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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
Shelby Wilson, Edward Dere, David Klein, Christoph Schorl, Susan Hall, Kim Boekelheide
We examined the precise localization of dimethylated histone three lysine four (H3K4me2) in mature rat sperm. Within non-intergenic enriched regions, half of the DNA peaks associated with H3K4me2 retention fell in gene bodies and the other half in promoter regions. The most significant peaks near annotated DNA regions in the composite data included loci known to be associated with RNA metabolism, cell cycle regulation and spermatogenesis. Regions associated with differential retention of H3K4me2 within gene bodies were significantly enriched for housekeeping gene and cell-cycle functionality...
February 28, 2018: Biology of Reproduction
Tamara Maes, Cristina Mascaró, Iñigo Tirapu, Angels Estiarte, Filippo Ciceri, Serena Lunardi, Nathalie Guibourt, Alvaro Perdones, Michele M P Lufino, Tim C P Somervaille, Dan H Wiseman, Cihangir Duy, Ari Melnick, Christophe Willekens, Alberto Ortega, Marc Martinell, Nuria Valls, Guido Kurz, Matthew Fyfe, Julio Cesar Castro-Palomino, Carlos Buesa
The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia...
February 23, 2018: Cancer Cell
Ralph Stadhouders, Bobby W S Li, Marjolein J W de Bruijn, Antonio Gomez, Tata Nageswara Rao, Hans Jörg Fehling, Wilfred F J van IJcken, Ai Ing Lim, James P Di Santo, Thomas Graf, Rudi W Hendriks
BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are major producers of cytokines driving allergic asthma and elevated numbers of ILC2s have been detected in blood and sputum of asthma patients. Asthma susceptibility has a strong genetic component, but the underlying mechanisms and whether asthma genetics impact ILC2 biology remains unclear. OBJECTIVE: To study the ILC2 transcriptome and epigenome during airway inflammation (AI) in order to couple these to genes and genetic variants associated with asthma pathogenesis...
February 24, 2018: Journal of Allergy and Clinical Immunology
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
Isuru R Kumarasinghe, Patrick M Woster
Lysine-specific demethylase 1 (LSD1) is a chromatin-remodeling enzyme that plays an important role in cancer. Over-expression of LSD1 decreases methylation at histone 3 lysine 4, and aberrantly silences tumor suppressor genes. Inhibitors of LSD1 have been designed as chemical probes and potential antitumor agents. We recently reported the cyclic peptide 9, which potently and reversibly inhibits LSD1 (IC50 2.1 μM; Ki 385 nM). Systematic alanine mutagenesis of 9 revealed residues that are critical for LSD1 inhibition, and these mutated peptides were evaluated as LSD1 inhibitors...
February 7, 2018: European Journal of Medicinal Chemistry
Moo Rim Kang, Ki Hwan Park, Chang Woo Lee, Myeong Youl Lee, Sang-Bae Han, Long-Cheng Li, Jong Soon Kang
Recent studies have reported that chemically synthesized double-stranded RNAs (dsRNAs), also known as small activating RNA (saRNAs), can specifically induce gene expression by targeting promoter sequences by a mechanism termed RNA activation (RNAa). In the present study, we designed 4 candidate saRNAs targeting the Von Hippel-Lindau (VHL) gene promoter. Among these saRNAs, dsVHL-821 significantly inhibited cell growth by up-regulating VHL at both the mRNA and protein levels in renal cell carcinoma 769-P cells...
February 6, 2018: International Journal of Biochemistry & Cell Biology
Zhan-Ling Liang, Dan-Dan Wu, Yue Yao, Fei-Yuan Yu, Lei Yang, Heng Wee Tan, Machteld N Hylkema, Marianne G Rots, Yan-Ming Xu, Andy T Y Lau
Cadmium (Cd), a carcinogenic toxic metal, is pervasively distributed in the soil, water and air. Chronic exposure to Cd has been correlated to lung disease development including cancers. Although many studies have been conducted to investigate the proteome response of cells challenged with Cd, the epiproteomic responses (i.e., global histone post-translational modifications [PTMs]), particularly in human lung cells, are largely unexplored. Here, we provide an epiproteome profiling of human bronchial epithelial cells (BEAS-2B) chronically treated with cadmium chloride (CdCl2 ), with the aim of identifying global epiproteomic signatures in response to Cd epigenotoxicity...
February 9, 2018: Journal of Applied Toxicology: JAT
Zhang Yu, Teng Wang, Mei Lan, Xin-Wei Zang, Yi-Lun Li, Xiang-Shun Cui, Nam-Hyung Kim, Shao-Chen Sun
In 2011, DEHP (plasticizer) was reported to illegally be added in food and beverage products in Taiwan, which caused great concerns about food safety worldwide. DHEP has multiple toxic effects to human and animals like endocrine disruption, cardiotoxicity, reproductive function and development defects. However, the toxic effects of DEHP on mammalian oocyte quality are still unclear. Since MEHP is the active metabolite of DEHP in vivo, in present study we used porcine oocyte as model to explore the effects of MEHP on oocyte maturation and we also studied the effects of melatonin administration on MEHP exposure-induced meiosis defects...
January 2, 2018: Biology of Reproduction
Meagan Jezek, Alison Jacques, Deepika Jaiswal, Erin M Green
Histone post-translational modifications (PTMs), such as acetylation, methylation and phosphorylation, are dynamically regulated by a series of enzymes that add or remove these marks in response to signals received by the cell. These PTMS are key contributors to the regulation of processes such as gene expression control and DNA repair. Chromatin immunoprecipitation (chIP) has been an instrumental approach for dissecting the abundance and localization of many histone PTMs throughout the genome in response to diverse perturbations to the cell...
December 29, 2017: Journal of Visualized Experiments: JoVE
Peng Wang, Fan Fan, Xiao Li, Xiaolei Sun, Leilei Ma, Jian Wu, Cheng Shen, Hong Zhu, Zhen Dong, Cong Wang, Shuqi Zhang, Xiaona Zhao, Xin Ma, Yunzeng Zou, Kai Hu, Aijun Sun, Junbo Ge
The underlying mechanisms responsible for the cardioprotective effects of riboflavin remain elusive. Current study tested the hypothesis that riboflavin protects injured myocardium via epigenetic modification of LSD1. Here we showed that myocardial injury was attenuated and cardiac function was improved in riboflavin-treated mice with experimental myocardial infarction (MI), while these protective effects of riboflavin could be partly blocked by cotreatment with LSD1 inhibitor. Riboflavin also reduced apoptosis in hypoxic (1% oxygen) H9C2 cell lines...
January 8, 2018: Journal of Molecular and Cellular Cardiology
Ibrahim Avi Cemel, Nati Ha, Geza Schermann, Shusuke Yonekawa, Michael Brunner
BACKGROUND: Long non protein coding RNAs (lncRNAs) have been identified in many different organisms and cell types. Emerging examples emphasize the biological importance of these RNA species but their regulation and functions remain poorly understood. In the filamentous fungus Neurospora crassa, the annotation and characterization of lncRNAs is incomplete. RESULTS: We have performed a comprehensive transcriptome analysis of Neurospora crassa by using ChIP-seq, RNA-seq and polysome fractionation datasets...
December 19, 2017: BMC Genomics
Yanhui Zhai, Wei Li, Zhiren Zhang, Yunqing Cao, Zhengzhu Wang, Sheng Zhang, Ziyi Li
The type and pattern of epigenetic modification in donor cells can significantly affect the developmental competency of somatic cell nuclear transfer (SCNT) embryos. Here, we investigated the developmental capacity, gene expression, and epigenetic modifications of SCNT embryos derived from porcine bone marrow-derived mesenchymal stem cells (BMSCs) and fetal fibroblasts (FFs) donor cells compared to embryos obtained from in vitro fertilization (IVF). Compared to FFs, the donor BMSCs had more active epigenetic markers (Histone H3 modifications: H3K9Ac, H3K4me3, and H3K4me2) and fewer repressive epigenetic markers (H3K9me3, H3K9me2, and DNA methyltransferase 1)...
January 2018: Molecular Reproduction and Development
Jianwu Fang, Haiyan Ying, Ting Mao, Yanjia Fang, Yuan Lu, He Wang, Irene Zang, Zhaofu Wang, Ying Lin, Mengxi Zhao, Xiao Luo, Zongyao Wang, Yan Zhang, Chao Zhang, Wei Xiao, Yan Wang, Wei Tan, Zhui Chen, Chris Lu, Peter Atadja, En Li, Kehao Zhao, Jianfeng Liu, Justin Gu
LSD1 (Lysine Specific Demethylase1)/KDM1A (Lysine Demethylase 1A), a flavin adenine dinucleotide (FAD)-dependent histone H3K4/K9 demethylase, sustains oncogenic potential of leukemia stem cells in primary human leukemia cells. However, the pro-differentiation and anti-proliferation effects of LSD1 inhibition in acute myeloid leukemia (AML) are not yet fully understood. Here, we report that small hairpin RNA (shRNA) mediated LSD1 inhibition causes a remarkable transcriptional activation of myeloid lineage marker genes (CD11b/ITGAM and CD86), reduction of cell proliferation and decrease of clonogenic ability of human AML cells...
October 17, 2017: Oncotarget
Claire Molony, Jennifer McIntyre, Adrian Maguire, Roya Hakimjavadi, Denise Burtenshaw, Gillian Casey, Mariana Di Luca, Bryan Hennelly, Hugh J Byrne, Paul A Cahill
The accumulation of vascular smooth muscle (SMC)-like cells and stem cell-derived myogenic and osteogenic progeny contributes significantly to arteriosclerotic disease. This study established whether label-free vibrational spectroscopy can discriminate de-differentiated 'synthetic' SMCs from undifferentiated stem cells and their myogenic and osteogenic progeny in vitro, compared with conventional immunocytochemical and genetic analyses. TGF-β1- and Jagged1-induced myogenic differentiation of CD44+ mesenchymal stem cells was confirmed in vitro by immunocytochemical analysis of specific SMC differentiation marker expression (α-actin, calponin and myosin heavy chain 11), an epigenetic histone mark (H3K4me2) at the myosin heavy chain 11 locus, promoter transactivation and mRNA transcript levels...
February 2018: Biochimica et Biophysica Acta
Lisheng Cai, Qiuxian Chen, Shunyong Fang, Mingqiao Lian, Mingzhi Cai
OBJECTIVE: Altered expression of microRNA (miRNA) is strongly implicated in gastric cancer (GC). Here, we demonstrated a decreased expression of miRNA-329 in GC. Then we explored the regulatory mechanisms responsible for its effect on GC cells. METHODS: GC tissues and their adjacent non-tumor tissues were collected. Complete follow-up was updated. A series of inhibitors, mimics, and siRNA against KDM1A were introduced to validate regulatory mechanisms for miR-497 and KDM1A in BGC-823 cells...
November 11, 2017: Journal of Cellular Biochemistry
Luis M Soares, P Cody He, Yujin Chun, Hyunsuk Suh, TaeSoo Kim, Stephen Buratowski
Various factors differentially recognize trimethylated histone H3 lysine 4 (H3K4me3) near promoters, H3K4me2 just downstream, and promoter-distal H3K4me1 to modulate gene expression. This methylation "gradient" is thought to result from preferential binding of the H3K4 methyltransferase Set1/complex associated with Set1 (COMPASS) to promoter-proximal RNA polymerase II. However, other studies have suggested that location-specific cues allosterically activate Set1. Chromatin immunoprecipitation sequencing (ChIP-seq) experiments show that H3K4 methylation patterns on active genes are not universal or fixed and change in response to both transcription elongation rate and frequency as well as reduced COMPASS activity...
November 16, 2017: Molecular Cell
Qi Guo, Simone Sidoli, Benjamin A Garcia, Xiaolu Zhao
Histone post-translational modifications (PTMs) are fundamental players of chromatin regulation, as they contribute to editing histone chemical properties and recruiting proteins for gene transcription and DNA repair. Mass spectrometry (MS)-based proteomics is currently the most widely adopted strategy for high-throughput quantification of hundreds of histone PTMs. Samples such as primary tissues, complex model systems, and biofluids are hard to retrieve in large quantities. Because of this, it is critical to know whether the amount of sample available would lead to an exhaustive analysis if subjected to MS...
November 21, 2017: Journal of Proteome Research
João C T Penteado, Rodolpho J Borduchi, Mariângela B C Maldonado, Juliano R Sangalli, Tiago H C de Bem, Flavio V Meirelles, Daniel R Arnold, Flavia L Lopes
Embryonic and placental development is highly orchestrated by epigenetic processes. Disruptions in normal placental development, commonly observed in pregnancies produced by nuclear transfer, are associated with abnormal gene expression and altered epigenetic regulation of imprinted and vital placental genes. The objective of this study was to evaluate expression and epigenetic regulation of the imprinted gene TSSC4 in cotyledonary and intercotyledonary tissues from day 60 pregnancies produced by embryo transfer (ET), in vitro fertilization (IVF) and nuclear transfer (NT) in cattle...
November 4, 2017: Animal Reproduction Science
Qing Li, Nan Jia, Xiang Tao, Keqin Hua, Weiwei Feng
Histone modifications of lysine residues have been implicated as having diagnostic and/or prognostic significance in numerous types of cancer. In the present study, the significance of the histone H3 methylation of lysine 4 (H3K4) and lysine 27 (H3K27) were investigated in endometrial cancer. Specifically, immunohistochemical analysis was used to detect the cellular expression levels of H3K27 trimethylation (H3K27me3), H3K4 trimethylation (H3K4me3) and H3K4 dimethylation (H3K4me2) in glandular epithelial tissues and stromal tissues...
November 2017: Oncology Letters
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