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      Impacts of cannabinoid epigenetics on human development: reflections on Murphy et. al. ‘cannabinoid exposure and altered DNA methylation in rat and human sperm’ epigenetics 2018; 13: 1208-1221.

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          ABSTRACT

          Recent data from the Kollins lab (‘Cannabinoid exposure and altered DNA methylation in rat and human sperm’ Epigenetics 2018; 13: 1208–1221) indicated epigenetic effects of cannabis use on sperm in man parallel those in rats and showed substantial shifts in both hypo- and hyper-DNA methylation with the latter predominating. This provides one likely mechanism for the transgenerational transmission of epigenomic instability with sperm as the vector. It therefore contributes important pathophysiological insights into the probable mechanisms underlying the epidemiology of prenatal cannabis exposure potentially explaining diverse features of cannabis-related teratology including effects on the neuraxis, cardiovasculature, immune stimulation, secondary genomic instability and carcinogenesis related to both adult and pediatric cancers. The potentially inheritable and therefore multigenerational nature of these defects needs to be carefully considered in the light of recent teratological and neurobehavioural trends in diverse jurisdictions such as the USA nationally, Hawaii, Colorado, Canada, France and Australia, particularly relating to mental retardation, age-related morbidity and oncogenesis including inheritable cancerogenesis. Increasing demonstrations that the epigenome can respond directly and in real time and retain memories of environmental exposures of many kinds implies that the genome-epigenome is much more sensitive to environmental toxicants than has been generally realized. Issues of long-term multigenerational inheritance amplify these concerns. Further research particularly on the epigenomic toxicology of many cannabinoids is also required.

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          Most cited references 179

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          Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs.

          Noncoding RNAs (ncRNA) participate in epigenetic regulation but are poorly understood. Here we characterize the transcriptional landscape of the four human HOX loci at five base pair resolution in 11 anatomic sites and identify 231 HOX ncRNAs that extend known transcribed regions by more than 30 kilobases. HOX ncRNAs are spatially expressed along developmental axes and possess unique sequence motifs, and their expression demarcates broad chromosomal domains of differential histone methylation and RNA polymerase accessibility. We identified a 2.2 kilobase ncRNA residing in the HOXC locus, termed HOTAIR, which represses transcription in trans across 40 kilobases of the HOXD locus. HOTAIR interacts with Polycomb Repressive Complex 2 (PRC2) and is required for PRC2 occupancy and histone H3 lysine-27 trimethylation of HOXD locus. Thus, transcription of ncRNA may demarcate chromosomal domains of gene silencing at a distance; these results have broad implications for gene regulation in development and disease states.
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            Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals.

            Cells of a multicellular organism are genetically homogeneous but structurally and functionally heterogeneous owing to the differential expression of genes. Many of these differences in gene expression arise during development and are subsequently retained through mitosis. Stable alterations of this kind are said to be 'epigenetic', because they are heritable in the short term but do not involve mutations of the DNA itself. Research over the past few years has focused on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation and histone modifications. Here, we review advances in the understanding of the mechanism and role of DNA methylation in biological processes. Epigenetic effects by means of DNA methylation have an important role in development but can also arise stochastically as animals age. Identification of proteins that mediate these effects has provided insight into this complex process and diseases that occur when it is perturbed. External influences on epigenetic processes are seen in the effects of diet on long-term diseases such as cancer. Thus, epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression. The extent to which environmental effects can provoke epigenetic responses represents an exciting area of future research.
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              DNA methylation age of human tissues and cell types

              Background It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure. Results I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance. Conclusions I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research.
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                Author and article information

                Journal
                Epigenetics
                Epigenetics
                KEPI
                kepi20
                Epigenetics
                Taylor & Francis
                1559-2294
                1559-2308
                2019
                11 July 2019
                11 July 2019
                : 14
                : 11
                : 1041-1056
                Affiliations
                [a ]Division of Psychiatry, University of Western Australia , Crawley, Western Australia Australia
                [b ]School of Medical and Health Sciences, Edith Cowan University , Joondalup, Western Australia, Australia
                Author notes
                CONTACT Albert Stuart Reece stuart.reece@ 123456bigpond.com 39 Gladstone Rd., Highgate Hill, Brisbane, Queensland, Australia
                Article
                1633868
                10.1080/15592294.2019.1633868
                6773386
                31293213
                © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

                Page count
                References: 206, Pages: 16
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