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Joanna Przybyl, Lukasz Kidzinski, Trevor Hastie, Maria Debiec-Rychter, Roel Nusse, Matt van de Rijn
OBJECTIVE: Low-grade endometrial stromal sarcomas (LGESS) harbor chromosomal translocations that affect proteins associated with chromatin remodeling Polycomb Repressive Complex 2 (PRC2), including SUZ12, PHF1 and EPC1. Roughly half of LGESS also demonstrate nuclear accumulation of β-catenin, which is a hallmark of Wnt signaling activation. However, the targets affected by the fusion proteins and the role of Wnt signaling in the pathogenesis of these tumors remain largely unknown. METHODS: Here we report the results of a meta-analysis of three independent gene expression profiling studies on LGESS and immunohistochemical evaluation of nuclear expression of β-catenin and Lef1 in 112 uterine sarcoma specimens obtained from 20 LGESS and 89 LMS patients...
March 12, 2018: Gynecologic Oncology
Shanshan Zhang, Dongfang Wang, Huajian Zhang, Megan I Skaggs, Alan Lloyd, Di Ran, Lingling An, Karen S Schumaker, Gary N Drews, Ramin Yadegari
Early endosperm development presents a unique system to uncover epigenetic regulatory mechanisms because the contributing maternal and paternal genomes possess differential epigenetic modifications. In Arabidopsis (Arabidopsis thaliana), the initiation of endosperm coenocytic growth upon fertilization and the transition to endosperm cellularization are regulated by the FERTILIZATION-INDEPENDENT SEED (FIS)-Polycomb Repressive Complex 2 (PRC2), a putative H3K27 methyltransferase. Here, we address the possible role of the FIS-PRC2 complex in regulating the type I MADS-box gene family, which has previously been shown to regulate early endosperm development...
March 9, 2018: Plant Physiology
Marc-Werner Dobenecker, Joon Seok Park, Jonas Marcello, Michael T McCabe, Richard Gregory, Steven D Knight, Inmaculada Rioja, Anna K Bassil, Rabinder K Prinjha, Alexander Tarakhovsky
Differentiation and activation of T cells require the activity of numerous histone lysine methyltransferases (HMT) that control the transcriptional T cell output. One of the most potent regulators of T cell differentiation is the HMT Ezh2. Ezh2 is a key enzymatic component of polycomb repressive complex 2 (PRC2), which silences gene expression by histone H3 di/tri-methylation at lysine 27. Surprisingly, in many cell types, including T cells, Ezh2 is localized in both the nucleus and the cytosol. Here we show the presence of a nuclear-like PRC2 complex in T cell cytosol and demonstrate a role of cytosolic PRC2 in T cell antigen receptor (TCR)-mediated signaling...
March 9, 2018: Journal of Experimental Medicine
Xiaomeng Li, Xianhui Ruan, Peitao Zhang, Yang Yu, Ming Gao, Shukai Yuan, Zewei Zhao, Jie Yang, Li Zhao
The T-box transcription factor TBX3 has been implicated in the patterning and differentiation of a number of tissues during embryonic development, and is overexpressed in a variety of cancers; however, the precise function of TBX3 in papillary thyroid carcinoma (PTC) development remains to be determined. In the current study, we report downregulation of TBX3 in PTC cells delays the G1/S-phase transition, decreases cell growth in vitro, and inhibits tumor formation in vivo. We identified p57KIP2 as a novel downstream target that serves as the key mediator of TBX3's control over PTC cell proliferation...
March 7, 2018: Oncogene
Ling Wang, Zongliang Jiang, Delun Huang, Jingyue Duan, Chang Huang, Shannon Sullivan, Kaneha Vali, Yexuan Yin, Ming Zhang, Jill Wegrzyn, Xiuchun Cindy Tian, Young Tang
BACKGROUND: The generation of induced pluripotent stem cells (iPSCs) has underdefined mechanisms. In addition, leukemia inhibitory factor (LIF) activated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway is the master regulator for naïve-state pluripotency achievement and maintenance. However, the regulatory process to attain naïve pluripotent iPSCs is not well understood. RESULTS: We performed transcriptome analysis to dissect the genomic expression during mouse iPSC induction, with or without blocking the JAK/STAT3 activity...
March 6, 2018: BMC Genomics
Jafar Sharif, Haruhiko Koseki
No abstract text is available yet for this article.
March 2018: Nature Structural & Molecular Biology
Ting Wang, Beibei Mao, Chi Cheng, Zhuangzhi Zou, Junling Gao, Yanglu Yang, Tong Lei, Xiaolong Qi, Zengqiang Yuan, Wentong Xu, Zhongbing Lu
The transcriptional co-activator Yes-associated protein (YAP) has been implicated as an oncogene and is found to promote breast cancer metastasis. However, the pro-metastatic mechanism of YAP remains unclear. Here, we demonstrated that YAP functions as a transcriptional repressor of growth differentiation factor-15 (GDF15), a divergent member of the transforming growth factor superfamily, in several breast cancer cell lines. Functionally, knockdown of YAP decreased, whereas knockdown of GDF15 increased, the metastatic potential of breast cancer cells...
February 27, 2018: Biochimica et Biophysica Acta
Siming Chen, Lianying Jiao, Murtada Shubbar, Xin Yang, Xin Liu
Developmentally regulated accessory subunits dictate PRC2 function. Here, we report the crystal structures of a 120 kDa heterotetrameric complex consisting of Suz12, Rbbp4, Jarid2, and Aebp2 fragments that is minimally active in nucleosome binding and of an inactive binary complex of Suz12 and Rbbp4. Suz12 contains two unique structural platforms that define distinct classes of PRC2 holo complexes for chromatin binding. Aebp2 and Phf19 compete for binding of a non-canonical C2 domain of Suz12; Jarid2 and EPOP occupy an overlapped Suz12 surface required for chromatin association of PRC2...
March 1, 2018: Molecular Cell
Saravana Kumar Kailasam Mani, Ourania Andrisani
Chronic Hepatitis B Virus (HBV) infection is linked to hepatocellular carcinoma (HCC) pathogenesis. Despite the availability of a HBV vaccine, current treatments for HCC are inadequate. Globally, 257 million people are chronic HBV carriers, and children born from HBV-infected mothers become chronic carriers, destined to develop liver cancer. Thus, new therapeutic approaches are needed to target essential pathways involved in HCC pathogenesis. Accumulating evidence supports existence of hepatic cancer stem cells (hCSCs), which contribute to chemotherapy resistance and cancer recurrence after treatment or surgery...
March 2, 2018: Genes
Aishwarya Pawar, Paradesi Naidu Gollavilli, Shaomeng Wang, Irfan A Asangani
BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program...
February 27, 2018: Cell Reports
Jonas W Højfeldt, Anne Laugesen, Berthe M Willumsen, Helene Damhofer, Lin Hedehus, Andrey Tvardovskiy, Faizaan Mohammad, Ole N Jensen, Kristian Helin
Polycomb repressive complex 2 (PRC2) catalyzes methylation on lysine 27 of histone H3 (H3K27) and is required for maintaining transcriptional patterns and cellular identity, but the specification and maintenance of genomic PRC2 binding and H3K27 methylation patterns remain incompletely understood. Epigenetic mechanisms have been proposed, wherein pre-existing H3K27 methylation directs recruitment and regulates the catalytic activity of PRC2 to support its own maintenance. Here we investigate whether such mechanisms are required for specifying H3K27 methylation patterns in mouse embryonic stem cells (mESCs)...
February 26, 2018: Nature Structural & Molecular Biology
Zhen Cai, Zhen-Yu Qian, Hao Jiang, Ning Ma, Zhi Li, Li-Yu Liu, Xin-Xin Ren, Yu-Rong Shang, Jing-Jing Wang, Jing-Jing Li, Dong-Ping Liu, Xiu-Ping Zhang, Dan Feng, Qian-Zhi Ni, Yuan-Yuan Feng, Nan Li, Xiao-Yan Zhou, Xiang Wang, Ying Bao, Xue-Li Zhang, Yue-Zhen Deng, Dong Xie
Two isoforms of human Polycomb-like protein 3 (hPCL3) have been reported as components of the nuclear Polycomb repressive complex 2 (PRC2) with the short isoform (hPCL3s) showing a dominant cytoplasmic localization. The function of cytoplasmic hPCL3s has however not been addressed. In this study, we report that hPCL3s is upregulated in clinical hepatocellular carcinoma (HCC) samples and its expression correlated with HCC clinical features. hPCL3s positively regulated the migration, invasion, and metastasis of HCC cells...
February 26, 2018: Cancer Research
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
Amy Ferreccio, Julie Mathieu, Damien Detraux, Somasundaram Logeshwaran, Christopher Cavanaugh, Bryce Sopher, Karin Fischer, Thomas Bello, Assis M Hussein, Shiri Levy, Savannah Cook, Sonia B Sidhu, Filippo Artoni, Nathan J Palpant, Hans Reinecke, Yuliang Wang, Patrick Paddison, Charles Murry, Suman Jayadev, Carol Ware, Hannele Ruohola-Baker
To easily edit the genome of naïve human embryonic stem cells (hESC), we introduced a dual cassette encoding an inducible Cas9 into the AAVS1 site of naïve hESC (iCas9). The iCas9 line retained karyotypic stability, expression of pluripotency markers, differentiation potential, and stability in 5iLA and EPS pluripotency conditions. The iCas9 line induced efficient homology-directed repair (HDR) and non-homologous end joining (NHEJ) based mutations through CRISPR-Cas9 system. We utilized the iCas9 line to study the epigenetic regulator, PRC2 in early human pluripotency...
February 22, 2018: Cell Cycle
Run-Shan Duan, Gang-Bin Tang, Hong-Zhen Du, Yi-Wen Hu, Pei-Pei Liu, Ya-Jie Xu, Yu-Qiang Zeng, Shuang-Feng Zhang, Rui-Ying Wang, Zhao-Qian Teng, Chang-Mei Liu
Neurons in the central nervous system (CNS) lose their intrinsic ability and fail to regenerate, but the underlying mechanisms are largely unknown. Polycomb group (PcG) proteins, which include PRC1 and PRC2 complexes function as gene repressors and are involved in many biological processes. Here we report that PRC1 components (polycomb chromobox (CBX) 2, 7, and 8) are novel regulators of axon growth and regeneration. Especially, knockdown of CBX7 in either embryonic cortical neurons or adult dorsal root ganglion (DRG) neurons enhances their axon growth ability...
February 19, 2018: Cell Death and Differentiation
Houliang Deng, Jianming Zeng, Ting Zhang, Longcai Gong, Hongjie Zhang, Edwin Cheung, Chris Jones, Gang Li
Lysine to Methionine mutations at position 27 (K27M) in the histone H3 (H3.3 and H3.1) are highly prevalent in pediatric high-grade gliomas (HGG) that arise in the midline of the central nervous system. H3K27M perturbs the activity of polycomb repressor complex 2 (PRC2) and correlates with DNA hypomethylation; however, the pathways whereby H3K27M drive the development of pediatric HGG remain poorly understood. To understand the mechanism of pediatric HGG development driven by H3.3K27M and discover potential therapeutic targets or biomarkers, we established pediatric glioma cell model systems harboring H3...
February 16, 2018: Molecular Cancer Research: MCR
Marcela Dotto, María Sol Gómez, María Soledad Soto, Paula Casati
UV-B is a high-energy component of the solar radiation perceived by the plant and induces a number of modifications in plant growth and development, including changes in flowering time. However, the molecular mechanisms underlying these changes are largely unknown. In the present work, we demonstrate that Arabidopsis plants grown under white light supplemented with UV-B show a delay in flowering time, and this developmental reprogramming is mediated by the UVR8 photoreceptor. Using a combination of gene expression analyses and UV-B irradiation of different flowering mutants, we gained insight into the pathways involved in the observed flowering time delay in UV-B exposed Arabidopsis plants...
February 15, 2018: Plant, Cell & Environment
Yingbin Zhong, Qiang Ye, Chengyan Chen, Mingyong Wang, Han Wang
EZH2 is a subunit of polycomb repressive complex 2 (PRC2) that silences gene transcription via H3K27me3 and was shown to be essential for mammalian liver circadian regulation and hematopoiesis through gene silencing. Much less, however, is known about how Ezh2 acts in live zebrafish. Here, we show that zebrafish ezh2 is regulated directly by the circadian clock via both E-box and RORE motif, while core circadian clock genes per1a, per1b, cry1aa and cry1ab are down-regulated in ezh2 null mutant and ezh2 morphant zebrafish, and either knockdown or overexpression of ezh2 alters locomotor rhythms, indicating that Ezh2 is required for zebrafish circadian regulation...
February 13, 2018: Nucleic Acids Research
J P Joos, A R Saadatmand, C Schnabel, I Viktorinová, T Brand, M Kramer, S Nattel, D Dobrev, P Tomancak, J Backs, P Kleinbongard, G Heusch, K Lorenz, E Koch, S Weber, A El-Armouche
Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo, we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress...
February 13, 2018: Scientific Reports
Nolwenn Briand, Anne-Claire Guénantin, Dorota Jeziorowska, Akshay Shah, Matthieu Mantecon, Emilie Capel, Marie Garcia, Anja Oldenburg, Jonas Paulsen, Jean-Sebastien Hulot, Corinne Vigouroux, Philippe Collas
The p.R482W hotspot mutation in A-type nuclear lamins causes familial partial lipodystrophy of Dunnigan-type (FPLD2), a lipodystrophic syndrome complicated by early-onset atherosclerosis. Molecular mechanisms underlying endothelial cell dysfunction conferred by the lamin A mutation remain elusive. However, lamin A regulates epigenetic developmental pathways and mutations could perturb these functions. Here, we demonstrate that lamin A R482W elicits endothelial differentiation defects in a developmental model of FPLD2...
February 9, 2018: Human Molecular Genetics
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