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Maxime Wc Rousseaux, Maria de Haro, Cristian A Lasagna-Reeves, Antonia De Maio, Jeehye Park, Paymaan Jafar-Nejad, Ismael Al-Ramahi, Ajay Sharma, Lauren See, Nan Lu, Luis Vilanova-Velez, Tiemo J Klisch, Thomas F Westbrook, Juan C Troncoso, Juan Botas, Huda Y Zoghbi
Several neurodegenerative diseases are driven by the toxic gain-of-function of specific proteins within the brain. Elevated levels of alpha-synuclein (α-Syn) appear to drive neurotoxicity in Parkinson's disease (PD); neuronal accumulation of tau is a hallmark of Alzheimer's disease (AD); and their increased levels cause neurodegeneration in humans and model organisms. Despite the clinical differences between AD and PD, several lines of evidence suggest that α-Syn and tau overlap pathologically. The connections between α-Syn and tau led us to ask whether these proteins might be regulated through a shared pathway...
October 25, 2016: ELife
Melissa Resto, Bong-Hyun Kim, Alfonso G Fernandez, Brian J Abraham, Keji Zhao, Brian A Lewis
We describe here the identification and functional characterization of the enzyme O-GlcNAcase (OGA) as an RNA polymerase II elongation factor. Using in vitro transcription elongation assays, we show that OGA activity is required for elongation in a crude nuclear extract system, while in a purified system devoid of OGA, the addition of rOGA inhibited elongation. Furthermore, OGA is physically associated with the known RNA pol II pausing/elongation factors SPT5 and TRIM28/KAP1/TIF1b, and a purified OGA/SPT5/TIF1b complex has elongation properties...
September 6, 2016: Journal of Biological Chemistry
Heeyoun Bunch, Brian P Lawney, Adam Burkholder, Duanduan Ma, Xiaofeng Zheng, Shmulik Motola, David C Fargo, Stuart S Levine, Yaoyu E Wang, Guang Hu
Mammalian genomes encode a large number of non-coding RNAs (ncRNAs) that greatly exceed mRNA genes. While the physiological and pathological roles of ncRNAs have been increasingly understood, the mechanisms of regulation of ncRNA expression are less clear. Here, our genomic study has shown that a significant number of long non-coding RNAs (lncRNAs, >1000 nucleotides) harbor RNA polymerase II (Pol II) engaged with the transcriptional start site. A pausing and transcriptional elongation factor for protein-coding genes, tripartite motif-containing 28 (TRIM28) regulates the transcription of a subset of lncRNAs in mammalian cells...
August 2016: Genomics
X Ma, Z C Zhai, M L Zhang, B H Song, Y R Zhu, S B Yang, X Q Dong, L Y Su, C F Wang, H X Ma, W M Luan
The bovine TRIM28 gene was amplified from ovary tissue by using RT-PCR. The TRIM28 gene was inserted into the eukaryotic expression vector pIRES2-EGFP and transfected into bovine fetal fibroblasts by using Lipofectamine 3000. TRIM28 mRNA and protein were detected by fluorescence microscope and western blotting. The results showed that the full length of TRIM28 was cloned and pIRES2-EGFP-TRIM28 was constructed successfully. EGFP expression was observed, and the pIRES2-EGFP-TRIM28 transfected group expressed more TRIM28 protein than that by the pIRES2-EGFP group...
2016: Genetics and Molecular Research: GMR
Chunli Wei, Jingliang Cheng, Boxv Zhou, Li Zhu, Md Asaduzzaman Khan, Tao He, Sufang Zhou, Jian He, Xiaoling Lu, Hanchun Chen, Dianzheng Zhang, Yongxiang Zhao, Junjiang Fu
TRIM28 regulates its target genes at both transcriptional and posttranscriptional levels. Here we report that a TRIM28-TWIST1-EMT axis exists in breast cancer cells and TRIM28 promotes breast cancer metastasis by stabilizing TWIST1 and subsequently enhancing EMT. We find that TRIM28 is highly expressed in both cancer cell lines and advanced breast cancer tissues, and the levels of TRIM28 and TWIST1 are positively correlated with the aggressiveness of breast carcinomas. Overexpression and depletion of TRIM28 up- and down-regulates the protein, but not the mRNA levels of TWIST1, respectively, suggesting that TRIM28 upregulates TWIST1 post-transcriptionally...
July 14, 2016: Scientific Reports
Chun-Ting Cheng, Ching-Ying Kuo, Ching Ouyang, Chien-Feng Li, Yiyin Chung, David C Chan, Hsing-Jien Kung, David K Ann
Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here, we report that KAP1 (TRIM28), a transcriptional coadaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473 phosphorylation of KAP1 (pS473-KAP1) in a ROS- and p38-dependent manner. Results from live-cell imaging and molecular studies revealed that during the first 6 to 8 hours of glucose starvation, mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473-KAP1-dependent manner...
September 1, 2016: Cancer Research
Denise Catherine Miles, Nienke Alexandra de Vries, Santiago Gisler, Cor Lieftink, Waseem Akhtar, Ewa Gogola, Inka Pawlitzky, Danielle Hulsman, Ellen Tanger, Martijn Koppens, Roderick Leonardus Beijersbergen, Maarten van Lohuizen
Since the discovery of induced pluripotent stem cells there has been intense interest in understanding the mechanisms that allow a somatic cell to be reprogrammed back to a pluripotent state. Several groups have studied the alterations in gene expression that occur as somatic cells modify their genome to that of an embryonic stem cell. Underpinning many of the gene expression changes are modifications to the epigenetic profile of the associated chromatin. We have used a large-scale shRNA screen to identify epigenetic modifiers that act as barriers to reprogramming...
June 28, 2016: Stem Cells
Iván D'Orso
RNA polymerase II (Pol II) pausing at promoter-proximal regions is a highly regulated step in the transcription cycle. Pause release is facilitated by the P-TEFb kinase, which phosphorylates Pol II and negative elongation factors. Recent studies suggest that P-TEFb (as part of the inhibitory 7SK snRNP) is recruited to promoter-proximal regions through interaction with KAP1/TRIM28/TIF1β to facilitate 'on-site' kinase activation and transcription elongation. Here, I discuss features of this model and future challenges to further hone our understanding of transcriptional regulation including Pol II pausing and pause release...
June 2, 2016: RNA Biology
David Valle-García, Zulekha A Qadeer, Domhnall S McHugh, Flávia G Ghiraldini, Asif H Chowdhury, Dan Hasson, Michael A Dyer, Félix Recillas-Targa, Emily Bernstein
ATRX is a SWI/SNF chromatin remodeler proposed to govern genomic stability through the regulation of repetitive sequences, such as rDNA, retrotransposons, and pericentromeric and telomeric repeats. However, few direct ATRX target genes have been identified and high-throughput genomic approaches are currently lacking for ATRX. Here we present a comprehensive ChIP-sequencing study of ATRX in multiple human cell lines, in which we identify the 3' exons of zinc finger genes (ZNFs) as a new class of ATRX targets...
June 2, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Ryan P McNamara, Carlos Guzman, Jonathan E Reeder, Iván D'Orso
The transition of RNA polymerase II (Pol II) from transcription initiation into productive elongation in eukaryotic cells is regulated by the P-TEFb kinase, which phosphorylates the C-terminal domain of paused Pol II at promoter-proximal regions. Our recent study found that P-TEFb (in an inhibited state bound to the 7SK snRNP complex) interacts with the KAP1/TRIM28 transcriptional regulator, and that KAP1 and the 7SK snRNP co-occupy most gene promoters containing paused Pol II. Here we provide a detailed experimental description and analysis of the ChIP-seq datasets that have been deposited into Gene Expression Omnibus (GEO): GS72622, so that independent groups can replicate and expand upon these findings...
March 2016: Genomics Data
Kevin Dalgaard, Kathrin Landgraf, Steffen Heyne, Adelheid Lempradl, John Longinotto, Klaus Gossens, Marius Ruf, Michael Orthofer, Ruslan Strogantsev, Madhan Selvaraj, Tess Tsai-Hsiu Lu, Eduard Casas, Raffaele Teperino, M Azim Surani, Ilona Zvetkova, Debra Rimmington, Y C Loraine Tung, Brian Lam, Rachel Larder, Giles S H Yeo, Stephen O'Rahilly, Tanya Vavouri, Emma Whitelaw, Josef M Penninger, Thomas Jenuwein, Ching-Lung Cheung, Anne C Ferguson-Smith, Anthony P Coll, Antje Körner, J Andrew Pospisilik
More than one-half billion people are obese, and despite progress in genetic research, much of the heritability of obesity remains enigmatic. Here, we identify a Trim28-dependent network capable of triggering obesity in a non-Mendelian, "on/off" manner. Trim28(+/D9) mutant mice exhibit a bi-modal body-weight distribution, with isogenic animals randomly emerging as either normal or obese and few intermediates. We find that the obese-"on" state is characterized by reduced expression of an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1 and that independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype...
January 28, 2016: Cell
Kristien Mortelmans, Feng Wang-Johanning, Gary L Johanning
Endogenous retroviral sequences are spread throughout the genome of all humans, and make up about 8% of the genome. Despite their prevalence, the function of human endogenous retroviruses (HERVs) in humans is largely unknown. In this review we focus on the brain, and evaluate studies in animal models that address mechanisms of endogenous retrovirus activation in the brain and central nervous system (CNS). One such study in mice found that TRIM28, a protein critical for mouse early development, regulates transcription and silencing of endogenous retroviruses in neural progenitor cells...
January 2016: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
Milena Leseva, Barbara B Knowles, Daniel M Messerschmidt, Davor Solter
The genetic information is largely identical across most cell types in a given organism but the epigenome, which controls expression of the genome, is cell type- and context-dependent. Although most mature mammalian cells appear to have a stable, heritable epigenome, a dynamic intricate process reshapes it as these cells transition from soma to germline and back again. During normal embryogenesis, primordial germ cells, of somatic origin, are set aside to become gametes. In doing so their genome is reprogrammed-that is, the epigenome of specific regions is replaced in a sex-specific fashion as they terminally differentiate into oocytes or spermatocytes in the gonads...
2015: Cold Spring Harbor Symposia on Quantitative Biology
Katherine A Alexander, Xu Wang, Maho Shibata, Andrew G Clark, María J García-García
Genomic imprinting depends on the establishment and maintenance of DNA methylation at imprinting control regions. However, the mechanisms by which these heritable marks influence allele-specific expression are not fully understood. By analyzing maternal, zygotic, maternal-zygotic, and conditional Trim28 mutants, we found that the transcription factor TRIM28 controls genomic imprinting through distinct mechanisms at different developmental stages. During early genome-wide reprogramming, both maternal and zygotic TRIM28 are required for the maintenance of methylation at germline imprints...
November 10, 2015: Cell Reports
Zeng-Xin Qi, Jia-Jun Cai, Ling-Chao Chen, Qi Yue, Yan Gong, Yu Yao, Ying Mao
Tripartite motif (TRIM) proteins are involved in tumorigenesis. Here, we examined the expression, biological function, and clinical significance of tripartite motif containing 28 (TRIM28) in glioma, a locally aggressive brain tumor. First, TRIM28 expression was significantly higher in glioma (n = 138) than in non-glioma controls (n = 6). TRIM28 expression was positively correlated with tumor malignancy, and associated with poor overall survival (OS) and progression-free survival (PFS). Notably, TRIM28 expression was negatively correlated with p21 expression in patients with glioblastoma multiforme (GBM)...
January 2016: Journal of Neuro-oncology
Bin Xia Yang, Chadi A El Farran, Hong Chao Guo, Tao Yu, Hai Tong Fang, Hao Fei Wang, Sharon Schlesinger, Yu Fen Samantha Seah, Germaine Yen Lin Goh, Suat Peng Neo, Yinghui Li, Matthew C Lorincz, Vinay Tergaonkar, Tit-Meng Lim, Lingyi Chen, Jayantha Gunaratne, James J Collins, Stephen P Goff, George Q Daley, Hu Li, Frederic A Bard, Yuin-Han Loh
Embryonic stem cells (ESCs) repress the expression of exogenous proviruses and endogenous retroviruses (ERVs). Here, we systematically dissected the cellular factors involved in provirus repression in embryonic carcinomas (ECs) and ESCs by a genome-wide siRNA screen. Histone chaperones (Chaf1a/b), sumoylation factors (Sumo2/Ube2i/Sae1/Uba2/Senp6), and chromatin modifiers (Trim28/Eset/Atf7ip) are key determinants that establish provirus silencing. RNA-seq analysis uncovered the roles of Chaf1a/b and sumoylation modifiers in the repression of ERVs...
September 24, 2015: Cell
Gry H Dihazi, Olaf Jahn, Björn Tampe, Michael Zeisberg, Claudia Müller, Gerhard A Müller, Hassan Dihazi
Elucidation of the mechanisms underlying the nephrogenesis will boost enormously the regenerative medicine. Here we performed 2-D gel-based comparative proteome analyses of rat embryonic kidney from different developmental stages. Out of 288 non-redundant identified proteins, 102 were common in all developmental stages. 86% of the proteins found in E14 and E16 were identical, in contrast only 37% of the identified proteins overlap between E14 and P1. Bioinformatics analysis suggests developmental stage-specific pathway activation and highlighted heterochromatin protein 1 (Cbx1, Cbx3, Cbx5) and Trim28 as potential key players in nephrogenesis...
2015: Scientific Reports
Heeyoun Bunch, Stuart K Calderwood
TRIM28 is a multidomain protein with versatile functions in transcription and DNA repair. Recently it was shown that this factor plays unanticipated roles in transcriptional elongation. TRIM28 was shown to stabilize the pausing of RNA polymerase II (Pol II) close to the transcriptional start site in many unactivated genes, permitting Pol II accumulation and readying genes for induction. In addition, the factor was shown to respond rapidly to signals accompanying transcriptional activation permitting the productive elongation of RNA by previously paused Pol II...
2015: BMC Molecular Biology
Gargee Mukherjee, Claudia Claudia Röwer, Cornelia Koy, Chris Protzel, Peter Lorenz, Hans-Jürgen Thiesen, Oliver W Hakenberg, Michael O Glocker
A solidified ionic liquid matrix (SILM) consisting of 3-aminoquinoline, α-cyano-4- hydroxycinnamic acid and ammonium dihydrogen phosphate combines the benefits of liquid and solid MALDI matrices and proves to be well suitable for phosphopeptide analysis using MALDI-MS in the low femtomole range. Desalting and buffer exchange that typically follow after phosphopeptide elution from metal oxide affinity chromatography (MOAC) materials can be omitted. Shifting the pH from acidic to basic during target preparation causes slow matrix crystallization and homogeneous embedding of the analyte molecules, forming a uniform preparation from which (phospho)peptides can be ionized in high yields over long periods of time...
2015: European Journal of Mass Spectrometry
Hironori Nishitsuji, Leila Sawada, Ryuichi Sugiyama, Hiroshi Takaku
Kruppel-associated box-containing zinc finger (KRAB-ZNF) genes constitute the single largest gene family of transcriptional repressors in the genomes of higher organisms. In this study, we isolated 52 cDNA clones of KRAB-ZFPs from U1 cell lines and screened them to identify which were capable of regulating HIV-1 gene expression. We identified 5 KRAB-ZFPs that suppressed ⩾50% of HIV-1 LTR. Of the 5 identified KRAB-ZFPs, the expression of ZNF10 significantly enhanced the transcriptional repression activity of the LTR compared with other ZNFs...
July 8, 2015: FEBS Letters
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