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Zinc Fingers

Jing Wen, Ruitu Lv, Honghui Ma, Hongjie Shen, Chenxi He, Jiahua Wang, Fangfang Jiao, Hang Liu, Pengyuan Yang, Li Tan, Fei Lan, Yujiang Geno Shi, Chuan He, Yang Shi, Jianbo Diao
N6 -methyladenosine (m6 A) is an abundant modification in eukaryotic mRNA, regulating mRNA dynamics by influencing mRNA stability, splicing, export, and translation. However, the precise m6 A regulating machinery still remains incompletely understood. Here we demonstrate that ZC3H13, a zinc-finger protein, plays an important role in modulating RNA m6 A methylation in the nucleus. We show that knockdown of Zc3h13 in mouse embryonic stem cell significantly decreases global m6 A level on mRNA. Upon Zc3h13 knockdown, a great majority of WTAP, Virilizer, and Hakai translocate to the cytoplasm, suggesting that Zc3h13 is required for nuclear localization of the Zc3h13-WTAP-Virilizer-Hakai complex, which is important for RNA m6 A methylation...
March 15, 2018: Molecular Cell
Evgenia N Nikolova, Robyn L Stanfield, Jane Dyson, Peter E Wright
Many eukaryotic transcription factors recognize the epigenetic marker 5-methylcytosine (mC) at CpG sites in DNA. Despite their structural diversity, methyl-CpG-binding proteins (MBPs) share a common mode of recognition of mC methyl groups that involves hydrophobic pockets and weak hydrogen bonds of the CH---O type. The zinc finger protein Kaiso possesses a remarkably high specificity for methylated over unmethylated CpG sites. A key contribution to this specificity is provided by glutamate 535 (E535), which is optimally positioned to form multiple interactions with mCpG, including direct CH---O hydrogen bonds...
March 16, 2018: Biochemistry
Sini M Kinnunen, Marja Tölli, Mika J Välimäki, Erhe Gao, Zoltan Szabo, Jaana Rysä, Mónica P A Ferreira, Pauli Ohukainen, Raisa Serpi, Alexandra Correia, Ermei Mäkilä, Jarno Salonen, Jouni Hirvonen, Hélder A Santos, Heikki Ruskoaho
Transcription factors are fundamental regulators of gene transcription, and many diseases, such as heart diseases, are associated with deregulation of transcriptional networks. In the adult heart, zinc-finger transcription factor GATA4 is a critical regulator of cardiac repair and remodelling. Previous studies also suggest that NKX2-5 plays function role as a cofactor of GATA4. We have recently reported the identification of small molecules that either inhibit or enhance the GATA4-NKX2-5 transcriptional synergy...
March 15, 2018: Scientific Reports
Hamid Reza Mirzaei, Hossein Pourghadamyari, Majid Rahmati, Abbas Mohammadi, Javid Sadri Nahand, Abbas Rezaei, Hamed Mirzaei, Jamshid Hadjati
Recently clinical trials utilizing genetically engineered T cells expressing a chimeric antigen receptor (CAR) that is half monoclonal antibody and half T-cell receptor have demonstrated remarkable response in patients with advanced cancers like relapsed or refractory acute lymphoblastic leukemia (ALL) and lymphoma. Moreover, emerging chimeric genome editing tools such as zinc-finger nucleases (ZNFs), transcription activator-like effector nucleases (TALENs) and clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas composed of sequence-specific DNA binding module(s) linked to a non-specific DNA cleavage domain have made possible to dramatically expand the ability to manipulate cells aim to treat and/or study a wide range of diseases including cancer...
March 12, 2018: Cancer Letters
Jinbo Huang, Xu Dong, Zhou Gong, Ling-Yun Qin, Shuai Yang, Yue-Ling Zhu, Xiang Wang, Delin Zhang, Tingting Zou, Ping Yin, Chun Tang
N6 -methyladenosine (m6 A), a ubiquitous RNA modification, is installed by METTL3-METTL14 complex. The structure of the heterodimeric complex between the methyltransferase domains (MTDs) of METTL3 and METTL14 has been previously determined. However, the MTDs alone possess no enzymatic activity. Here we present the solution structure for the zinc finger domain (ZFD) of METTL3, the inclusion of which fulfills the methyltransferase activity of METTL3-METTL14. We show that the ZFD specifically binds to an RNA containing 5'-GGACU-3' consensus sequence, but does not to one without...
March 14, 2018: Protein & Cell
Sheng Huang, Jie Gao, Jiangfeng You, Yanan Liang, Kexing Guan, Siqi Yan, Meiqi Zhan, Zhenming Yang
Aluminum (Al) toxicity in acidic soils affects crop production worldwide. C2 H2 -type zinc finger transcription factor STOP1/ART1-mediated expression of Al tolerance genes has been shown to be important for Al resistance in Arabidopsis , rice and other crop plants. Here, we identified and characterized four STOP1-like proteins (SbSTOP1a, SbSTOP1b, SbSTOP1c, and SbSTOP1d) in sweet sorghum, a variant of grain sorghum ( Sorghum bicolor L.). Al induced the transcription of the four SbSTOP1 genes in both time- and Al concentration-dependent manners...
2018: Frontiers in Plant Science
Girak Kim, Min Jeong Gu, Soo Ji Kim, Kwang Hyun Ko, Yoon-Chul Kye, Cheol Gyun Kim, Jae-Ho Cho, Woon-Kyu Lee, Ki-Duk Song, Hyuk Chu, Yeong-Min Park, Seung Hyun Han, Cheol-Heui Yun
γδ T cells, known to be an important source of innate IL-17 in mice, provide critical contributions to host immune responses. Development and function of γδ T cells are directed by networks of diverse transcription factors (TFs). Here, we examine the role of the zinc finger TFs, Kruppel-like factor 10 (KLF10), in the regulation of IL-17-committed CD27- γδ T (γδ27- -17) cells. We found selective augmentation of Vγ4+ γδ27- cells with higher IL-17 production in KLF10-deficient mice. Surprisingly, KLF10-deficient CD127hi Vγ4+ γδ27- -17 cells expressed higher levels of CD5 than their wild-type counterparts, with hyper-responsiveness to cytokine, but not T-cell receptor, stimuli...
2018: Frontiers in Immunology
Antoine Abou Jaoude, Lise Badiqué, Mohamed Mlih, Sara Awan, Sunning Guo, Alexandre Lemle, Clauda Abboud, Sophie Foppolo, Lionel Host, Jérôme Terrand, Hélène Justiniano, Joachim Herz, Rachel L Matz, Philippe Boucher
ShcA is an adaptor protein that binds to the cytoplasmic tail of receptor tyrosine kinases and of the Low Density Lipoprotein-related receptor 1 (LRP1), a trans-membrane receptor that protects against atherosclerosis. Here, we examined the role of endothelial ShcA in atherosclerotic lesion formation. We found that atherosclerosis progression was markedly attenuated in mice deleted for ShcA in endothelial cells, that macrophage content was reduced at the sites of lesions, and that adhesion molecules such as the intercellular adhesion molecule-1 (ICAM-1) were severely reduced...
March 14, 2018: Scientific Reports
Hyeonseok Ko, Seongrak Kim, Kyungmi Yang, Kunhong Kim
Epithelial-mesenchymal transition (EMT) is a critical process in invasion and metastasis of cancer cells. E-cadherin to N-cadherin switching is considered a molecular hallmark of EMT. Recently, we reported that increased CK2 activity fully induces E-cadherin to N-cadherin switching, but the molecular mechanisms of N-cadherin upregulation are unknown. In this study, we examined how N-cadherin is upregulated by CK2. N-cadherin promoter analysis and ChIP analysis identified and confirmed myeloid zinc finger 1 (MZF1) as an N-cadherin transcription factor...
March 13, 2018: Oncogenesis
Manuela Germeshausen, Phil Ancliff, Jaime Estrada, Markus Metzler, Eva Ponstingl, Horst Rütschle, Dirk Schwabe, Richard H Scott, Sule Unal, Angela Wawer, Bernward Zeller, Matthias Ballmaier
Heterozygous mutations in MECOM (MDS1 and EVI1 complex locus) have been reported to be causative of a rare association of congenital amegakaryocytic thrombocytopenia and radioulnar synostosis. Here we report on 12 patients with congenital hypomegakaryocytic thrombocytopenia caused by MECOM mutations (including 10 novel mutations). The mutations affected different functional domains of the EVI1 protein. The spectrum of phenotypes was much broader than initially reported for the first 3 patients; we found familial as well as sporadic cases, and the clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality...
March 27, 2018: Blood Advances
Paulo P Amaral, Tommaso Leonardi, Namshik Han, Emmanuelle Viré, Dennis K Gascoigne, Raúl Arias-Carrasco, Magdalena Büscher, Luca Pandolfini, Anda Zhang, Stefano Pluchino, Vinicius Maracaja-Coutinho, Helder I Nakaya, Martin Hemberg, Ramin Shiekhattar, Anton J Enright, Tony Kouzarides
BACKGROUND: The mammalian genome is transcribed into large numbers of long noncoding RNAs (lncRNAs), but the definition of functional lncRNA groups has proven difficult, partly due to their low sequence conservation and lack of identified shared properties. Here we consider promoter conservation and positional conservation as indicators of functional commonality. RESULTS: We identify 665 conserved lncRNA promoters in mouse and human that are preserved in genomic position relative to orthologous coding genes...
March 15, 2018: Genome Biology
Min Hu, Shuwei Lv, Wenguang Wu, Yongcai Fu, Fengxia Liu, Bingbing Wang, Weiguo Li, Ping Gu, Hongwei Cai, Chuanqing Sun, Zuofeng Zhu
Plant architecture is a key agronomical factor determining crop yield, which has been a major target of cereal crop domestication. The plant architecture transition from the prostrate tiller of typical African wild rice (O. barthii) to the erect tiller of African cultivated rice (Oryza glaberrima) was a key step during African rice domestication. Here we show that PROG7 (PROSTRATE GROWTH 7), a zinc-finger transcription factor gene on chromosome 7, was required for the prostrate growth of African wild rice. Mutations in the promoter region of prog7 reduced the level of gene expression in the tiller base, leading to erect growth in African cultivated rice...
March 14, 2018: Plant Journal: for Cell and Molecular Biology
Chieun Song, Jimin Lee, Taeyoon Kim, Jong Chan Hong, Chae Oh Lim
Under normal growth conditions, Arabidopsis VOZ1 interacts with DREB2C and acts as a transcriptional repressor by reducing DNA binding of DREB2C. Under heat stress conditions, VOZ1 is degraded by ubiquitination, and DREB2C, which is freed from VOZ1, functions as a transcription activator. To investigate the mechanism by which the DEHYDRATION-RESPONSIVE ELEMENT-BINDING FACTOR 2C (DREB2C)-dependent signaling cascade regulates heat stress (HS) responses, we performed a yeast two-hybrid screening using the DREB2C APETALA2 (AP2) DNA-binding domain as the bait against a cDNA library derived from Arabidopsis...
March 13, 2018: Planta
Tomohisa Okamura, Kazuhiko Yamamoto, Keishi Fujio
Regulatory T cells (Tregs) are necessary for the maintenance of immune tolerance. Tregs are divided into two major populations: one is thymus derived and the other develops in the periphery. Among these Tregs, CD4+ CD25+ Tregs, which mainly originate in the thymus, have been extensively studied. Transcription factor Foxp3 is well known as a master regulatory gene for the development and function of CD4+ CD25+ Tregs. On the other hand, peripheral Tregs consist of distinct cell subsets including Foxp3-dependent extrathymically developed Tregs and interleukin (IL)-10-producing type I regulatory T (Tr1) cells...
2018: Frontiers in Immunology
Motoki Takaku, Sara A Grimm, John D Roberts, Kaliopi Chrysovergis, Brian D Bennett, Page Myers, Lalith Perera, Charles J Tucker, Charles M Perou, Paul A Wade
GATA3 is frequently mutated in breast cancer; these mutations are widely presumed to be loss-of function despite a dearth of information regarding their effect on disease course or their mechanistic impact on the breast cancer transcriptional network. Here, we address molecular and clinical features associated with GATA3 mutations. A novel classification scheme defines distinct clinical features for patients bearing breast tumors with mutations in the second GATA3 zinc-finger (ZnFn2). An engineered ZnFn2 mutant cell line by CRISPR-Cas9 reveals that mutation of one allele of the GATA3 second zinc finger (ZnFn2) leads to loss of binding and decreased expression at a subset of genes, including Progesterone Receptor...
March 13, 2018: Nature Communications
Philip Knuckles, Tina Lence, Irmgard U Haussmann, Dominik Jacob, Nastasja Kreim, Sarah H Carl, Irene Masiello, Tina Hares, Rodrigo Villaseñor, Daniel Hess, Miguel A Andrade-Navarro, Marco Biggiogera, Mark Helm, Matthias Soller, Marc Bühler, Jean-Yves Roignant
N 6 -methyladenosine (m6 A) is the most abundant mRNA modification in eukaryotes, playing crucial roles in multiple biological processes. m6 A is catalyzed by the activity of methyltransferase-like 3 (Mettl3), which depends on additional proteins whose precise functions remain poorly understood. Here we identified Zc3h13 (zinc finger CCCH domain-containing protein 13)/Flacc [Fl(2)d-associated complex component] as a novel interactor of m6 A methyltransferase complex components in Drosophila and mice. Like other components of this complex, Flacc controls m6 A levels and is involved in sex determination in Drosophila We demonstrate that Flacc promotes m6 A deposition by bridging Fl(2)d to the mRNA-binding factor Nito...
March 13, 2018: Genes & Development
Murali Aarthy, Deepak Kumar, Rajanish Giri, Sanjeev Kumar Singh
Human papillomavirus (HPV) has been the primary causative agent of cervical cancer, the most threatening cancer affecting millions of women worldwide. HPV, a small non enveloped DNA virus of high and low risk types contain intrinsically disordered region and it also plays significant role in the development of cervical cancer. HPV E7 contains an ordered Zinc finger motif that binds to pRB and alters its function. It utilizes both disordered N-terminal and structured C-terminal regions for cellular transformation...
March 10, 2018: Gene
Qiang Zhang, Chuan Xia, Lichao Zhang, Chunhao Dong, Xu Liu, Xiuying Kong
Leaf senescence is an important agronomic trait that affects both crop yield and quality. In this study, we characterized a premature leaf senescence mutant of wheat ( Triticum aestivum L.) obtained by ethylmethane sulfonate (EMS) mutagenesis, named m68 . Genetic analysis showed that the leaf senescence phenotype of m68 is controlled by a single recessive nuclear gene. We compared the transcriptome of wheat leaves between the wild type (WT) and the m68 mutant at four time points. Differentially expressed gene (DEG) analysis revealed many genes that were closely related to senescence genes...
March 10, 2018: International Journal of Molecular Sciences
Laurie Galvan, Laetitia Francelle, Marie-Claude Gaillard, Lucie de Longprez, Maria-Angeles Carrillo-de Sauvage, Géraldine Liot, Karine Cambon, Lev Stimmer, Sophie Luccantoni, Julien Flament, Julien Valette, Michel de Chaldée, Gwenaelle Auregan, Martine Guillermier, Charlène Joséphine, Fanny Petit, Caroline Jan, Margot Jarrige, Noëlle Dufour, Gilles Bonvento, Sandrine Humbert, Frédéric Saudou, Philippe Hantraye, Karine Merienne, Alexis-Pierre Bemelmans, Anselme L Perrier, Nicole Déglon, Emmanuel Brouillet
The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (doublecortin like kinase 3), which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington's disease. Recent data obtained in studies related to cancer suggest DCLK3 could have an anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington's disease may render striatal neurons more susceptible to mutant huntingtin (mHtt)...
March 9, 2018: Brain: a Journal of Neurology
Zhipeng Zhang, Hongxi Chen, Yebin Lu, Tiecheng Feng, Weijia Sun
This study examined the effects of long non‑coding RNA (lncRNA) BC032020 on the development of human pancreatic ductal adenocarcinoma (PDAC), and the potential molecular mechanisms responsible for these effects. The expression of BC032020 was assessed in 20 pairs of PDAC tumor tissues and adjacent normal tissues. The overexpression of BC032020 was enforced in the AsPC‑1 and PANC‑1 cells, and the effects on cell proliferation, cell cycle distribution, cell migration and apoptosis were determined. We also analyzed the functions of zinc finger protein 451 (ZNF451), which shares a gene sequence with two exons of BC032020 and a non‑coding region with another two exons, in PDAC cells...
April 2018: International Journal of Oncology
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