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Xiao-Fen Ruan, Yong-Jun Li, Cheng-Wei Ju, Yan Shen, Wei Lei, Can Chen, Yang Li, Hong Yu, Yu-Tao Liu, Il-Man Kim, Xiao-Long Wang, Neal L Weintraub, Yao-Liang Tang
Suxiao Jiuxin Pill (SJP) is a traditional Chinese medicine for the treatment of acute coronary syndrome in China, which contains two principal components, tetramethylpyrazine (TMP) and borneol (BOR). Thus far, however, the molecular mechanisms underlying the beneficial effects of SJP on the cardiac microenvironment are unknown. Cardiac mesenchymal stem cells (C-MSCs) communicate with cardiomyocytes (CMs) through the release of microvesicles (exosomes) to restore cardiac homeostasis and elicit repair, in part through epigenetic regulatory mechanisms...
March 15, 2018: Acta Pharmacologica Sinica
Gamze Kuser-Abali, Lu Gong, Jiawei Yan, Qingqing Liu, Weiqi Zeng, Amanda Williamson, Chuan Bian Lim, Mary Ellen Molloy, John B Little, Lei Huang, Zhi-Min Yuan
Renewable tissues exhibit heightened sensitivity to DNA damage, which is thought to result from a high level of p53. However, cell proliferation in renewable tissues requires p53 down-regulation, creating an apparent discrepancy between the p53 level and elevated sensitivity to DNA damage. Using a combination of genetic mouse models and pharmacologic inhibitors, we demonstrate that it is p53-regulated MDM2 that functions together with MDMX to regulate DNA damage sensitivity by targeting EZH2 (enhancer of zeste homolog 2) for ubiquitination/degradation...
March 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Marta Fontcuberta-PiSunyer, Sara Cervantes, Eulàlia Miquel, Sergio Mora-Castilla, Louise C Laurent, Angel Raya, Ramon Gomis, Rosa Gasa
Posttranscriptional modifications of histones constitute an epigenetic mechanism that is closely linked to both gene silencing and activation events. Trimethylation of Histone3 at lysine 27 (H3K27me3) is a repressive mark that associates with developmental gene regulation during differentiation programs. In the developing pancreas, expression of the transcription factor Neurogenin3 in multipotent progenitors initiates endocrine differentiation that culminates in the generation of all pancreatic islet cell lineages, including insulin-producing beta cells...
March 9, 2018: Biochimica et Biophysica Acta
Maria Gomes Fernandes, Monika Bialecka, Daniela C F Salvatori, Susana M Chuva de Sousa Lopes
STUDY QUESTION: Which set of antibodies can be used to identify migratory and early post-migratory human primordial germ cells (hPGCs)? STUDY FINDING: We validated the specificity of 33 antibodies for 31 markers, including POU5F1, NANOG, PRDM1 and TFAP2C as specific markers of hPGCs at 4.5 weeks of development of Carnegie stage (CS12-13), whereas KIT and SOX17 also marked the intra-aortic hematopoietic stem cell cluster in the aorta-gonad-mesonephros (AGM). WHAT IS KNOWN ALREADY: The dynamics of gene expression during germ cell development in mice is well characterized and this knowledge has proved crucial to allow the development of protocols for the in-vitro derivation of functional gametes...
March 8, 2018: Molecular Human Reproduction
Yongyao Xie, Yaling Zhang, Jingluan Han, Jikai Luo, Gousi Li, Jianle Huang, Haibin Wu, Qingwei Tian, Qinlong Zhu, Yuanling Chen, Yoji Kawano, Yao-Guang Liu, Letian Chen
Plant height has a major effect on grain yield in crops such as rice (Oryza sativa), and the hormone gibberellic acid (GA) regulates many developmental processes that feed into plant height. Rice ELONGATED UPPERMOST INTERNODE 1 (Eui1) encodes a GA-deactivating enzyme governing elongation of uppermost internode. The expression of Eui1 is finely tuned, thereby maintaining homeostasis of endogenous bioactive GA and producing plants of normal plant height. Here, we identified a dominant dwarf mutant, dEui1, caused by the deletion of an RY motif-containing cis silencing element (SE1) in the intron of Eui1...
March 7, 2018: Molecular Plant
Pan Pan, Kiyoko Oshima, Yi-Wen Huang, Kimberle A Agle, William R Drobyski, Xiao Chen, Jianying Zhang, Martha M Yearsley, Jianhua Yu, Li-Shu Wang
Free fatty acid receptor 2 (FFAR2, also named GPR43), is activated by short-chain fatty acids (SCFAs), such as butyrate, that are produced when gut bacteria ferment dietary fiber. FFAR2 has been suggested to regulate colonic inflammation, which is a major risk factor for the development of colon cancer and is also linked to epigenetic dysregulation in colon carcinogenesis. The current study assessed whether FFAR2, acting as an epigenetic regulator, protects against colon carcinogenesis. To mimic the mild inflammation that promotes human colon cancer, we treated mice with dextran sodium sulfate (DSS) overnight, which avoids excessive inflammation but induces mild inflammation that promotes colon carcinogenesis in the ApcMin/+ and the azoxymethane (AOM)-treated mice...
March 9, 2018: International Journal of Cancer. Journal International du Cancer
Lexie Prokopuk, Kirsten Hogg, Patrick S Western
Background: Recently discovered drugs that target epigenetic modifying complexes are providing new treatment options for a range of cancers that affect patients of reproductive age. Although these drugs provide new therapies, it is likely that they will also affect epigenetic programming in sperm and oocytes. A promising target is Enhancer of Zeste 2 (EZH2), which establishes the essential epigenetic modification, H3K27me3, during development. Results: In this study, we demonstrate that inhibition of EZH1/2 with the clinically relevant drug, tazemetostat, severely depletes H3K27me3 in growing oocytes of adult female mice...
2018: Clinical Epigenetics
Yutaka Mizuno, Kentaro Maemura, Yoshihisa Tanaka, Azumi Hirata, Sugiko Futaki, Hiroki Hamamoto, Kohei Taniguchi, Michihiro Hayashi, Kazuhisa Uchiyama, Masa-Aki Shibata, Yoshinori Otsuki, Yoichi Kondo
Delta-like 3 (DLL3) is a member of the Delta/Serrate/Lag-2 family of ligands for the Notch receptor and plays a role in Notch signaling. We have previously revealed that the expression of DLL3 is silenced by aberrant DNA methylation and that overexpression of DLL3 in the HuH2 hepatocellular carcinoma (HCC) cell line induced apoptosis. In the present study, we first confirmed the methylation of DLL3 in HuH2 cells and analyzed the methylation status of the DLL3 promoter region by bisulfite sequencing. Furthermore, we investigated whether other epigenetic modifications, such as histone acetylation and histone methylation, affected the expression of DLL3...
March 5, 2018: Oncology Reports
Zhenghao Li, Hisanori Takenobu, Amallia Nuggetsiana Setyawati, Nobuhiro Akita, Masayuki Haruta, Shunpei Satoh, Yoshitaka Shinno, Koji Chikaraishi, Kyosuke Mukae, Jesmin Akter, Ryuichi P Sugino, Atsuko Nakazawa, Akira Nakagawara, Hiroyuki Aburatani, Miki Ohira, Takehiko Kamijo
The polycomb repressor complex 2 molecule EZH2 is now known to play a role in essential cellular processes, namely, cell fate decisions, cell cycle regulation, senescence, cell differentiation, and cancer development/progression. EZH2 inhibitors have recently been developed; however, their effectiveness and underlying molecular mechanisms in many malignancies have not yet been elucidated in detail. Although the functional role of EZH2 in tumorigenesis in neuroblastoma (NB) has been investigated, mutations of EZH2 have not been reported...
March 6, 2018: Oncogene
Abdullah Al Emran, Diego M Marzese, Dinoop Ravindran Menon, Mitchell S Stark, Joachim Torrano, Heinz Hammerlindl, Gao Zhang, Patricia Brafford, Matthew P Salomon, Nellie Nelson, Sabrina Hammerlindl, Deepesh Gupta, Gordon B Mills, Yiling Lu, Richard A Sturm, Keith Flaherty, Dave S B Hoon, Brian Gabrielli, Meenhard Herlyn, Helmut Schaider
Besides somatic mutations or drug efflux, epigenetic reprogramming can lead to acquired drug resistance. We recently have identified early stress-induced multi-drug tolerant cancer cells termed induced drug-tolerant cells (IDTCs). Here, IDTCs were generated using different types of cancer cell lines; melanoma, lung, breast and colon cancer. A common loss of the H3K4me3 and H3K27me3 and gain of H3K9me3 mark was observed as a significant response to drug exposure or nutrient starvation in IDTCs. These epigenetic changes were reversible upon drug holidays...
February 2, 2018: Oncotarget
Imari Mimura, Yosuke Hirakawa, Yasuharu Kanki, Ryo Nakaki, Yutaka Suzuki, Tetsuhiro Tanaka, Hiroyuki Aburatani, Masaomi Nangaku
Tubulointerstitial fibrosis has been recently reported to be caused by the collapse of the epigenetic regulation of kidney diseases. We examined whether pharmacological inhibition of histone modification is effective against renal fibrosis. DZNep (3-deazaneplanocin A) was originally developed as an anti-cancer drug to inhibit the repressive histone mark, H3K27me3. We used a model of chronic tubulointerstitial fibrosis induced by unilateral ischaemia/reperfusion and administered DZNep intravenously to the mice for 8 weeks...
February 28, 2018: Scientific Reports
Aline F de Souza, Naira C Godoy Pieri, Kelly C S Roballo, Fabiana F Bressan, Juliana B Casals, Carlos E Ambrósio, Felipe Perecin, Daniele S Martins
Primordial germ cells (PGCs) are precursors of gametes that can generate new individuals throughout life in both males and females. Additionally, PGCs have been shown to differentiate into embryonic germ cells (EGCs) after in vitro culture. Most studies investigating germinative cells have been performed in rodents and humans but not dogs (Canis lupus familiaris). Here, we elucidated the dynamics of the expression of pluripotent (POU5F1 and NANOG), germline (DDX4, DAZL and DPPA3), and epigenetic (5mC, 5hmC, H3K27me3 and H3K9me2) markers that are important for the development of male canine germ cells during the early (22-30 days post-fertilization (dpf)), middle (35-40 dpf) and late (45-50 dpf) gestational periods...
2018: PloS One
Naohiro Makise, Masaya Sekimizu, Takashi Kubo, Susumu Wakai, Shun-Ichi Watanabe, Tomoyasu Kato, Takayuki Kinoshita, Nobuyoshi Hiraoka, Masashi Fukayama, Akira Kawai, Hitoshi Ichikawa, Akihiko Yoshida
AIMS: Extraskeletal osteosarcoma (ESOS) is a sarcoma in the non-skeletal tissue that directly produces neoplastic osteoid or bone. Dedifferentiated liposarcoma (DDLPS) and malignant peripheral nerve sheath tumor (MPNST) are the two most common types of sarcoma that can harbor heterologous osteosarcomatous differentiation. We aimed to determine the potential relationship of ESOS to DDLPS and MPNST. METHODS AND RESULTS: We investigated MDM2 and H3K27me3 status in 19 cases of ESOS, 2 of which contained a low-grade component...
February 28, 2018: Histopathology
Bo Gao, Xisheng Lin, Huan Jing, Jing Fan, Chenchen Ji, Qiang Jie, Chao Zheng, Di Wang, Xiaolong Xu, Yaqian Hu, Weiguang Lu, Zhuojing Luo, Liu Yang
Aging drives the accumulation of senescent cells (SnCs) including stem/progenitor cells in bone marrow, which contributes to aging-related bone degenerative pathologies. Local elimination of SnCs has been shown as potential treatment for degenerative diseases. As LepR+ mesenchymal stem/progenitor cells (MSPCs) in bone marrow are the major population for forming bone/cartilage and maintaining HSCs niche, whether local elimination of senescent LepR+ MSPCs delays aging-related pathologies and improves local microenvironment need to be well defined...
February 28, 2018: Aging Cell
Barbara H Rath, Isabella Waung, Kevin Camphausen, Philip J Tofilon
The processes mediating the repair of DNA double strand breaks (DSBs) are critical determinants of radiosensitivity and provide a source of potential targets for tumor radiosensitization. Among the events required for efficient DSB repair are a variety of post-translational histone modifications including methylation. Because trimethylation of histone H3 on lysine 27 (H3K27me3) has been associated with chromatin condensation, which can influence DSB repair, we determined the effects of radiation on H3K27me3 levels in tumor and normal cell lines...
February 26, 2018: Molecular Cancer Therapeutics
Hiroshi Otsuka, Kenichi Kohashi, Masato Yoshimoto, Shin Ishihara, Yu Toda, Yuichi Yamada, Hidetaka Yamamoto, Yasuharu Nakashima, Yoshinao Oda
The histological definitive diagnosis of malignant peripheral nerve sheath tumor (MPNST) is quite difficult because the morphological features are not specific and no useful immunohistochemical marker has been identified. Loss-of-function mutations in EED or SUZ12, which encode the core subunit of polycomb repressive complex 2 (PRC2), were reported in MPNSTs, and the mutations were shown to cause inactivation of PRC2, leading to loss of trimethylation of histone H3 at lysine 27 (H3K27me3). Immunohistochemistry of H3K27me3 is expected to be a specific marker for MPNSTs...
January 31, 2018: Pathology, Research and Practice
Guochao Li, Dong Wang, Wencui Ma, Ke An, Zongzhi Liu, Xinyu Wang, Caiyun Yang, Fengxia Du, Xiao Han, Shuang Chang, Hui Yu, Zilong Zhang, Zitong Zhao, Yan Zhang, Junyun Wang, Yingli Sun
AIM: Cancer stem cells (CSCs) drive triple-negative breast cancer recurrence via their properties of self-renewal, invasiveness and radio/chemotherapy resistance. This study examined how CSCs might sustain these properties. MATERIALS & METHODS: Transcriptomes, DNA methylomes and histone modifications were compared between CSCs and non-CSCs. RESULTS: Transcriptome analysis revealed several pathways that were activated in CSCs, whereas cell cycle regulation pathways were inhibited...
February 26, 2018: Epigenomics
Agatha Schlüter, Juan Sandoval, Stéphane Fourcade, Angel Díaz-Lagares, Montserrat Ruiz, Patrizia Casaccia, Manel Esteller, Aurora Pujol
Epigenomic changes may either cause disease or modulate its expressivity, adding a layer of complexity to mendelian diseases. X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic condition exhibiting discordant phenotypes, ranging from a childhood cerebral inflammatory demyelination (cALD) to an adult-onset mild axonopathy in spinal cords (AMN). The AMN form may occur with superimposed inflammatory brain demyelination (cAMN). All patients harbor loss of function mutations in the ABCD1 peroxisomal transporter of very-long chain fatty acids...
February 24, 2018: Brain Pathology
Naichong Chen, Vijaykumar Veerappan, Haggag Abdelmageed, Miyoung Kang, Randy D Allen
Gene expression during seed development in Arabidopsis thaliana is controlled by transcription factors including LEAFY COTYLEDON 1 and 2 (LEC1 and LEC2), ABA INSENSITIVE 3 (ABI3), FUSCA3 (FUS3), known as LAFL proteins, and AGAMOUS-LIKE 15 (AGL15). The transition from seed maturation to germination and seedling growth requires the transcriptional silencing of these seed maturation-specific factors leading to down-regulation of structural genes including those that encode seed storage proteins, oleosins, and dehydrins...
February 23, 2018: Plant Cell
Shijie Zheng, Lirong Xiao, Yu Liu, Yujiao Wang, Lin Cheng, Junjun Zhang, Naihong Yan, Danian Chen
Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases causing progressive loss of photoreceptors. Numerous gene mutations are identified to be related with RP, but epigenetic modifications may also be involved in the pathogenesis. Previous studies suggested that both DNA methylation and histone acetylation regulate photoreceptor cell death in RP mouse models. However, the role of histone methylation in RP has never been investigated. In this study, we found that trimethylation of several lysine sites of histone H3, including lysine 27 (H3K27me3), increased in the retinas of rd1 mice...
February 22, 2018: Cell Death & Disease
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