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Global Histone Modification Profiling Reveals the Epigenomic Dynamics Zhao et al. Clinical Epigenetics (2016) 8:34 DOI 10.1186/s13148-016-0201-x RESEARCH Open Access Global histone modification profiling reveals the epigenomic dynamics during malignant transformation in a four-stage breast cancer model Quan-Yi Zhao1†, Pin-Ji Lei1†, Xiaoran Zhang3, Jun-Yi Zheng1, Hui-Yi Wang1, Jiao Zhao2, Yi-Ming Li2, Mei Ye2, Lianyun Li1, Gang Wei3* and Min Wu1* 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. Keywords: H3K9 methylation, Epigenomics, Breast cancer transformation, KDM3A, Transcription regulation Background implicated in cancer as well. Early studies have shown that Recent advances in epigenetics and epigenomics have re- histone modification patterns can be used to predict tumor vealed that epigenetic abnormality is one of the critical phenotypes and the risk of cancer recurrence [8–10]. His- causesfortumorigenesis[1–5]. DNA methylation inhibi- tone acetylation and deacetylation have been extensively tors have already used for cancer treatment [6, 7]. Besides studied and histone deacetylases (HDACs) are frequently DNA methylation, abnormality of histone methylation is reported to inhibit the expression of tumor suppressors [11]. Inhibitors of histone deacetylase (HDAC) are proved * Correspondence: [email protected]; [email protected] to be useful in clinical cancer treatment [11]. However, the †Equal contributors 3CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for relationship between cancer and other histone modifica- Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China tions, such as histone methylation, is still not conclusive. 1Department of Biochemistry and Molecular Biology, College of Life Sciences, Histone methylation usually occurs on lysines and argi- Wuhan University, Wuhan 430072Hubei, China Full list of author information is available at the end of the article nines, and each site has three different forms [12, 13]. In © 2016 Zhao et al. Open Access This 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. Zhao et al. Clinical Epigenetics (2016) 8:34 Page 2 of 15 comparison with acetylation, histone methylation and de- (RAS (V12)), the engineered primary cell will extend life methylation have more complicated regulatory steps, mak- span, become immortalized, and finally gain tumorigenic ing them promising drug targets [1, 14]. Recently, several capacity, which is considered to represent different stages well-studied histone methyltransferases emerged to be key of tumor cell transformation [33, 34]. Considering the dif- regulators in multiple cancer types. For example, enhancer ficulties in studying human cancers, the in vitro model still of zeste 2 polycomb repressive complex 2 subunit (EZH2), serves as one of the best platforms to study the molecular the major enzyme for H3K27me3, was demonstrated as an mechanisms of tumor transformation. Recently, profiling oncogene in prostate cancer [15]. Its mutation has also been of global gene expression in the above model has provided frequently found in lymphoma [16, 17]. An enzymatic in- valuable information for tumor transformation study and hibitor of EZH2 was shown to inhibit lymphoma cell prolif- suggested a link between malignant transformation to de- eration in a mouse model [18]. SET domain containing 2 differentiation [35]. But due to the difficulty in making the (SETD2) is the major H3K36me3 methyltransferase in model, no epigenetic study was reported. mammalian cells and frequently mutated in clear cell kidney In this study, we took advantage of the in vitro tumor carcinoma, acute leukemia, gliomas, and other cancers [2, transformation model and made a series of transformed 19–22]. H3K36me3 catalyzed by SETD2 is required for gen- cell lines starting from human primary mammary cell ome stability and DNA repair process after damage [23–25]. (HMC). By combining biochemical and epigenomic ap- Myeloid/lymphoid or mixed-lineage leukemia 1-4 (MLL1- proaches, we demonstrate that histones H3K9me2 and 4), the methyltransferases for H3K4, was found to be mu- H3K9me3 decrease during breast cancer transformation tated in multiple types of cancers [2, 4]. On the other hand, and contribute to the process with different mechanisms. demethylation is another critical aspect for the dynamic Furthermore, we identified that KDM3A/JMJD1A, an regulation of histone methylation. Clinical studies from dif- H3K9me2 demethylase, is responsible for the H3K9me2 ferent groups found that the demethylases of H3K9me2 and reduction and critical for breast tumor transformation. me3, such as lysine (K)-specific demethylase 3A (KDM3A, also known as JMJD1A or JHDM2A) and lysine (K)-specific Results demethylase 4A/B/C (KDM4A/B/C), are highly expressed Gene expression profile of tumor transformation model in cancer tissues and regulate tumorigenesis [26–29]. More- mimics clinical samples over, KDM4A was reported to induce site-specific copy gain To study the underlying mechanisms of breast cancer and DNA re-replication and promote cellular transform- transformation, we utilized an established cell-based ation by inhibiting p53 signaling [26, 30]. A histone H3K4 transformation model [34, 35]. Large T antigen, TERT, demethylase, lysine (K)-specific demethylase 5A (KDM5A), and RAS (V12) were stably expressed in human primary is involved in the cancer cell drug tolerance [31]. All these mammary cell respectively via retroviral infection. Four information suggests that histone methylation is critical in cell lines were generated for following studies, namely the genesis and development of multiple cancer types. HMC-p6 (human primary mammary cell, passage 6), However, the molecular mechanisms of these enzymes in HMC-L (HMC with large T stable expression), HMC-LT tumorigenesis still remain elusive. (HMC with large T and TERT stable expression), and The early diagnosis and treatment are the most effect- HMC-LTR (HMC with large T, TERT, and HRAS (V12) ive ways to cure cancer. But we are still lack of good stable expression) (Additional file 1: Figure S1A, B). markers and drugs for precision medicine. During trans- HMC-p6 and HMC-LT can be passaged for 1 and formation, the epigenetic programs in cells change dra- 2 months, respectively, and HMC-LT is immortalized matically, helping them to survive and gain growth (Additional file 1: Figure S1C). Only HMC-LTR can form advantage [1, 3]. Along with the development of func- colonies in soft agar and grow into tumors in nude mice tional genomics, some studies have investigated the dy- (Additional file 1: Figure S1D). These observations are in namic changes during differentiation [32], but the full accordance with previously reported results [34]. epigenetic dynamics at the genome-wide scale during Based on their ability in proliferation and tumorigenicity, transformation are still not known. However, due to the the four cell lines are considered to represent different individual variation, cell heterogeneity, and limited transformation stages. To further confirm the validity of sample size, patient tissues are difficult for mechanistic the tumor cell model, we clustered the transformed cell studies. Thus, a transformation model with clean back- lines with clinical samples based on their expression pro- ground and high reproducibility is required. More than a files of differentially expressed genes (DEGs). Gene expres-
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