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

ABSTRACT: 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.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.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.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.

SUBMITTER: Zhao QY

PROVIDER: S-EPMC4815258 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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

Zhao Quan-Yi QY Lei Pin-Ji PJ Zhang Xiaoran X Zheng Jun-Yi JY Wang Hui-Yi HY Zhao Jiao J Li Yi-Ming YM Ye Mei M Li Lianyun L Wei Gang G Wu Min M

Clinical epigenetics 20160331

<h4>Background</h4>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.<h4>Methods</h4>A breast cancer transformation model was established via stably expressing three oncogenes in primary breast epithelial cells. Chromatin immunoprecipitation followed ...[more]

PMID: 27034728

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Project description:Introduction: Abdominal aortic aneurysms (AAA) are characterized by localized inflammation, extracellular matrix degradation, and apoptosis of smooth muscle cells, which together lead to progressive and irreversible aortic dilation. Major risk factors for AAA include smoking and aging, both of which prominently alter gene expression via epigenetic mechanisms, including histone methylation (me) and acetylation (ac).However, little is known about epigenomic dynamics during AAA formation. Here, we profiled histone modification patterns in aortic tissues during AAA formation in two distinct mouse models; (1) angiotensin II (AngII) infusion in low density lipoprotein receptor (LDLR) knockout (KO) mice, and (2) calcium chloride (CaCl2) application in wild type mice. Methods and Results: AAA formed in both models, in conjunction with enhanced macrophage infiltration, elastin degradation and matrix metalloproteinases expression as evaluated by immunohistochemistry. To investigate the histone modification patterns during AAA formation, total histone proteins were extracted from AAA tissues, and histone H3 modifications were quantified using profiling kits. Intriguingly, we observed dynamic changes in histone H3 modifications of lysine (K) residues at different time points during AAA formation. In mature aneurysmal tissues at 3 weeks after AngII infusion, we detected reduced K4/K27/K36 monomethylation, K9 trimethylation K9, and K9/K56 acetylation (<70%), and increased K4 trimethylation (>130%). Conversely, in CaCl2-induced AAA, K4/K9/K27/K36/K79 monomethylation and K9/K18/K56 acetylation were reduced in AAA tissues, whereas K27 di-/tri-methylation and K14 acetylation were upregulated. Interestingly, K4/K27/K36 monomethylation, K9 trimethylation, and K9/K56 acetylation were commonly downregulated in both animal models, while no H3 modifications were uniformly upregulated. Western blot of AAA tissues confirmed markedly reduced levels of key H3 modifications, including H3K4me1, H3K9me3, and H3K56ac. Furthermore, pathway enrichment analysis using an integrative bioinformatics approach identified specific molecular pathways, including endocytosis, exon guidance and focal adhesion signaling, that may potentially be linked to these histone H3 modifications during AAA formation. Conclusions: Dynamic modifications of histone H3 occur during AAA formation in both animal models. We identified 6 discreet H3 modifications that are consistently downregulated in both models, suggesting a possible role in AAA pathobiology. Identifying the functional mechanisms may facilitate development of novel strategies for AAA prevention or treatment.

Dataset Information

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

Publications

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

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