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Histone demethylases

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
Tingchao Mao, Chengquan Han, Ruizhi Deng, Biao Wei, Peng Meng, Yan Luo, Yong Zhang
Epigenetic modifications extensively occur in mammalian embryonic development and cell differentiation process. They play an essential role in the reprogramming of nuclei during somatic cell nuclear transfer (SCNT) and subsequent in vitro embryonic development. Recently, SCNT embryos have been verified to contain a subnormal level of histone H3K4 dimethylation (H3K4me2) in contrast to in vitro fertilized embryos. This finding suggested that increasing H3K4me2 levels may ameliorate the aberrant development of cloned embryos...
March 15, 2018: Systems Biology in Reproductive Medicine
John R Horton, Xu Liu, Lizhen Wu, Kai Zhang, John Shanks, Xing Zhang, Ganesha Rai, Bryan T Mott, Daniel J Jansen, Stephen C Kales, Mark J Henderson, Katherine Pohida, Yuhong Fang, Xin Hu, Ajit Jadhav, David J Maloney, Matthew D Hall, Anton Simeonov, Haian Fu, Paula M Vertino, Qin Yan, Xiaodong Cheng
Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely (R)- and (S)-2-((2-chlorophenyl)(2-(piperidin-1-yl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (compounds N51 and N52) and (R)- and (S)-N-(1-(3-isopropyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropane-carboxamide (compounds N54 and N55)...
March 14, 2018: Journal of Medicinal Chemistry
Adam J Krieg, Sarah R Mullinax, Frances Grimstad, Kaitlin Marquis, Elizabeth Constance, Yan Hong, Sacha A Krieg, Katherine F Roby
PURPOSE: To assess expression of the histone demethylases KDM4A and KDM4B in granulosa collected from women undergoing oocyte retrieval and to determine if expression was related to pregnancy outcome. METHODS: Cumulus and mural granulosa cells were obtained from women undergoing oocyte retrieval. KDM4A and KDM4B mRNA expression was determined by qRT-PCR. KDM4A and KDM4B proteins were immunohistochemically localized in ovarian tissue sections obtained from archival specimens...
March 14, 2018: Journal of Assisted Reproduction and Genetics
Jaclyn Andricovich, Stephanie Perkail, Yan Kai, Nicole Casasanta, Weiqun Peng, Alexandros Tzatsos
KDM6A, an X chromosome-encoded histone demethylase and member of the COMPASS-like complex, is frequently mutated in a broad spectrum of malignancies and contributes to oncogenesis with poorly characterized mechanisms. We found that KDM6A loss induced squamous-like, metastatic pancreatic cancer selectively in females through deregulation of the COMPASS-like complex and aberrant activation of super-enhancers regulating ΔNp63, MYC, and RUNX3 oncogenes. This subtype of tumor developed in males had concomitant loss of UTY and KDM6A, suggesting overlapping roles, and points to largely demethylase independent tumor suppressor functions...
March 12, 2018: Cancer Cell
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
Werner Giehl Glanzner, Vitor Braga Rissi, Mariana Priotto de Macedo, Lady Katerine Serrano Mujica, Karina Gutierrez, Alessandra Bridi, João Ricardo Malheiros de Souza, Paulo Bayard Dias Gonçalves, Vilceu Bordignon
Epigenetic modifications in the C-terminal domain of histones coordinate important events during early development including embryo genome activation (EGA) and cell differentiation. In this study, the mRNA expression profile of the main lysine demethylases (KDMs) acting on the lysine 4 (H3K4), 9 (H3K9) and 27 (H3K27) of the histone H3 was determined at pre-, during and post- EGA stages of bovine and porcine embryos produced by in vitro fertilization (IVF) and somatic cell nuclear transfer (SCNT). In IVF embryos, mRNA abundance of most KDMs revealed a bell-shaped profile with peak expression around the EGA period, i...
March 8, 2018: Biology of Reproduction
Jan C Peeken, Jonas S Jutzi, Julius Wehrle, Christoph Koellerer, Felix Staehle, Heiko Becker, Elias Schoenwandt, Thalia S Seeger, Daniel H Schanne, Monika Gothwal, Christopher J Ott, Albert Gründer, Heike L Pahl
The transcription factor "Nuclear Factor Erythroid 2" (NFE2) is overexpressed in the majority of patients with Myeloproliferative Neoplasms (MPN). In murine models, elevated NFE2 levels cause an MPN phenotype with spontaneous leukemic transformation. However, both the molecular mechanisms leading to NFE2 overexpression and its downstream targets remain incompletely understood. Here we show that the histone demethylase JMJD1C constitutes a novel NFE2 target gene. JMJD1C levels are significantly elevated in PV and PMF patients; concomitantly, global H3K9me1 and H3K9me2 levels are significantly decreased...
March 8, 2018: Blood
Sumati Gupta, Kelly Doyle, Timothy L Mosbruger, Andrew Butterfield, Alexis Weston, Allison Ast, Mohan Kaadige, Anupam Verma, Sunil Sharma
Lysine-Specific Demethylase 1 (LSD1) over-expression correlates with poorly differentiated neuroblastoma and predicts poor outcome despite multimodal therapy. We have studied the efficacy of reversible and specific LSD1 inhibition with HCI-2509 in neuroblastoma cell lines and particularly the effect of HCI-2509 on the transcriptomic profile in MYCN amplified NGP cells. Cell survival assays show that HCI-2509 is cytotoxic to poorly differentiated neuroblastoma cell lines in low micromole or lower doses. Transcriptional profiling of NGP cells treated with HCI-2509 shows a significant effect on p53, cell cycle, MYCN and hypoxia pathway gene sets...
February 9, 2018: Oncotarget
Jinjin Zhang, Juchao Ren, Shengjie Hao, Fang Ma, Yan Xin, Wenxiao Jia, Yundong Sun, Zhifang Liu, Han Yu, Jihui Jia, Wenjuan Li
Our previous work discovered that the histone demethylase JMJD2B (KDM4B) plays oncogenic roles in gastric carcinogenesis, but the regulatory mechanism of JMJD2B in gastric cancer has not been well defined. It has been revealed that microRNAs function as gene regulators by binding to the 3'UTR of mRNAs to inhibit gene expression. In this study, we found that miR-491-5p suppressed cell proliferation, invasion and migration by directly targeting the JMJD2B 3'UTR in gastric cancer. Moreover, miR-491-5p was decreased in GC tissues compared with adjacent normal tissues, and JMJD2B had the inverse expression pattern...
2018: American Journal of Translational Research
Hongyang Lu, Shifeng Yang, Huineng Zhu, Xiaoling Tong, Fajun Xie, Jing Qin, Na Han, Xue Wu, Yun Fan, Yang W Shao, Weimin Mao
BACKGROUND: Esophageal sarcomatoid carcinoma (ESC) is a rare disease with a mixture of both carcinomatous and sarcomatous components in the tumor. Its genetic background and mechanisms of oncogenesis remain largely unknown. METHODS: Here we performed targeted next generation sequencing (NGS) on a pan-cancer gene panel in 15 ESC tumors to explore their genetic alterations, and aimed to identify clinically actionable mutations for future treatment instructions. RESULTS: TP53 alterations were identified in all patients...
March 5, 2018: BMC Cancer
Ana Banito, Xiang Li, Aimée N Laporte, Jae-Seok Roe, Francisco Sanchez-Vega, Chun-Hao Huang, Amanda R Dancsok, Katerina Hatzi, Chi-Chao Chen, Darjus F Tschaharganeh, Rohit Chandwani, Nilgun Tasdemir, Kevin B Jones, Mario R Capecchi, Christopher R Vakoc, Nikolaus Schultz, Marc Ladanyi, Torsten O Nielsen, Scott W Lowe
Synovial sarcoma is an aggressive cancer invariably associated with a chromosomal translocation involving genes encoding the SWI-SNF complex component SS18 and an SSX (SSX1 or SSX2) transcriptional repressor. Using functional genomics, we identify KDM2B, a histone demethylase and component of a non-canonical polycomb repressive complex 1 (PRC1.1), as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX1 physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands...
February 22, 2018: Cancer Cell
Andrea Milelli, Chiara Marchetti, Eleonora Turrini, Elena Catanzaro, Roberta Mazzone, Daniela Tomaselli, Carmela Fimognari, Vincenzo Tumiatti, Anna Minarini
Epigenetic modulators Histone deacetylases (HDACs) and Lysine demethylase (LSD1) are validated targets for anticancer therapy. Both HDAC1/2 and LSD1 are found in association with the repressor protein CoREST in a transcriptional co-repressor complex, which is responsible for gene silencing. Combined modulation of both targets results in a synergistic antiproliferative activity. In the present investigation, we report about the design and synthesis of a series of polyamine-based HDACs-LSD1 dual binding inhibitors obtained by coupling Vorinostat and Tranylcypromine...
February 17, 2018: Bioorganic & Medicinal Chemistry Letters
Toshia R Myers, Pier Giorgio Amendola, Yvonne C Lussi, Anna Elisabetta Salcini
Post-translational modifications of histones, constitutive components of chromatin, regulate chromatin compaction and control all DNA-based cellular processes. C. elegans JMJD-1.2, a member of the KDM7 family, is a demethylase active towards several lysine residues on Histone 3 (H3), but its contribution in regulating histone methylation in germ cells has not been fully investigated. Here, we show that jmjd-1.2 is expressed abundantly in the germline where it controls the level of histone 3 lysine 9, lysine 23 and lysine 27 di-methylation (H3K9/K23/K27me2) both in mitotic and meiotic cells...
February 28, 2018: Scientific Reports
Sumaira Zamurrad, Hayden A M Hatch, Coralie Drelon, Helen M Belalcazar, Julie Secombe
Mutations in KDM5 family histone demethylases cause intellectual disability in humans. However, the molecular mechanisms linking KDM5-regulated transcription and cognition remain unknown. Here, we establish Drosophila as a model to understand this connection by generating a fly strain harboring an allele analogous to a disease-causing missense mutation in human KDM5C (kdm5A512P ). Transcriptome analysis of kdm5A512P flies revealed a striking downregulation of genes required for ribosomal assembly and function and a concomitant reduction in translation...
February 27, 2018: Cell Reports
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
Wanwan Jia, Weijun Wu, Di Yang, Chenxi Xiao, Zhenghua Su, Zheng Huang, Zhongzheng Li, Ming Qin, Mengwei Huang, Siyu Liu, Fen Long, Xinhua Liu, Yi Zhun Zhu
Rheumatoid arthritis (RA) is an immune-mediated disease with the characteristics of progressive joint destruction, deformity, and disability. Epigenetic changes have been implicated in the development of some autoimmune disorders, resulting in an alteration of gene transcription. Here, we investigated how Jumonji C family of histone demethylases (JMJD3) regulated the proliferation and activation of fibroblast-like synoviocytes (FLSs), which are involved in RA joint destruction and pathologic process. The JMJD3 expression and proliferation markers in RA-FLS were higher than those in healthy-FLS and were upregulated in platelet-derived growth factor (PDGF)-induced FLS...
February 26, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Wendy Rosales, Fernando Lizcano
The development of cardiovascular pathologies is partly attributed to epigenetic causes, including histone methylation, which appears to be an important marker in hearts that develop cardiac hypertrophy. Previous studies showed that the histone demethylase JMJD2A can regulate the hypertrophic process in murine cardiomyocytes. However, the influence of JMJD2A on cardiac hypertrophy in a human cardiomyocyte model is still poorly understood. In the present study, cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) were used...
2018: Frontiers in Genetics
Liting Zheng, Longyong Xu, Qing Xu, Lu Yu, Danfeng Zhao, Pu Chen, Wei Wang, Yiqin Wang, Gang Han, Charlie Degui Chen
Recurrent somatic loss-of-function mutations in histone demethylases are frequently detected in cancer. However, whether loss of a histone demethylase can cause cancer has not been determined. Here, we report that knockout of the histone demethylase Utx in mice causes a chronic myelomonocytic leukemia (CMML)-like disease with splenomegaly, monocytosis, and extramedullary hematopoiesis. Mutational analysis of patient data indicated that UTX mutations occur simultaneously with TP53 mutations in myeloid malignancies, and combined inactivation of Utx and Trp53 accelerated the development of CMML in a cell-autonomous manner...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Jin Woo Park, Hana Cho, Hyein Oh, Ji-Young Kim, Sang-Beom Seo
Aberrations in histone modifications are being studied in mixed-lineage leukemia (MLL)-AF9-driven acute myeloid leukemia (AML). In this study, we focused on the regulation of the differentiation of the MLL-AF9 type AML cell line THP-1. We observed that, upon phorbol 12-myristate 13-acetate (PMA) treatment, THP-1 cells differentiated into monocytes by down-regulating Aurora kinase A (AURKA), resulting in a reduction in H3S10 phosphorylation. We revealed that the AURKA inhibitor alisertib accelerates the expression of the H3K27 demethylase KDM6B, thereby dissociating AURKA and YY1 from the KDM6B promoter region...
February 23, 2018: Molecules and Cells
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