation in 60 drug abusers (30 heroin and 30 METH addicts) and 52 controls, observed to exhibit no significant differences in age or gender. The results indicated that levels of OPRK1 promoter methylation were significantly higher in drug addicts when compared with controls (P=2.43×10−4). Significant correlations between OPRK1 promoter methylation and the length and frequency of drug use were also observed in male heroin addicts (length: r=0.661, P=0.007; frequency: r=−0.684, P=0.005). In addition, a luciferase reporter gene assay indicated that the OPRK1 promoter fragment was able to regulate gene expression (fold change between two groups >32.12, P≤0.0001). In conclusion, results of the present study indicate that methylation of the OPRK1 promoter contributes to the pathophysiology of drug addiction.
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Affiliation(s)
- Huihui Ji
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Guili Liu
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Xuting Xu
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Huifen Liu
- Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, Ningbo, Zhejiang 315010, P.R. China
| | - Lei Xu
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Haochang Hu
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Yingmin Chen
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Qinxiao Hong
- Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, Ningbo, Zhejiang 315010, P.R. China
| | - Qinwen Wang
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
| | - Wenwen Shen
- Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, Ningbo, Zhejiang 315010, P.R. China
| | - Longhui Li
- Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, Ningbo, Zhejiang 315010, P.R. China
| | - Xiaohu Xie
- Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, Ningbo, Zhejiang 315010, P.R. China
| | - Wenhua Zhou
- Laboratory of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, Ningbo, Zhejiang 315010, P.R. China
| | - Shiwei Duan
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
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Ponnaluri VKC, Estève PO, Ruse CI, Pradhan S. S-adenosylhomocysteine Hydrolase Participates in DNA Methylation Inheritance. J Mol Biol 2018; 430:2051-2065. [PMID: 29758262 DOI: 10.1016/j.jmb.2018.05.014] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 05/05/2018] [Accepted: 05/08/2018] [Indexed: 01/06/2023]
Abstract
DNA (cytosine-5) methyltransferase 1 (DNMT1) is essential for mammalian development and maintenance of DNA methylation following DNA replication in cells. The DNA methylation process generates S-adenosyl-l-homocysteine, a strong inhibitor of DNMT1. Here we report that S-adenosylhomocysteine hydrolase (SAHH/AHCY), the only mammalian enzyme capable of hydrolyzing S-adenosyl-l-homocysteine binds to DNMT1 during DNA replication. SAHH enhances DNMT1 activity in vitro, and its overexpression in mammalian cells led to hypermethylation of the genome, whereas its inhibition by adenosine periodate or siRNA-mediated knockdown resulted in hypomethylation of the genome. Hypermethylation was consistent in both gene bodies and repetitive DNA elements leading to aberrant gene regulation. Cells overexpressing SAHH specifically up-regulated metabolic pathway genes and down-regulated PPAR and MAPK signaling pathways genes. Therefore, we suggest that alteration of SAHH level affects global DNA methylation levels and gene expression.
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Affiliation(s)
| | | | - Cristian I Ruse
- New England Biolabs Inc, 240 County Road, Ipswich, MA 01938, USA
| | - Sriharsa Pradhan
- New England Biolabs Inc, 240 County Road, Ipswich, MA 01938, USA.
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20
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Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating and lethal neurodegenerative diseases seen comorbidly in up to 15% of patients. Despite several decades of research, no effective treatment or disease-modifying strategies have been developed. We now understand more than before about the genetics and biology behind ALS and FTD, but the genetic etiology for the majority of patients is still unknown and the phenotypic variability observed across patients, even those carrying the same mutation, is enigmatic. Additionally, susceptibility factors leading to neuronal vulnerability in specific central nervous system regions involved in disease are yet to be identified. As the inherited but dynamic epigenome acts as a cell-specific interface between the inherited fixed genome and both cell-intrinsic mechanisms and environmental input, adaptive epigenetic changes might contribute to the ALS/FTD aspects we still struggle to comprehend. This chapter summarizes our current understanding of basic epigenetic mechanisms, how they relate to ALS and FTD, and their potential as therapeutic targets. A clear understanding of the biological mechanisms driving these two currently incurable diseases is urgent-well-needed therapeutic strategies need to be developed soon. Disease-specific epigenetic changes have already been observed in patients and these might be central to this endeavor.
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Affiliation(s)
- Mark T W Ebbert
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
| | - Rebecca J Lank
- Department of Neurology, University of Michigan, Ann Arbor, MI, USA
| | - Veronique V Belzil
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. .,Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
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21
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Roth TL. Epigenetic Advances in Behavioral and Brain Sciences have Relevance for Public Policy. ACTA ACUST UNITED AC 2017; 4:202-209. [PMID: 29202007 DOI: 10.1177/2372732217719091] [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: 11/17/2022]
Abstract
Nature and nurture work together to drive development, behavior, and health. Behavioral epigenetics research has uncovered the underlying mechanisms for how this happens. Children's early years in development may offer the greatest opportunity for environmental and experiential factors to influence epigenome (chemical compounds telling our genes what to do), but evidence suggests it is never too late. The policy implications of this research are vast, including relevance for child development, health, and disease intervention and prevention.
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Affiliation(s)
- Tania L Roth
- Department of Psychological and Brain Sciences, University of Delaware, Newark DE
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22
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Mastrototaro G, Zaghi M, Sessa A. Epigenetic Mistakes in Neurodevelopmental Disorders. J Mol Neurosci 2017; 61:590-602. [DOI: 10.1007/s12031-017-0900-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 02/15/2017] [Indexed: 12/28/2022]
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23
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Testicular Dnmt3 expression and global DNA methylation are down-regulated by gonadotropin releasing hormones in the ricefield eel Monopterus albus. Sci Rep 2017; 7:43158. [PMID: 28225069 PMCID: PMC5320511 DOI: 10.1038/srep43158] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 01/19/2017] [Indexed: 02/06/2023] Open
Abstract
In vertebrates, DNA methyltransferase 3 (Dnmt3) homologues are responsible for de novo DNA methylation and play important roles in germ cell development. In the present study, four dnmt3 genes, dnmt3aa, dnmt3ab, dnmt3ba and dnmt3bb.1, were identified in ricefield eels. Real-time quantitative PCR analysis showed that all four dnmt3 mRNAs were detected broadly in tissues examined, with testicular expression at relatively high levels. In the testis, immunostaining for all four Dnmt3 forms was mainly localized to spermatocytes, which also contained highly methylated DNA. All three forms of Gonadotropin-releasing hormone (Gnrh) in the ricefield eel were shown to decrease the expression of dnmt3 genes in the in vitro incubated testicular fragments through cAMP and IP3/Ca2+ pathways. Moreover, in vivo treatment of male fish with three forms of Gnrh decreased significantly the testicular Dnmt3 expression at both mRNA and protein levels, and the global DNA methylation levels. These results suggest that the expression of Dnmt3 and global DNA methylation in the testis of ricefield eels are potentially down-regulated by Gnrh, and reveal a novel regulatory mechanism of testicular Dnmt3 expression in vertebrates.
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Breton CV, Yao J, Millstein J, Gao L, Siegmund KD, Mack W, Whitfield-Maxwell L, Lurmann F, Hodis H, Avol E, Gilliland FD. Prenatal Air Pollution Exposures, DNA Methyl Transferase Genotypes, and Associations with Newborn LINE1 and Alu Methylation and Childhood Blood Pressure and Carotid Intima-Media Thickness in the Children's Health Study. ENVIRONMENTAL HEALTH PERSPECTIVES 2016; 124:1905-1912. [PMID: 27219456 PMCID: PMC5132634 DOI: 10.1289/ehp181] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Revised: 11/05/2015] [Accepted: 05/03/2016] [Indexed: 05/08/2023]
Abstract
BACKGROUND Although exposure to ambient air pollutants increases cardiovascular disease risk in adults little is known about the effects of prenatal exposure. Genetic variation and epigenetic alterations are two mechanisms that may influence the effects of early-life exposures on cardiovascular phenotypes. OBJECTIVES We investigated whether genetic and epigenetic variation modify associations between prenatal air pollution on markers of cardiovascular risk in childhood. METHODS We used linear regression analysis to investigate the associations between prenatal pollutants (PM2.5, PM10, NO2, O3), long interspersed nuclear elements (LINE1) and AluYb8 DNA methylation levels measured in newborn blood spot tests, and carotid intima-media thickness (CIMT) and blood pressure (BP) in 459 participants as part of the Children's Health Study. Interaction terms were also included to test for effect modification of these associations by genetic variation in methylation reprogramming genes. RESULTS Prenatal exposure to NO2 in the third trimester of pregnancy was associated with higher systolic BP in 11-year-old children. Prenatal exposure to multiple air pollutants in the first trimester was associated with lower DNA methylation in LINE1, whereas later exposure to O3 was associated with higher LINE1 methylation levels in newborn blood spots. The magnitude of associations with prenatal air pollution varied according to genotype for 11 SNPs within DNA methyltransferase 1 (DNMT1), DNA methyltransferase 3 Beta (DNMT3B), Tet methylcytosine dioxygenase 2 (TET2), and Thymine DNA glycosylase (TDG) genes. Although first-trimester O3 exposure was not associated with CIMT and systolic BP overall, associations within strata of DNMT1 or DNMT3B were observed, and the magnitude and the direction of these associations depended on DNMT1 genotypes. CONCLUSIONS Genetic and epigenetic variation in DNA methylation reprogramming genes and in LINE1 retrotransposons may play important roles in downstream cardiovascular consequences of prenatal air pollution exposure. Citation: Breton CV, Yao J, Millstein J, Gao L, Siegmund KD, Mack W, Whitfield-Maxwell L, Lurmann F, Hodis H, Avol E, Gilliland FD. 2016. Prenatal air pollution exposures, DNA methyl transferase genotypes, and associations with newborn LINE1 and Alu methylation and childhood blood pressure and carotid intima-media thickness in the Children's Health Study. Environ Health Perspect 124:1905-1912; http://dx.doi.org/10.1289/EHP181.
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Affiliation(s)
- Carrie V. Breton
- Department of Preventive Medicine, and
- Address correspondence to C.V. Breton, Department of Preventive Medicine, USC Keck School of Medicine, 2001 N. Soto St., Los Angeles, CA 90089 USA. Telephone: (323) 442-7383. E-mail:
| | - Jin Yao
- Department of Preventive Medicine, and
| | | | - Lu Gao
- Department of Preventive Medicine, and
| | | | - Wendy Mack
- Department of Preventive Medicine, and
- Atherosclerosis Research Unit, University of Southern California, Los Angeles, California, USA
| | - Lora Whitfield-Maxwell
- Atherosclerosis Research Unit, University of Southern California, Los Angeles, California, USA
| | - Fred Lurmann
- Sonoma Technology, Inc., Petaluma, California, USA
| | - Howard Hodis
- Department of Preventive Medicine, and
- Atherosclerosis Research Unit, University of Southern California, Los Angeles, California, USA
| | - Ed Avol
- Department of Preventive Medicine, and
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Benetatos L, Vartholomatos G. On the potential role of DNMT1 in acute myeloid leukemia and myelodysplastic syndromes: not another mutated epigenetic driver. Ann Hematol 2016; 95:1571-82. [PMID: 26983918 DOI: 10.1007/s00277-016-2636-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 03/04/2016] [Indexed: 12/19/2022]
Abstract
DNA methylation is the most common epigenetic modification in the mammalian genome. DNA methylation is governed by the DNA methyltransferases mainly DNMT1, DNMT3A, and DNMT3B. DNMT1 methylates hemimethylated DNA ensuring accurate DNA methylation maintenance. DNMT1 is involved in the proper differentiation of hematopoietic stem cells (HSCs) through the interaction with effector molecules. DNMT1 is deregulated in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) as early as the leukemic stem cell stage. Through the interaction with fundamental transcription factors, non-coding RNAs, fusion oncogenes and by modulating core members of signaling pathways, it can affect leukemic cells biology. DNMT1 action might be also catalytic-independent highlighting a methylation-independent mode of action. In this review, we have gathered some current facts of DNMT1 role in AML and MDS and we also propose some perspectives for future studies.
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26
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Cadet JL, McCoy MT, Jayanthi S. Epigenetics and addiction. Clin Pharmacol Ther 2016; 99:502-11. [PMID: 26841306 DOI: 10.1002/cpt.345] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 01/18/2016] [Accepted: 01/26/2016] [Indexed: 12/13/2022]
Abstract
Addictions are public health menaces. However, despite advances in addiction research, the cellular or molecular mechanisms that cause transition from recreational use to addiction remain to be elucidated. We have recently suggested that addiction may be secondary to long-term epigenetic modifications that determine the clinical course of substance use disorders. A better understanding of epigenetic mechanisms in animal models that mimic human conditions should help to usher in a new area of drug development against addiction.
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Affiliation(s)
- J L Cadet
- Molecular Neuropsychiatry Research Branch, NIH/NIDA Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA
| | - M T McCoy
- Molecular Neuropsychiatry Research Branch, NIH/NIDA Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA
| | - S Jayanthi
- Molecular Neuropsychiatry Research Branch, NIH/NIDA Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA
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27
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Ren Y, Zhou Y, Liu M, Zhang S. Associations of Promoter Methylations and mRNA Expressions of MMP-2, MMP-7 and MMP-9 with Primary Fallopian Tube Carcinoma. Gynecol Obstet Invest 2016; 81:367-74. [PMID: 26785083 DOI: 10.1159/000443639] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 12/23/2015] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To explore the associations of matrix metalloprotease-2 (MMP-2), MMP-7 and MMP-9 methylations and messenger ribonucleic acid (mRNA) expressions with primary fallopian tube carcinoma (PFTC) development and prognosis. METHODS We recruited 48 patients with PFTC into the case group and 48 healthy individuals into the control group; PFTC tissues and normal fallopian tube tissues were obtained from subjects in both groups. Methylation specific polymerase chain reaction (PCR), reverse transcription PCR and the immunohistochemical method were used to examine methylation, mRNA expressions and protein expressions of MMP-2, MMP-7 and MMP-9, respectively. RESULTS The methylation rates of MMP-2, MMP-7 and MMP-9 in the case group were significantly lower than those in the control group (all p < 0.05); MMP-2, MMP-7 and MMP-9 protein and mRNA expressions of PFTC tissues were enormously higher than those of normal tissues (all p < 0.05); univariate survival analysis indicated that MMP-2 and MMP-9 methylations and their protein expressions were associated with PFTC prognosis (all p < 0.05), which was further confirmed by the Cox regression model (all p < 0.05). CONCLUSION The protein and mRNA expressions of MMP-2, MMP-7 and MMP-9 might be related to PFTC, while the methylations and protein expressions of MMP-2 and MMP-9 might be associated with PFTC progression and prognosis.
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Affiliation(s)
- Yuefang Ren
- Department of Gynecology, Huzhou Maternity and Child Care Hospital, Huzhou, PR China
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Cadet JL. Epigenetics of Stress, Addiction, and Resilience: Therapeutic Implications. Mol Neurobiol 2016; 53:545-560. [PMID: 25502297 PMCID: PMC4703633 DOI: 10.1007/s12035-014-9040-y] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 11/30/2014] [Indexed: 12/12/2022]
Abstract
Substance use disorders (SUDs) are highly prevalent. SUDs involve vicious cycles of binges followed by occasional periods of abstinence with recurrent relapses despite treatment and adverse medical and psychosocial consequences. There is convincing evidence that early and adult stressful life events are risks factors for the development of addiction and serve as cues that trigger relapses. Nevertheless, the fact that not all individuals who face traumatic events develop addiction to licit or illicit drugs suggests the existence of individual and/or familial resilient factors that protect these mentally healthy individuals. Here, I give a brief overview of the epigenetic bases of responses to stressful events and of epigenetic changes associated with the administration of drugs of abuse. I also discuss the psychobiology of resilience and alterations in epigenetic markers that have been observed in models of resilience. Finally, I suggest the possibility that treatment of addiction should involve cognitive and pharmacological approaches that enhance resilience in at risk individuals. Similar approaches should also be used with patients who have already succumbed to the nefarious effects of addictive substances.
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Affiliation(s)
- Jean Lud Cadet
- Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
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Egg-specific expression of protein with DNA methyltransferase activity in the biocarcinogenic liver fluke Clonorchis sinensis. Parasitology 2015; 142:1228-38. [PMID: 26036304 DOI: 10.1017/s0031182015000566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Despite recent reports regarding the biology of cytosine methylation in Schistosoma mansoni, the impact of the regulatory machinery remains unclear in diverse platyhelminthes. This ambiguity is reinforced by discoveries of DNA methyltransferase 2 (DNMT2)-only organisms and the substrate specificity of DNMT2 preferential to RNA molecules. Here, we characterized a novel DNA methyltransferase, named CsDNMT2, in a liver fluke Clonorchis sinensis. The protein exhibited structural properties conserved in other members of the DNMT2 family. The native and recombinant CsDNMT2 exhibited considerable enzymatic activity on DNA. The spatiotemporal expression of CsDNMT2 mirrored that of 5-methylcytosine (5 mC), both of which were elevated in the C. sinensis eggs. However, CsDNMT2 and 5 mC were marginally detected in other histological regions of C. sinensis adults including ovaries and seminal receptacle. The methylation site seemed not related to genomic loci occupied by progenies of an active long-terminal-repeat retrotransposon. Taken together, our data strongly suggest that C. sinensis has preserved the functional DNA methylation machinery and that DNMT2 acts as a genuine alternative to DNMT1/DNMT3 to methylate DNA in the DNMT2-only organism. The epigenetic regulation would target functional genes primarily involved in the formation and/or maturation of eggs, rather than retrotransposons.
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Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation. Nat Commun 2015; 6:7023. [PMID: 25960197 PMCID: PMC4432644 DOI: 10.1038/ncomms8023] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 03/25/2015] [Indexed: 12/25/2022] Open
Abstract
DNMT1 is an important epigenetic regulator that plays a key role in the maintenance of DNA methylation. Here we determined the crystal structure of DNMT1 in complex with USP7 at 2.9 Å resolution. The interaction between the two proteins is primarily mediated by an acidic pocket in USP7 and Lysine residues within DNMT1's KG linker. This intermolecular interaction is required for USP7-mediated stabilization of DNMT1. Acetylation of the KG linker Lysine residues impair DNMT1–USP7 interaction and promote the degradation of DNMT1. Treatment with HDAC inhibitors results in an increase in acetylated DNMT1 and decreased total DNMT1 protein. This negative correlation is observed in differentiated neuronal cells and pancreatic cancer cells. Our studies reveal that USP7-mediated stabilization of DNMT1 is regulated by acetylation and provide a structural basis for the design of inhibitors, targeting the DNMT1–USP7 interaction surface for therapeutic applications. DNMT1 is a methyl-transferase involved in maintaining tissue-specific patterns of DNA methylation. Here the authors solve the structure of a DNMT1-USP7 complex and demonstrate the mechanism by which DNMT1 stability is regulated through acetylation by preventing association with the deubiquitinase USP7.
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31
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Murphy TM, O'Donovan A, Mullins N, O'Farrelly C, McCann A, Malone K. Anxiety is associated with higher levels of global DNA methylation and altered expression of epigenetic and interleukin-6 genes. Psychiatr Genet 2015; 25:71-8. [PMID: 25350786 DOI: 10.1097/ypg.0000000000000055] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVES Anxiety is associated with elevated levels of the inflammatory cytokine interleukin-6 (IL-6) and an increased risk for diseases with an inflammatory aetiology. In cancer, higher levels of IL-6 have been associated with increased expression of the epigenetic enzymes DNMT1 and Enhancer of Zeste Homolog 2 (EZH2). However, the relationship between IL-6 and DNA methyltransferases (DNMTs) and EZH2 expression has not previously been examined in anxious individuals. METHODS Global DNA methylation levels were measured using the Methylflash Methylated DNA Quantification Kit and gene expression levels of the DNMT and EZH2 genes in anxious (n=25) and nonanxious individuals (n=22) were compared using quantitative real-time PCR. Specifically, we investigated whether global DNA methylation or aberrant expression of these genes was correlated with IL-6 mRNA and protein serum levels in anxious individuals. RESULTS Anxious participants had significantly higher levels of global DNA methylation compared with controls (P=0.001). There were no differences in the mean mRNA expression levels of the DNMT1/3A/3B, EZH2 and IL-6 genes in anxious individuals compared with controls. However, the expression of DNMT1/3A, EZH2 and IL-6 genes increases with increasing Hospital Anxiety and Depression Scale-Anxiety scores in the anxious cohort only. Interestingly, IL-6 gene expression was correlated strongly with DNMT1/3A/3B and EZH2 expression, highlighting a potential relationship between IL-6 and important epigenetic regulatory enzymes. CONCLUSION This study provides novel insight into the relationship between anxiety, epigenetics and IL-6. Moreover, our findings support the hypothesis that changes in DNA methylation profiles may contribute to the biology of anxiety.
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Affiliation(s)
- Therese M Murphy
- aMedical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter, UK bDepartment of Psychiatry, San Francisco & San Francisco VA Medical Center, University of California, USA cDepartment of Psychiatry and Mental Health Research, Education and Research Centre, St. Vincent's University Hospital dThe UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, UCD School of Medicine and Medical Science, Dublin eSchool of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
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32
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Robaina MC, Mazzoccoli L, Arruda VO, Reis FRDS, Apa AG, de Rezende LMM, Klumb CE. Deregulation of DNMT1, DNMT3B and miR-29s in Burkitt lymphoma suggests novel contribution for disease pathogenesis. Exp Mol Pathol 2015; 98:200-7. [PMID: 25746661 DOI: 10.1016/j.yexmp.2015.03.006] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Revised: 01/23/2015] [Accepted: 03/02/2015] [Indexed: 12/24/2022]
Abstract
Methylation of CpG islands in promoter gene regions is frequently observed in lymphomas. DNA methylation is established by DNA methyltransferases (DNMTs). DNMT1 maintains methylation patterns, while DNMT3A and DNMT3B are critical for de novo DNA methylation. Little is known about the expression of DNMTs in lymphomas. DNMT3A and 3B genes can be regulated post-transcriptionally by miR-29 family. Here, we demonstrated for the first time the overexpression of DNMT1 and DNMT3B in Burkitt lymphoma (BL) tumor samples (69% and 86%, respectively). Specifically, the treatment of two BL cell lines with the DNMT inhibitor 5-aza-dC decreased DNMT1 and DNMT3B protein levels and inhibited cell growth. Additionally, miR-29a, miR-29b and miR-29c levels were significantly decreased in the BL tumor samples. Besides, the ectopic expression of miR-29a, miR-29b and miR-29c reduced the DNMT3B expression and miR-29a and miR-29b lead to increase of p16(INK4a) mRNA expression. Altogether, our data suggest that deregulation of DNMT1, DNMT3B and miR29 may be involved in BL pathogenesis.
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Affiliation(s)
- Marcela C Robaina
- Programa de Pesquisa em Hemato-Oncologia Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | - Luciano Mazzoccoli
- Programa de Pesquisa em Hemato-Oncologia Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | - Viviane Oliveira Arruda
- Programa de Pesquisa em Hemato-Oncologia Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | | | | | | | - Claudete Esteves Klumb
- Programa de Pesquisa em Hemato-Oncologia Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
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Song J, Du Z, Ravasz M, Dong B, Wang Z, Ewing RM. A Protein Interaction between β-Catenin and Dnmt1 Regulates Wnt Signaling and DNA Methylation in Colorectal Cancer Cells. Mol Cancer Res 2015; 13:969-81. [PMID: 25753001 DOI: 10.1158/1541-7786.mcr-13-0644] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 01/26/2015] [Indexed: 01/03/2023]
Abstract
UNLABELLED Aberrant activation of the Wnt signaling pathway is an important step in the initiation and progression of tumor development in diverse cancers. The central effector of canonical Wnt signaling, β-catenin (CTNNB1), is a multifunctional protein, and has been extensively studied with respect to its roles in cell-cell adhesion and in regulation of Wnt-driven transcription. Here, a novel mass spectrometry-based proteomics technique in colorectal cancer cells expressing stabilized β-catenin, was used to identify a protein-protein interaction between β-catenin and DNA methyltransferase I (Dnmt1) protein, the primary regulator of DNA methylation patterns in mammalian cells. Dnmt1 and β-catenin strongly colocalized in the nuclei of colorectal cancer cells, and the interaction is mediated by the central domain of the Dnmt1 protein. Dnmt1 protein abundance is dependent upon the levels of β-catenin, and is increased in cells expressing stabilized mutant β-catenin. Conversely, the Dnmt1 regulates the levels of nuclear β-catenin and β-catenin/TCF-driven transcription. In addition, lysine-specific demethylase 1 (LSD1/KDM1A), a regulator of DNMT1 stability, was identified as a component of the Dnmt1-β-catenin protein complex and perturbation of the Dnmt1-β-catenin interaction altered DNA methylation. In summary, a functional protein-protein interaction was identified between two critically important oncoproteins, in turn revealing a link between Wnt signaling and downstream nuclear functions mediated by Dnmt1. IMPLICATIONS Two critical oncoproteins, Dnmt1 and β-catenin, mutually regulate one each other's levels and activities in colorectal cancer cells.
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Affiliation(s)
- Jing Song
- Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio
| | - Zhanwen Du
- Department of Genetics and Genome Science, Case Western Reserve University, Cleveland, Ohio
| | - Mate Ravasz
- Centre for Biological Sciences, University of Southampton, Southampton, United Kingdom
| | - Bohan Dong
- Department of Genetics and Genome Science, Case Western Reserve University, Cleveland, Ohio. Department of Biochemistry, Wan Nan Medical College, Wu Hu, An Hui, China
| | - Zhenghe Wang
- Department of Genetics and Genome Science, Case Western Reserve University, Cleveland, Ohio.
| | - Rob M Ewing
- Centre for Biological Sciences, University of Southampton, Southampton, United Kingdom.
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Xia L, Ma S, Zhang Y, Wang T, Zhou M, Wang Z, Zhang J. Daily variation in global and local DNA methylation in mouse livers. PLoS One 2015; 10:e0118101. [PMID: 25689298 PMCID: PMC4331433 DOI: 10.1371/journal.pone.0118101] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Accepted: 01/05/2015] [Indexed: 01/01/2023] Open
Abstract
DNA methylation is one of the best-characterized epigenetic modifications and has an important biological relevance. Here we showed that global DNA methylation level in mouse livers displayed a daily variation where the peak phases occurred during the end of the day and the lowest level at the beginning of the day in the light-dark or dark-dark cycles. Typical repeat sequence long interspersed nucleotide element-1 (LINE-1) had a similar methylation rhythm to global DNA. DNA methyltransferase 3A (DNMT3A) and ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) brought a relative forward daily variation to global DNA methylation, and the temporary change in ratio of SAM to SAH had no influence on the DNA methylation level. The rhythm of global DNA methylation was lost and DNA methylation level was increased in Per1-/-Per2-/- double knockout mice, which were in accordance with changes of Dnmt3a mRNA levels and its rhythm. Our results suggest that the daily variation in global DNA methylation was associated with the change of Dnmt3a expression rather than ratio of SAM to SAH.
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Affiliation(s)
- Lin Xia
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, 210094, China
| | - Shihong Ma
- Nanjing Institute for the Comprehensive Utilization of Wild Plant, Nanjing, 210042, China
| | - Ying Zhang
- Department of Biochemistry and Molecular Biology, Jiangsu University School of Medicine, Zhenjiang, 212013, China
| | - Tao Wang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, 210094, China
| | - Mengyi Zhou
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, 210094, China
| | - Zhongqiu Wang
- Department of Radiology, Nanjing University of Chinese Medicine, Nanjing, 210000, China
- * E-mail: (JZ); (ZW)
| | - Jianfa Zhang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, 210094, China
- * E-mail: (JZ); (ZW)
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Abstract
Epigenetic and genetic alterations contribute to cancer initiation and progression. Epigenetics refers to the study of heritable changes in gene expression without alterations in DNA sequences. Epigenetic changes are reversible and include key processes of DNA methylation, chromatin modifications, nucleosome positioning, and alterations in noncoding RNA profiles. Disruptions in epigenetic processes can lead to altered gene function and cellular neoplastic transformation. Epigenetic modifications precede genetic changes and usually occur at an early stage in neoplastic development. Recent technological advances offer a better understanding of the underlying epigenetic alterations during carcinogenesis and provide insight into the discovery of putative epigenetic biomarkers for detection, prognosis, risk assessment, and disease monitoring. In this chapter we provide information on various epigenetic mechanisms and their role in carcinogenesis, in particular, epigenetic modifications causing genetic changes and the potential clinical impact of epigenetic research in the future.
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Affiliation(s)
- Rajnee Kanwal
- Department of Urology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA
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Farinelli P, Perera A, Arango-Gonzalez B, Trifunovic D, Wagner M, Carell T, Biel M, Zrenner E, Michalakis S, Paquet-Durand F, Ekström PAR. DNA methylation and differential gene regulation in photoreceptor cell death. Cell Death Dis 2014; 5:e1558. [PMID: 25476906 PMCID: PMC4649831 DOI: 10.1038/cddis.2014.512] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 10/17/2014] [Accepted: 10/21/2014] [Indexed: 01/09/2023]
Abstract
Retinitis pigmentosa (RP) defines a group of inherited degenerative retinal diseases causing progressive loss of photoreceptors. To this day, RP is still untreatable and rational treatment development will require a thorough understanding of the underlying cell death mechanisms. Methylation of the DNA base cytosine by DNA methyltransferases (DNMTs) is an important epigenetic factor regulating gene expression, cell differentiation, cell death, and survival. Previous studies suggested an involvement of epigenetic mechanisms in RP, and in this study, increased cytosine methylation was detected in dying photoreceptors in the rd1, rd2, P23H, and S334ter rodent models for RP. Ultrastructural analysis of photoreceptor nuclear morphology in the rd1 mouse model for RP revealed a severely altered chromatin structure during retinal degeneration that coincided with an increased expression of the DNMT isozyme DNMT3a. To identify disease-specific differentially methylated DNA regions (DMRs) on a genomic level, we immunoprecipitated methylated DNA fragments and subsequently analyzed them with a targeted microarray. Genome-wide comparison of DMRs between rd1 and wild-type retina revealed hypermethylation of genes involved in cell death and survival as well as cell morphology and nervous system development. When correlating DMRs with gene expression data, we found that hypermethylation occurred alongside transcriptional repression. Consistently, motif analysis showed that binding sites of several important transcription factors for retinal physiology were hypermethylated in the mutant model, which also correlated with transcriptional silencing of their respective target genes. Finally, inhibition of DNMTs in rd1 organotypic retinal explants using decitabine resulted in a substantial reduction of photoreceptor cell death, suggesting inhibition of DNA methylation as a potential novel treatment in RP.
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Affiliation(s)
- P Farinelli
- 1] Division of Ophthalmology, Department of Clinical Sciences, University of Lund, BMC-B11, Lund 22184, Sweden [2] Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen 72076, Germany
| | - A Perera
- Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Munich 81377, Germany
| | - B Arango-Gonzalez
- Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen 72076, Germany
| | - D Trifunovic
- Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen 72076, Germany
| | - M Wagner
- Center for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, Ludwig-Maximilians-Universität München, Munich 81377, Germany
| | - T Carell
- Center for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, Ludwig-Maximilians-Universität München, Munich 81377, Germany
| | - M Biel
- Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Munich 81377, Germany
| | - E Zrenner
- Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen 72076, Germany
| | - S Michalakis
- Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Munich 81377, Germany
| | - F Paquet-Durand
- Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen 72076, Germany
| | - P A R Ekström
- Division of Ophthalmology, Department of Clinical Sciences, University of Lund, BMC-B11, Lund 22184, Sweden
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Pezzi JC, Ens CMB, Borba EM, Schumacher-Schuh AF, de Andrade FM, Chaves MLF, Fiegenbaum M, Camozzato AL. DNA methyltransferase haplotype is associated with Alzheimer's disease. Neurosci Lett 2014; 579:70-4. [PMID: 25038421 DOI: 10.1016/j.neulet.2014.07.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 06/06/2014] [Accepted: 07/08/2014] [Indexed: 11/15/2022]
Abstract
Epigenetic mechanisms have been implicated in syndromes associated with neuropsychiatric disorders, but little is known about the role of epigenetics in Alzheimer's disease (AD). DNA methylation, one of the main epigenetic mechanisms, is a complex process carried out by specific enzymes, such as DNMT1 and DNMT3B. This study aimed to investigate the association between DNMT1 and DNMT3B polymorphisms and AD. Two hundred and ten elderly subjects (108 healthy controls and 102 with AD-NINCDS/ARDA, DSM-IV-TR criteria) were assessed. DNA was obtained from whole blood, and genotypes were detected by an allelic discrimination assay using TaqMan(®) MGB probes on a real-time PCR system. The polymorphisms studied were rs2162560, rs759920 (DNMT1) and rs998382, rs2424913, rs2424932 (DNMT3B). For both genes, the polymorphisms were in strong linkage disequilibrium. Carriers of the DNMT3B TGG haplotype were associated with AD (OR=3.03, 95% CI 1.63 to 5.63, P<0.001). No significant difference between AD and the control group were observed for DNMT1 polymorphisms. This study is one of the first describing a significant association between DNMT3B polymorphisms and AD. This enzyme, which is responsible for methylation in a general way, may be involved in AD.
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Affiliation(s)
- Julio Carlos Pezzi
- Graduate Program in Health Science, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil.
| | - Cintia Monique Boschmann Ens
- Graduate Program in Health Science, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| | - Ericksen Mielle Borba
- Dementia Clinic, Neurology Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil
| | - Artur F Schumacher-Schuh
- Dementia Clinic, Neurology Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil
| | | | | | - Marilu Fiegenbaum
- Graduate Program in Health Science, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
| | - Ana Luiza Camozzato
- Graduate Program in Health Science, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
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Bacolla A, Cooper DN, Vasquez KM. Mechanisms of base substitution mutagenesis in cancer genomes. Genes (Basel) 2014; 5:108-46. [PMID: 24705290 PMCID: PMC3978516 DOI: 10.3390/genes5010108] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Revised: 02/07/2014] [Accepted: 02/11/2014] [Indexed: 01/24/2023] Open
Abstract
Cancer genome sequence data provide an invaluable resource for inferring the key mechanisms by which mutations arise in cancer cells, favoring their survival, proliferation and invasiveness. Here we examine recent advances in understanding the molecular mechanisms responsible for the predominant type of genetic alteration found in cancer cells, somatic single base substitutions (SBSs). Cytosine methylation, demethylation and deamination, charge transfer reactions in DNA, DNA replication timing, chromatin status and altered DNA proofreading activities are all now known to contribute to the mechanisms leading to base substitution mutagenesis. We review current hypotheses as to the major processes that give rise to SBSs and evaluate their relative relevance in the light of knowledge acquired from cancer genome sequencing projects and the study of base modifications, DNA repair and lesion bypass. Although gene expression data on APOBEC3B enzymes provide support for a role in cancer mutagenesis through U:G mismatch intermediates, the enzyme preference for single-stranded DNA may limit its activity genome-wide. For SBSs at both CG:CG and YC:GR sites, we outline evidence for a prominent role of damage by charge transfer reactions that follow interactions of the DNA with reactive oxygen species (ROS) and other endogenous or exogenous electron-abstracting molecules.
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Affiliation(s)
- Albino Bacolla
- Dell Pediatric Research Institute, Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, 1400 Barbara Jordan Blvd., Austin, TX 78723, USA.
| | - David N Cooper
- Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
| | - Karen M Vasquez
- Dell Pediatric Research Institute, Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, 1400 Barbara Jordan Blvd., Austin, TX 78723, USA.
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Barros SP, Offenbacher S. Modifiable risk factors in periodontal disease: epigenetic regulation of gene expression in the inflammatory response. Periodontol 2000 2014; 64:95-110. [PMID: 24320958 DOI: 10.1111/prd.12000] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Epigenetics as a modifiable risk factor in periodontal diseases has been investigated in light of the current knowledge of how chronic infection and inflammation can affect gene-specific epigenetic reprogramming in periodontal tissues. Epigenomic programming might be particularly sensitive to environmental influences, and a combination of physiological stressors and environmental exposures appears to affect the epigenomic program acquired by a cell during differentiation and throughout the cellular lineage lifespan. Viral and bacterial infections can establish several types of epigenetic modifications, which sometimes engage in a complex epigenetic crosstalk also reflecting in the establishment and progress of periodontal diseases. The inflammatory and metabolic states of the periodontal tissues are driven by the infectious stimuli, and the magnitude of the cellular and molecular signature response is further dictated by the host genetic and epigenetic traits associated with various systemic exposures, including smoking, obesity and diabetes/hyperglycemia. This review discusses the advances in epigenetics, focusing on the role of DNA methylation in the pathogenesis of periodontal disease and the potential of epigenetic therapy.
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Bellizzi D, D'Aquila P, Scafone T, Giordano M, Riso V, Riccio A, Passarino G. The control region of mitochondrial DNA shows an unusual CpG and non-CpG methylation pattern. DNA Res 2013; 20:537-47. [PMID: 23804556 PMCID: PMC3859322 DOI: 10.1093/dnares/dst029] [Citation(s) in RCA: 202] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 05/30/2013] [Indexed: 11/23/2022] Open
Abstract
DNA methylation is a common epigenetic modification of the mammalian genome. Conflicting data regarding the possible presence of methylated cytosines within mitochondrial DNA (mtDNA) have been reported. To clarify this point, we analysed the methylation status of mtDNA control region (D-loop) on human and murine DNA samples from blood and cultured cells by bisulphite sequencing and methylated/hydroxymethylated DNA immunoprecipitation assays. We found methylated and hydroxymethylated cytosines in the L-strand of all samples analysed. MtDNA methylation particularly occurs within non-C-phosphate-G (non-CpG) nucleotides, mainly in the promoter region of the heavy strand and in conserved sequence blocks, suggesting its involvement in regulating mtDNA replication and/or transcription. We observed DNA methyltransferases within the mitochondria, but the inactivation of Dnmt1, Dnmt3a, and Dnmt3b in mouse embryonic stem (ES) cells results in a reduction of the CpG methylation, while the non-CpG methylation shows to be not affected. This suggests that D-loop epigenetic modification is only partially established by these enzymes. Our data show that DNA methylation occurs in the mtDNA control region of mammals, not only at symmetrical CpG dinucleotides, typical of nuclear genome, but in a peculiar non-CpG pattern previously reported for plants and fungi. The molecular mechanisms responsible for this pattern remain an open question.
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Affiliation(s)
- Dina Bellizzi
- Department of Cell Biology, University of Calabria, Rende 87036, Italy
| | - Patrizia D'Aquila
- Department of Cell Biology, University of Calabria, Rende 87036, Italy
| | - Teresa Scafone
- Department of Cell Biology, University of Calabria, Rende 87036, Italy
| | - Marco Giordano
- Department of Cell Biology, University of Calabria, Rende 87036, Italy
| | - Vincenzo Riso
- Institute of Genetics and Biophysics—Adriano Buzzati Traverso, Napoli 80131, Italy
| | - Andrea Riccio
- Institute of Genetics and Biophysics—Adriano Buzzati Traverso, Napoli 80131, Italy
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Ammal Kaidery N, Tarannum S, Thomas B. Epigenetic landscape of Parkinson's disease: emerging role in disease mechanisms and therapeutic modalities. Neurotherapeutics 2013; 10:698-708. [PMID: 24030213 PMCID: PMC3805874 DOI: 10.1007/s13311-013-0211-8] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
Parkinson's disease (PD) is a complex multifactorial disorder marked by extensive system-wide pathology, including a substantial loss of nigrostriatal dopaminergic neurons. The etiology of PD remains elusive, but there is considerable evidence that, in addition to well-defined genetic mechanisms environmental factors play a crucial role in disease pathogenesis. How the environment might influence the genetic factors and contribute to disease development and progression remains unclear. In recent years, epigenetic mechanisms such as DNA methylation, chromatin remodeling and alterations in gene expression via non-coding RNAs have begun to be revealed as potential factors in PD pathogenesis. Epigenetic modulation exists throughout life, beginning in prenatal stages, is dependent on the lifestyle, environmental exposure and genetic makeup of an individual and may serve as a missing link between PD risk factors and development of the disease. This chapter sheds light on the emerging role of epigenetics in disease pathogenesis and on prospective interventional strategies for the therapeutic modulation of PD.
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Affiliation(s)
- Navneet Ammal Kaidery
- />Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, CB-3618, 30912 Augusta, Georgia
| | - Shaista Tarannum
- />Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, CB-3618, 30912 Augusta, Georgia
| | - Bobby Thomas
- />Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, CB-3618, 30912 Augusta, Georgia
- />Department of Neurology, Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, CB-3618, 30912 Augusta, Georgia
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Abstract
Gene activity is regulated by transcriptional and epigenetic mechanisms. A paper in 2005 by Zhang et al.1 showed that STAT3 binds to the DNA methyl transferase, DNMT1 and their data indicated that STAT3 may cause epigenetic gene silencing by targeting DNMT1 to the PTPN6 promoter. Now, a paper by Lee et al.2 has fleshed out the mechanism. They provide evidence that acetylation of STAT3 regulates the binding of DNMT1, CpG DNA methylation and regulation of several genes, including that encoding the estrogen receptor α (ESR1) in breast cancer cells.
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Affiliation(s)
- N Shaun B Thomas
- Department of Haematological Medicine; Rayne Institute; King's College London; London, UK
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Agarwal S, Amin KS, Jagadeesh S, Baishay G, Rao PG, Barua NC, Bhattacharya S, Banerjee PP. Mahanine restores RASSF1A expression by down-regulating DNMT1 and DNMT3B in prostate cancer cells. Mol Cancer 2013; 12:99. [PMID: 24001151 PMCID: PMC3851847 DOI: 10.1186/1476-4598-12-99] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 08/24/2013] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hypermethylation of the promoter of the tumor suppressor gene RASSF1A silences its expression and has been found to be associated with advanced grade prostatic tumors. The DNA methyltransferase (DNMT) family of enzymes are known to be involved in the epigenetic silencing of gene expression, including RASSF1A, and are often overexpressed in prostate cancer. The present study demonstrates how mahanine, a plant-derived carbazole alkaloid, restores RASSF1A expression by down-regulating specific members of the DNMT family of proteins in prostate cancer cells. RESULTS Using methylation-specific PCR we establish that mahanine restores the expression of RASSF1A by inducing the demethylation of its promoter in prostate cancer cells. Furthermore, we show that mahanine treatment induces the degradation of DNMT1 and DNMT3B, but not DNMT3A, via the ubiquitin-proteasome pathway; an effect which is rescued in the presence of a proteasome inhibitor, MG132. The inactivation of Akt by wortmannin, a PI3K inhibitor, results in a similar down-regulation in the levels DNMT1 and DNMT3B. Mahanine treatment results in a decline in phospho-Akt levels and a disruption in the interaction of Akt with DNMT1 and DNMT3B. Conversely, the exogenous expression of constitutively active Akt inhibits the ability of mahanine to down-regulate these DNMTs, suggesting that the degradation of DNMT1 and DNMT3B by mahanine occurs via Akt inactivation. CONCLUSIONS Taken together, we show that mahanine treatment induces the proteasomal degradation of DNMT1 and DNMT3B via the inactivation of Akt, which facilitates the demethylation of the RASSF1A promoter and restores its expression in prostate cancer cells. Therefore, mahanine could be a potential therapeutic agent for advanced prostate cancer in men when RASSF1A expression is silenced.
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Affiliation(s)
- Soumik Agarwal
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Karishma S Amin
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Shankar Jagadeesh
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA
- Current address: ACell, Inc., Columbia, MD, USA
| | - Gokul Baishay
- Natural Product Chemistry Division, North-East Institute of Science & Technology, Jorhat, Assam 785006, India
| | - Paruchuri G Rao
- Natural Product Chemistry Division, North-East Institute of Science & Technology, Jorhat, Assam 785006, India
| | - Nabin C Barua
- Natural Product Chemistry Division, North-East Institute of Science & Technology, Jorhat, Assam 785006, India
| | - Samir Bhattacharya
- Natural Product Chemistry Division, North-East Institute of Science & Technology, Jorhat, Assam 785006, India
- Cellular and Molecular Endocrinology Laboratory, Centre for Advanced Studies in Zoology, School of Life Science, Visva-Bharati University, Santiniketan 731235, India
| | - Partha P Banerjee
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA
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DNA methylation and cancer diagnosis. Int J Mol Sci 2013; 14:15029-58. [PMID: 23873296 PMCID: PMC3742286 DOI: 10.3390/ijms140715029] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 06/28/2013] [Accepted: 07/04/2013] [Indexed: 02/06/2023] Open
Abstract
DNA methylation is a major epigenetic modification that is strongly involved in the physiological control of genome expression. DNA methylation patterns are largely modified in cancer cells and can therefore be used to distinguish cancer cells from normal tissues. This review describes the main technologies available for the detection and the discovery of aberrantly methylated DNA patterns. It also presents the different sources of biological samples suitable for DNA methylation studies. We discuss the interest and perspectives on the use of DNA methylation measurements for cancer diagnosis through examples of methylated genes commonly documented in the literature. The discussion leads to our consideration for why DNA methylation is not commonly used in clinical practice through an examination of the main requirements that constitute a reliable biomarker. Finally, we describe the main DNA methylation inhibitors currently used in clinical trials and those that exhibit promising results.
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Ryley Parrish R, Albertson AJ, Buckingham SC, Hablitz JJ, Mascia KL, Davis Haselden W, Lubin FD. Status epilepticus triggers early and late alterations in brain-derived neurotrophic factor and NMDA glutamate receptor Grin2b DNA methylation levels in the hippocampus. Neuroscience 2013; 248:602-19. [PMID: 23811393 DOI: 10.1016/j.neuroscience.2013.06.029] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 06/13/2013] [Accepted: 06/17/2013] [Indexed: 10/26/2022]
Abstract
Status epilepticus (SE) triggers abnormal expression of genes in the hippocampus, such as glutamate receptor subunit epsilon-2 (Grin2b/Nr2b) and brain-derived neurotrophic factor (Bdnf), that is thought to occur in temporal lobe epilepsy (TLE). We examined the underlying DNA methylation mechanisms and investigated whether these mechanisms contribute to the expression of these gene targets in the epileptic hippocampus. Experimental TLE was provoked by kainic acid-induced SE. Bisulfite sequencing analysis revealed increased Grin2b/Nr2b and decreased Bdnf DNA methylation levels that corresponded to decreased Grin2b/Nr2b and increased Bdnf mRNA and protein expression in the epileptic hippocampus. Blockade of DNA methyltransferase (DNMT) activity with zebularine decreased global DNA methylation levels and reduced Grin2b/Nr2b, but not Bdnf, DNA methylation levels. Interestingly, we found that DNMT blockade further decreased Grin2b/Nr2b mRNA expression whereas GRIN2B protein expression increased in the epileptic hippocampus, suggesting that a posttranscriptional mechanism may be involved. Using chromatin immunoprecipitation analysis we found that DNMT inhibition restored the decreases in AP2alpha transcription factor levels at the Grin2b/Nr2b promoter in the epileptic hippocampus. DNMT inhibition increased field excitatory postsynaptic potential in hippocampal slices isolated from epileptic rats. Electroencephalography (EEG) monitoring confirmed that DNMT inhibition did not significantly alter the disease course, but promoted the latency to seizure onset or SE. Thus, DNA methylation may be an early event triggered by SE that persists late into the epileptic hippocampus to contribute to gene expression changes in TLE.
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Affiliation(s)
- R Ryley Parrish
- Evelyn F. McKnight Brain Institute, Department of Neurobiology, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA.
| | - A J Albertson
- Evelyn F. McKnight Brain Institute, Department of Neurobiology, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA.
| | - S C Buckingham
- Evelyn F. McKnight Brain Institute, Department of Neurobiology, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA.
| | - J J Hablitz
- Evelyn F. McKnight Brain Institute, Department of Neurobiology, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA.
| | - K L Mascia
- Evelyn F. McKnight Brain Institute, Department of Neurobiology, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA.
| | - W Davis Haselden
- Evelyn F. McKnight Brain Institute, Department of Neurobiology, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA.
| | - F D Lubin
- Evelyn F. McKnight Brain Institute, Department of Neurobiology, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA.
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Abstract
The GTC Cancer Summit: Novel Approaches to Drug Discovery was divided into two parallel tracks: the 2nd Cancer Epigenetics Conference, and the Protein Kinases and Drug Design Conference. The 2nd Cancer Epigenetics Conference focused on exciting changes in drug discovery that include an unprecedented private and public collaboration on drug discovery in epigenetics through the Structural Genomics Consortium (SGC), which has led to several major breakthroughs including: the development of small-molecule inhibitors that interfere with protein interactions, especially bromodomain-containing protein acetylation readers; the indirect but successful targeting of the elusive MYC oncogene; and the identification of epigenetic drugs that are disease-specific. Also reported were the development of clinically useful DNA methylation assays; cell, peptide and protein arrays for testing antibody- and protein-binding specificity; and tools for chromatin capture and DNA modification analysis. Several groups reported on the lack of specificity of some commercial, but unnamed, antibodies used for epigenetic studies.
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Pandi G, Nakka VP, Dharap A, Roopra A, Vemuganti R. MicroRNA miR-29c down-regulation leading to de-repression of its target DNA methyltransferase 3a promotes ischemic brain damage. PLoS One 2013; 8:e58039. [PMID: 23516428 PMCID: PMC3596316 DOI: 10.1371/journal.pone.0058039] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Accepted: 01/29/2013] [Indexed: 12/21/2022] Open
Abstract
Recent studies showed that stroke extensively alters cerebral microRNA (miRNA) expression profiles and several miRNAs play a role in mediating ischemic pathophysiology. We currently evaluated the significance of miR-29c, a highly expressed miRNA in rodent brain that was significantly down-regulated after focal ischemia in adult rats as well as after oxygen-glucose deprivation in PC12 cells. Bioinformatics indicated that DNA methyltransferase 3a (DNMT3a) is a major target of miR-29c and co-transfection with premiR-29c prevented DNMT3a 3'UTR vector expression. In PC12 cells, treatment with premiR-29c prevented OGD-induced cell death (by 58 ± 6%; p<0.05). Furthermore, treatment with antagomiR-29c resulted in a 46 ± 5% cell death in PC12 cells. When rats were treated with premiR-29c and subjected to transient focal ischemia, post-ischemic miR-29c levels were restored and the infarct volume decreased significantly (by 34 ± 6%; p<0.05) compared to control premiR treated group. DNMT3a siRNA treatment also significantly curtailed the post-OGD cell death in PC12 cells (by 54 ± 6%; p<0.05) and decreased the post-ischemic infarct volume in rats (by 30 ± 5%; p<0.05) compared to respective control siRNA treated groups. The miR-29c gene promoter showed specific binding sites for the transcription factor REST and the miR-29c promoter vector expression was curtailed when cotransfected with a REST expressing plasmid. Furthermore, treatment with REST siRNA prevented the post-ischemic miR-29c down-regulation and DNMT3a induction in PC12 cells and curtailed ischemic cell death (by 64 ± 9%; p<0.05) compared to control siRNA treatment. These studies suggest that miR-29c is a pro-survival miRNA and its down-regulation is a promoter of ischemic brain damage by acting through its target DNMT3a. Furthermore, REST is an upstream transcriptional controller of miR-29c and curtailing REST induction prevents miR-29c down-regulation and ischemic neuronal death.
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Affiliation(s)
- Gopal Pandi
- Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Venkata P. Nakka
- Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Ashutosh Dharap
- Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Avtar Roopra
- Department of Neuroscience, University of Wisconsin, Madison, Wisconsin, United States of America
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, United States of America
- * E-mail:
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Murphy TM, Mullins N, Ryan M, Foster T, Kelly C, McClelland R, O'Grady J, Corcoran E, Brady J, Reilly M, Jeffers A, Brown K, Maher A, Bannan N, Casement A, Lynch D, Bolger S, Buckley A, Quinlivan L, Daly L, Kelleher C, Malone KM. Genetic variation in DNMT3B and increased global DNA methylation is associated with suicide attempts in psychiatric patients. GENES, BRAIN, AND BEHAVIOR 2013; 12:125-32. [PMID: 23025623 DOI: 10.1111/j.1601-183x.2012.00865.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Revised: 08/17/2012] [Accepted: 09/27/2012] [Indexed: 11/28/2022]
Abstract
Recently, a significant epigenetic component in the pathology of suicide has been realized. Here we investigate candidate functional SNPs in epigenetic-regulatory genes, DNMT1 and DNMT3B, for association with suicide attempt (SA) among patients with co-existing psychiatric illness. In addition, global DNA methylation levels [5-methyl cytosine (5-mC%)] between SA and psychiatric controls were quantified using the Methylflash Methylated DNA Quantification Kit. DNA was obtained from blood of 79 suicide attempters and 80 non-attempters, assessed for DSM-IV Axis I disorders. Functional SNPs were selected for each gene (DNMT1; n = 7, DNMT3B; n = 10), and genotyped. A SNP (rs2424932) residing in the 3' UTR of the DNMT3B gene was associated with SA compared with a non-attempter control group (P = 0.001; Chi-squared test, Bonferroni adjusted P value = 0.02). Moreover, haplotype analysis identified a DNMT3B haplotype which differed between cases and controls, however this association did not hold after Bonferroni correction (P = 0.01, Bonferroni adjusted P value = 0.56). Global methylation analysis showed that psychiatric patients with a history of SA had significantly higher levels of global DNA methylation compared with controls (P = 0.018, Student's t-test). In conclusion, this is the first report investigating polymorphisms in DNMT genes and global DNA methylation quantification in SA risk. Preliminary findings suggest that allelic variability in DNMT3B may be relevant to the underlying diathesis for suicidal acts and our findings support the hypothesis that aberrant DNA methylation profiles may contribute to the biology of suicidal acts. Thus, analysis of global DNA hypermethylation in blood may represent a biomarker for increased SA risk in psychiatric patients.
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Affiliation(s)
- T M Murphy
- Department of Psychiatry and Mental Health Research & Education and Research Centre, St Vincent's University Hospital, and School of Medicine & Medical Science, University College Dublin, Dublin 4, Ireland
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Spellicy CJ, Kosten TR, Hamon SC, Harding MJ, Nielsen DA. The MTHFR C677T Variant is Associated with Responsiveness to Disulfiram Treatment for Cocaine Dependency. Front Psychiatry 2013; 3:109. [PMID: 23335901 PMCID: PMC3544007 DOI: 10.3389/fpsyt.2012.00109] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2012] [Accepted: 12/01/2012] [Indexed: 01/09/2023] Open
Abstract
OBJECTIVE Disulfiram is a one of the few pharmacotherapies for cocaine addiction that shows promise. Since disulfiram and cocaine both affect levels of global methylation we hypothesized the MTHFR gene, whose product is involved in supplying methyl groups for DNA and protein methylation, may be associated with responsiveness to disulfiram in cocaine-dependent individuals. METHODS Sixty-seven cocaine-dependent patients were stabilized on methadone for 2 weeks and then randomized into disulfiram (250 mg/day, N = 32) and placebo groups (N = 35) for 10 weeks. Patients were genotyped for the MTHFR (rs1801133, also known as C677T) polymorphism and the data was evaluated for association with cocaine-free urines in the disulfiram or placebo groups. Data from patients that completed all 10 weeks of the study (N = 56) were analyzed using repeated measures analysis of variance (ANOVA), corrected for population structure. RESULTS The CT or TT MTHFR genotype group (N = 32) dropped from 73 to 52% cocaine-positive urines on disulfiram (p = 0.0001), while the placebo group showed no treatment effect. The CC MTHFR genotype group (N = 24) showed a smaller, but still significant, reduction in cocaine-positive urines on disulfiram compared to placebo; 81-69% (p = 0.007). CONCLUSION This study indicates that a patient's MTHFR genotype may be used to identify individuals who might show improved response to disulfiram treatment for cocaine dependence. CLINICAL TRIAL Pharmacogenetics of Disulfiram for Cocaine, clinicaltrials.gov/ct2/show/NCT00149630, NIDA-18197-2, NCT00149630.
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Affiliation(s)
- Catherine J. Spellicy
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Michael E. DeBakey V. A. Medical CenterHouston, TX, USA
| | - Thomas R. Kosten
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Michael E. DeBakey V. A. Medical CenterHouston, TX, USA
| | - Sara C. Hamon
- Laboratory of Statistical Genetics, The Rockefeller UniversityNew York, NY, USA
| | - Mark J. Harding
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Michael E. DeBakey V. A. Medical CenterHouston, TX, USA
| | - David A. Nielsen
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Michael E. DeBakey V. A. Medical CenterHouston, TX, USA
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Gapp K, Woldemichael BT, Bohacek J, Mansuy IM. Epigenetic regulation in neurodevelopment and neurodegenerative diseases. Neuroscience 2012; 264:99-111. [PMID: 23256926 DOI: 10.1016/j.neuroscience.2012.11.040] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Revised: 11/08/2012] [Accepted: 11/21/2012] [Indexed: 01/25/2023]
Abstract
From fertilization throughout development and until death, cellular programs in individual cells are dynamically regulated to fulfill multiple functions ranging from cell lineage specification to adaptation to internal and external stimuli. Such regulation is of major importance in brain cells, because the brain continues to develop long after birth and incorporates information from the environment across life. When compromised, these regulatory mechanisms can have detrimental consequences on neurodevelopment and lead to severe brain pathologies and neurodegenerative diseases in the adult individual. Elucidating these processes is essential to better understand their implication in disease etiology. Because they are strongly influenced by environmental factors, they have been postulated to depend on epigenetic mechanisms. This review describes recent studies that have identified epigenetic dysfunctions in the pathophysiology of several neurodevelopmental and neurodegenerative diseases. It discusses currently known pathways and molecular targets implicated in pathologies including imprinting disorders, Rett syndrome, and Alzheimer's, Parkinson's and Hungtinton's disease, and their relevance to these diseases.
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Affiliation(s)
- K Gapp
- Brain Research Institute, Medical Faculty of the University of Zürich and Swiss Federal Institute of Technology, Neuroscience Center Zürich, Zürich, Switzerland
| | - B T Woldemichael
- Brain Research Institute, Medical Faculty of the University of Zürich and Swiss Federal Institute of Technology, Neuroscience Center Zürich, Zürich, Switzerland
| | - J Bohacek
- Brain Research Institute, Medical Faculty of the University of Zürich and Swiss Federal Institute of Technology, Neuroscience Center Zürich, Zürich, Switzerland
| | - I M Mansuy
- Brain Research Institute, Medical Faculty of the University of Zürich and Swiss Federal Institute of Technology, Neuroscience Center Zürich, Zürich, Switzerland.
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