Mouse Pcgf1 Conditional Knockout Project (CRISPR/Cas9)
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A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Identification of the Active Constituents and Significant Pathways of Cangfu Daotan Decoction for the Treatment of PCOS Based on Network Pharmacology
Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2020, Article ID 4086864, 15 pages https://doi.org/10.1155/2020/4086864 Research Article Identification of the Active Constituents and Significant Pathways of Cangfu Daotan Decoction for the Treatment of PCOS Based on Network Pharmacology Wenting Xu , Mengyu Tang , Jiahui Wang , and Lihong Wang Department of Reproduction, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Suzhou, Jiangsu, China Correspondence should be addressed to Lihong Wang; [email protected] Received 18 December 2019; Accepted 27 January 2020; Published 22 February 2020 Academic Editor: Deborah A. Kennedy Copyright © 2020 Wenting Xu et al. ,is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Polycystic ovary syndrome (PCOS) is the most common female endocrine disease. Cangfu Daotan Decoction (CDD) can effectively relieve the clinical symptoms of PCOS patients. Methods. To explore the active ingredients and related pathways of CDD for treating PCOS, a network pharmacology-based analysis was carried out. ,e active ingredients of CDD and their potential targets were obtained from the TCM system pharmacology analysis platform. ,e obtained PCOS-related genes from OMIM and GeneCards were imported to establish protein-protein interaction networks in STRING. Finally, GO analysis and significant pathway analysis were conducted with the RStudio (Bioconductor) database. Results. A total of 111 active compounds were obtained from 1433 ingredients present in the CDD, related to 118 protein targets. In addition, 736 genes were found to be closely related to PCOS, of which 44 overlapped with CDD and were thus considered therapeutically relevant. -
Mammalian PRC1 Complexes: Compositional Complexity and Diverse Molecular Mechanisms
International Journal of Molecular Sciences Review Mammalian PRC1 Complexes: Compositional Complexity and Diverse Molecular Mechanisms Zhuangzhuang Geng 1 and Zhonghua Gao 1,2,3,* 1 Departments of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, USA; [email protected] 2 Penn State Hershey Cancer Institute, Hershey, PA 17033, USA 3 The Stem Cell and Regenerative Biology Program, Penn State College of Medicine, Hershey, PA 17033, USA * Correspondence: [email protected] Received: 6 October 2020; Accepted: 5 November 2020; Published: 14 November 2020 Abstract: Polycomb group (PcG) proteins function as vital epigenetic regulators in various biological processes, including pluripotency, development, and carcinogenesis. PcG proteins form multicomponent complexes, and two major types of protein complexes have been identified in mammals to date, Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). The PRC1 complexes are composed in a hierarchical manner in which the catalytic core, RING1A/B, exclusively interacts with one of six Polycomb group RING finger (PCGF) proteins. This association with specific PCGF proteins allows for PRC1 to be subdivided into six distinct groups, each with their own unique modes of action arising from the distinct set of associated proteins. Historically, PRC1 was considered to be a transcription repressor that deposited monoubiquitylation of histone H2A at lysine 119 (H2AK119ub1) and compacted local chromatin. More recently, there is increasing evidence that demonstrates the transcription activation role of PRC1. Moreover, studies on the higher-order chromatin structure have revealed a new function for PRC1 in mediating long-range interactions. This provides a different perspective regarding both the transcription activation and repression characteristics of PRC1. -
The Changing Chromatome As a Driver of Disease: a Panoramic View from Different Methodologies
The changing chromatome as a driver of disease: A panoramic view from different methodologies Isabel Espejo1, Luciano Di Croce,1,2,3 and Sergi Aranda1 1. Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain 2. Universitat Pompeu Fabra (UPF), Barcelona, Spain 3. ICREA, Pg. Lluis Companys 23, Barcelona 08010, Spain *Corresponding authors: Luciano Di Croce ([email protected]) Sergi Aranda ([email protected]) 1 GRAPHICAL ABSTRACT Chromatin-bound proteins regulate gene expression, replicate and repair DNA, and transmit epigenetic information. Several human diseases are highly influenced by alterations in the chromatin- bound proteome. Thus, biochemical approaches for the systematic characterization of the chromatome could contribute to identifying new regulators of cellular functionality, including those that are relevant to human disorders. 2 SUMMARY Chromatin-bound proteins underlie several fundamental cellular functions, such as control of gene expression and the faithful transmission of genetic and epigenetic information. Components of the chromatin proteome (the “chromatome”) are essential in human life, and mutations in chromatin-bound proteins are frequently drivers of human diseases, such as cancer. Proteomic characterization of chromatin and de novo identification of chromatin interactors could thus reveal important and perhaps unexpected players implicated in human physiology and disease. Recently, intensive research efforts have focused on developing strategies to characterize the chromatome composition. In this review, we provide an overview of the dynamic composition of the chromatome, highlight the importance of its alterations as a driving force in human disease (and particularly in cancer), and discuss the different approaches to systematically characterize the chromatin-bound proteome in a global manner. -
A Central Role for Canonical PRC1 in Shaping the 3D Nuclear Landscape
Downloaded from genesdev.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press A central role for canonical PRC1 in shaping the 3D nuclear landscape Shelagh Boyle,2 Ilya M. Flyamer,2 Iain Williamson, Dipta Sengupta, Wendy A. Bickmore, and Robert S. Illingworth1 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom Polycomb group (PcG) proteins silence gene expression by chemically and physically modifying chromatin. A subset of PcG target loci are compacted and cluster in the nucleus; a conformation that is thought to contribute to gene silencing. However, how these interactions influence gross nuclear organization and their relationship with tran- scription remains poorly understood. Here we examine the role of Polycomb-repressive complex 1 (PRC1) in shaping 3D genome organization in mouse embryonic stem cells (mESCs). Using a combination of imaging and Hi-C anal- yses, we show that PRC1-mediated long-range interactions are independent of CTCF and can bridge sites at a megabase scale. Impairment of PRC1 enzymatic activity does not directly disrupt these interactions. We demon- strate that PcG targets coalesce in vivo, and that developmentally induced expression of one of the target loci dis- rupts this spatial arrangement. Finally, we show that transcriptional activation and the loss of PRC1-mediated interactions are separable events. These findings provide important insights into the function of PRC1, while highlighting the complexity of this regulatory system. [Keywords: polycomb; topologically associating domains (TADs); gene repression; nuclear organization; embryonic stem cells; gene regulation; epigenetics; histone modifications] Supplemental material is available for this article. -
Understanding Regulatory Mechanisms Underlying Stem Cells Helps to Identify Cancer Biomarkers
Understanding Regulatory Mechanisms Underlying Stem Cells Helps to Identify Cancer Biomarkers A dissertation submitted towards the degree Doctor of Engineering (Dr.-Ing) of the Faculty of Mathematics and Computer Science of Saarland University by Maryam Nazarieh Saarbrücken, June 2018 i iii Day of Colloquium Jun 28, 2018 Dean of the Faculty Prof. Dr. Sebastian Hack Chair of the Committee Prof. Dr. Hans-Peter Lenhof Reporters First reviewer Prof. Dr. Volkhard Helms Second reviewer Prof. Dr. Dr. Thomas Lengauer Academic Assistant Dr. Christina Backes Acknowledgements Firstly, I would like to thank Prof. Volkhard Helms for offering me a position at his group and for his supervision and support on the SFB 1027 project. I am grateful to Prof. Thomas Lengauer for his helpful comments. I am thankful to Prof. Andreas Wiese for his contribution and discussion. I would like to thank Prof. Jan Baumbach that allowed me to spend a training phase in his group during my PhD preparatory phase and the collaborative work which I performed with his PhD student Rashid Ibragimov where I proposed a heuristic algorithm based on the characteristics of protein-protein interaction networks for solving the graph edit dis- tance problem. I would like to thank Graduate School of Computer Science and Center for Bioinformatics at Saarland University, especially Prof. Raimund Seidel and Dr. Michelle Carnell for giving me an opportunity to carry out my PhD studies. Furthermore, I would like to thank to Prof. Helms for enhancing my experience by intro- ducing master students and working as their advisor for successfully accomplishing their master projects. -
Table S1. 103 Ferroptosis-Related Genes Retrieved from the Genecards
Table S1. 103 ferroptosis-related genes retrieved from the GeneCards. Gene Symbol Description Category GPX4 Glutathione Peroxidase 4 Protein Coding AIFM2 Apoptosis Inducing Factor Mitochondria Associated 2 Protein Coding TP53 Tumor Protein P53 Protein Coding ACSL4 Acyl-CoA Synthetase Long Chain Family Member 4 Protein Coding SLC7A11 Solute Carrier Family 7 Member 11 Protein Coding VDAC2 Voltage Dependent Anion Channel 2 Protein Coding VDAC3 Voltage Dependent Anion Channel 3 Protein Coding ATG5 Autophagy Related 5 Protein Coding ATG7 Autophagy Related 7 Protein Coding NCOA4 Nuclear Receptor Coactivator 4 Protein Coding HMOX1 Heme Oxygenase 1 Protein Coding SLC3A2 Solute Carrier Family 3 Member 2 Protein Coding ALOX15 Arachidonate 15-Lipoxygenase Protein Coding BECN1 Beclin 1 Protein Coding PRKAA1 Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 Protein Coding SAT1 Spermidine/Spermine N1-Acetyltransferase 1 Protein Coding NF2 Neurofibromin 2 Protein Coding YAP1 Yes1 Associated Transcriptional Regulator Protein Coding FTH1 Ferritin Heavy Chain 1 Protein Coding TF Transferrin Protein Coding TFRC Transferrin Receptor Protein Coding FTL Ferritin Light Chain Protein Coding CYBB Cytochrome B-245 Beta Chain Protein Coding GSS Glutathione Synthetase Protein Coding CP Ceruloplasmin Protein Coding PRNP Prion Protein Protein Coding SLC11A2 Solute Carrier Family 11 Member 2 Protein Coding SLC40A1 Solute Carrier Family 40 Member 1 Protein Coding STEAP3 STEAP3 Metalloreductase Protein Coding ACSL1 Acyl-CoA Synthetase Long Chain Family Member 1 Protein -
Live-Cell Single Particle Tracking of PRC1 Reveals a Highly Dynamic System with Low Target Site Occupancy ✉ Miles K
ARTICLE https://doi.org/10.1038/s41467-021-21130-6 OPEN Live-cell single particle tracking of PRC1 reveals a highly dynamic system with low target site occupancy ✉ Miles K. Huseyin 1 & Robert J. Klose 1 Polycomb repressive complex 1 (PRC1) is an essential chromatin-based repressor of gene transcription. How PRC1 engages with chromatin to identify its target genes and achieve gene 1234567890():,; repression remains poorly defined, representing a major hurdle to our understanding of Polycomb system function. Here, we use genome engineering and single particle tracking to dissect how PRC1 binds to chromatin in live mouse embryonic stem cells. We observe that PRC1 is highly dynamic, with only a small fraction stably interacting with chromatin. By integrating subunit-specific dynamics, chromatin binding, and abundance measurements, we discover that PRC1 exhibits low occupancy at target sites. Furthermore, we employ pertur- bation approaches to uncover how specific components of PRC1 define its kinetics and chromatin binding. Together, these discoveries provide a quantitative understanding of chromatin binding by PRC1 in live cells, suggesting that chromatin modification, as opposed to PRC1 complex occupancy, is central to gene repression. ✉ 1 Department of Biochemistry, University of Oxford, Oxford, United Kingdom. email: [email protected] NATURE COMMUNICATIONS | (2021) 12:887 | https://doi.org/10.1038/s41467-021-21130-6 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21130-6 ukaryotic DNA is wrapped around histones to form information about the mechanisms that enable specific PRC1 nucleosomes and chromatin that organise and package the complexes to bind chromatin. -
Spotting Genome-Wide Pigmentation Variation in a Brown Trout Admixture Context
bioRxiv preprint doi: https://doi.org/10.1101/2020.07.23.217109; this version posted July 25, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Admixture and pigmentation in the brown trout 1 Spotting genome-wide pigmentation variation in 2 a brown trout admixture context 3 4 5 6 T. VALETTE1*, M. LEITWEIN 1,4*, J.-M. LASCAUX2, E. DESMARAIS1, 7 P. BERREBI1,3 & B. GUINAND1# 8 9 10 11 12 1 : UMR ISEM - CNRS IRD UM EPHE – Montpellier, France 13 2 : ECOGEA – 352 Avenue Roger Tissandié - Muret, France 14 3 : GENOME – Recherche et Diagnostic, 697 Avenue de Lunel – Saint Just, France 15 4 : present address : Institut de Biologie Intégrative et des Systèmes (IBIS), Université Laval, 16 Québec, Canada 17 18 19 * : contributed equally 20 21 22 # : correspondence: [email protected] 23 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.23.217109; this version posted July 25, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Admixture and pigmentation in the brown trout 24 ABSTRACT 25 Colour and pigmentation variation attracted fish biologists for a while, but high-throughput 26 genomic studies investigating the molecular basis of body pigmentation remain still limited to 27 few species and conservation biology issues ignored. -
Evolving Role of RING1 and YY1 Binding Protein in the Regulation of Germ-Cell-Specific Transcription
G C A T T A C G G C A T genes Review Evolving Role of RING1 and YY1 Binding Protein in the Regulation of Germ-Cell-Specific Transcription Izabella Bajusz 1,*, Surya Henry 1,2, Enik˝oSutus 1,2, Gerg˝oKovács 1 and Melinda K. Pirity 1,* 1 Biological Research Centre, Temesvári krt. 62, H-6726 Szeged, Hungary; [email protected] (S.H.); [email protected] (E.S.); [email protected] (G.K.) 2 Doctoral School of Biology, Faculty of Science and Informatics University of Szeged, Dugonics tér 13, H-6720 Szeged, Hungary * Correspondence: [email protected] (I.B.); [email protected] (M.K.P.); Tel.: +36-62-599-520 (I.B.); +36-62-599-683 (M.K.P.) Received: 7 October 2019; Accepted: 14 November 2019; Published: 19 November 2019 Abstract: Separation of germline cells from somatic lineages is one of the earliest decisions of embryogenesis. Genes expressed in germline cells include apoptotic and meiotic factors, which are not transcribed in the soma normally, but a number of testis-specific genes are active in numerous cancer types. During germ cell development, germ-cell-specific genes can be regulated by specific transcription factors, retinoic acid signaling and multimeric protein complexes. Non-canonical polycomb repressive complexes, like ncPRC1.6, play a critical role in the regulation of the activity of germ-cell-specific genes. RING1 and YY1 binding protein (RYBP) is one of the core members of the ncPRC1.6. Surprisingly, the role of Rybp in germ cell differentiation has not been defined yet. -
RING1B Is an Autoinhibited RING E3 Ubiquitin Ligase
ARTICLE Received 14 Oct 2014 | Accepted 26 May 2015 | Published 7 Jul 2015 DOI: 10.1038/ncomms8621 BMI1–RING1B is an autoinhibited RING E3 ubiquitin ligase Asad M. Taherbhoy1,w, Oscar W. Huang1 & Andrea G. Cochran1 Polycomb repressive complex 1 (PRC1) is required for ubiquitination of histone H2A lysine 119, an epigenetic mark associated with repression of genes important in developmental regulation. The E3 ligase activity of PRC1 resides in the RING1A/B subunit when paired with one of six PCGF partners. The best known of these is the oncogene BMI1/PCGF4. We find that canonical PRC1 E3 ligases such as PCGF4–RING1B have intrinsically very low enzymatic activity compared with non-canonical PRC1 RING dimers. The structure of a high-activity variant in complex with E2 (PCGF5–RING1B–UbcH5c) reveals only subtle differences from an earlier PCGF4 complex structure. However, two charged residues present in the modelled interface with E2-conjugated ubiquitin prove critical: in BMI1/PCGF4, these residues form a salt bridge that may limit efficient ubiquitin transfer. The intrinsically low activity of the PCGF4–RING1B heterodimer is offset by a relatively favourable interaction with nucleosome substrates, resulting in an efficient site-specific monoubiquitination. 1 Department of Early Discovery Biochemistry, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA. w Present address: Nurix, Inc., 1700 Owens St. Suite 290, San Francisco, California 94158, USA. Correspondence and requests for materials should be addressed to A.G.C. (email: [email protected]). NATURE COMMUNICATIONS | 6:7621 | DOI: 10.1038/ncomms8621 | www.nature.com/naturecommunications 1 & 2015 Macmillan Publishers Limited. -
A Low-Density SNP Array for Analyzing Differential
Ferchaud et al. BMC Genomics 2014, 15:867 http://www.biomedcentral.com/1471-2164/15/867 METHODOLOGY ARTICLE Open Access A low-density SNP array for analyzing differential selection in freshwater and marine populations of threespine stickleback (Gasterosteus aculeatus) Anne-Laure Ferchaud1, Susanne H Pedersen1, Dorte Bekkevold2, Jianbo Jian3, Yongchao Niu3 and Michael M Hansen1* Abstract Background: The threespine stickleback (Gasterosteus aculeatus) has become an important model species for studying both contemporary and parallel evolution. In particular, differential adaptation to freshwater and marine environments has led to high differentiation between freshwater and marine stickleback populations at the phenotypic trait of lateral plate morphology and the underlying candidate gene Ectodysplacin (EDA). Many studies have focused on this trait and candidate gene, although other genes involved in marine-freshwater adaptation may be equally important. In order to develop a resource for rapid and cost efficient analysis of genetic divergence between freshwater and marine sticklebacks, we generated a low-density SNP (Single Nucleotide Polymorphism) array encompassing markers of chromosome regions under putative directional selection, along with neutral markers for background. Results: RAD (Restriction site Associated DNA) sequencing of sixty individuals representing two freshwater and onemarinepopulationledtotheidentificationof33,993SNPmarkers.Ninety-sixofthesewerechosenforthe low-density SNP array, among which 70 represented SNPs under putatively directional selection in freshwater vs. marine environments, whereas 26 SNPs were assumed to be neutral. Annotation of these regions revealed several genes that are candidates for affecting stickleback phenotypic variation, some of which have been observed in previous studies whereas others are new. Conclusions: We have developed a cost-efficient low-density SNP array that allows for rapid screening of polymorphisms in threespine stickleback.