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      Global histone modification profiling reveals the epigenomic dynamics during malignant transformation in a four-stage breast cancer model

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          Abstract

          Background

          Epigenetic regulation has emerged to be the critical steps for tumorigenesis and metastasis. Multiple histone methyltransferase and demethylase have been implicated as tumor suppressors or oncogenes recently. But the key epigenomic events in cancer cell transformation still remain poorly understood.

          Methods

          A breast cancer transformation model was established via stably expressing three oncogenes in primary breast epithelial cells. Chromatin immunoprecipitation followed by the next-generation sequencing of histone methylations was performed to determine epigenetic events during transformation. Western blot, quantitative RT-PCR, and immunostaining were used to determine gene expression in cells and tissues.

          Results

          Histones H3K9me2 and me3, two repressive marks of transcription, decrease in in vitro breast cancer cell model and in vivo clinical tissues. A survey of enzymes related with H3K9 methylation indicated that KDM3A/JMJD1A, a demethylase for H3K9me1 and me2, gradually increases during cancer transformation and is elevated in patient tissues. KDM3A/JMJD1A deficiency impairs the growth of tumors in nude mice and transformed cell lines. Genome-wide ChIP-seq analysis reveals that the boundaries of decreased H3K9me2 large organized chromatin K9 modifications (LOCKs) are enriched with cancer-related genes, such as MYC and PAX3. Further studies show that KDM3A/JMJD1A directly binds to these oncogenes and regulates their transcription by removing H3K9me2 mark.

          Conclusions

          Our study demonstrates reduction of histones H3K9 me2 and me3, and elevation of KDM3A/JMJD1A as important events for breast cancer, and illustrates the dynamic epigenomic mechanisms during breast cancer transformation.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13148-016-0201-x) contains supplementary material, which is available to authorized users.

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          Most cited references26

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          Epigenetics in cancer.

          Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies.
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            Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity.

            Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. We characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naïve, tolerized, and trained macrophages. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity. β-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in deoxyribonuclease I hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. Altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans. Copyright © 2014, American Association for the Advancement of Science.
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              Reflecting on 25 years with MYC.

              Just over 25 years ago, MYC, the human homologue of a retroviral oncogene, was identified. Since that time, MYC research has been intense and the advances impressive. On reflection, it is astonishing how each incremental insight into MYC regulation and function has also had an impact on numerous biological disciplines, including our understanding of molecular oncogenesis in general. Here we chronicle the major advances in our understanding of MYC biology, and peer into the future of MYC research.
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                Author and article information

                Contributors
                zhaoshuoxp@whu.edu.cn
                lpj@whu.edu.cn
                zhangxiaoran@picb.ac.cn
                jsyczjy@gmail.com
                wanghuihuiyi@gmail.com
                594196026@qq.com
                835290502@qq.com
                wumeiye08@163.com
                lilianyun@whu.edu.cn
                weigang77@gmail.com
                wumin@whu.edu.cn
                Journal
                Clin Epigenetics
                Clin Epigenetics
                Clinical Epigenetics
                BioMed Central (London )
                1868-7075
                1868-7083
                31 March 2016
                31 March 2016
                2016
                : 8
                : 34
                Affiliations
                [ ]Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, 430072 Hubei China
                [ ]Division of Gastroenterology, Department of Geriatrics, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430072 China
                [ ]CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
                Article
                201
                10.1186/s13148-016-0201-x
                4815258
                27034728
                81ba8188-a84f-4d97-b336-1a53a7a0f032
                © Zhao et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 15 December 2015
                : 21 March 2016
                Funding
                Funded by: National Basic Research Program of China
                Award ID: 2011CB504206
                Award ID: 2012CB518700
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31221061
                Award ID: 31200653
                Award ID: 31370866
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Genetics
                h3k9 methylation,epigenomics,breast cancer transformation,kdm3a,transcription regulation
                Genetics
                h3k9 methylation, epigenomics, breast cancer transformation, kdm3a, transcription regulation

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