Life Sciences Commons^™

Genes Adapt To Outsmart Gene-Targeting Strategies In Mutant Mouse Strains By Skipping Exons To Reinitiate Transcription And Translation., Vishnu Hosur, Benjamin E. Low, Daniel Li, Grace Stafford, Vivek Kohar, Leonard D. Shultz, Michael V. Wiles

Faculty Research 2020

BACKGROUND: Gene disruption in mouse embryonic stem cells or zygotes is a conventional genetics approach to identify gene function in vivo. However, because different gene disruption strategies use different mechanisms to disrupt genes, the strategies can result in diverse phenotypes in the resulting mouse model. To determine whether different gene disruption strategies affect the phenotype of resulting mutant mice, we characterized Rhbdf1 mouse mutant strains generated by three commonly used strategies-definitive-null, targeted knockout (KO)-first, and CRISPR/Cas9.

RESULTS: We find that Rhbdf1 responds differently to distinct KO strategies, for example, by skipping exons and reinitiating translation to potentially yield gain-of-function alleles …

3d-Gnome 2.0: A Three-Dimensional Genome Modeling Engine For Predicting Structural Variation-Driven Alterations Of Chromatin Spatial Structure In The Human Genome., Michal Wlasnowolski, Michal Sadowski, Tymon Czarnota, Karolina Jodkowska, Przemyslaw Szalaj, Zhonghui Tang, Yijun Ruan, Dariusz Plewczynski

Faculty Research 2020

Structural variants (SVs) that alter DNA sequence emerge as a driving force involved in the reorganisation of DNA spatial folding, thus affecting gene transcription. In this work, we describe an improved version of our integrated web service for structural modeling of three-dimensional genome (3D-GNOME), which now incorporates all types of SVs to model changes to the reference 3D conformation of chromatin. In 3D-GNOME 2.0, the default reference 3D genome structure is generated using ChIA-PET data from the GM12878 cell line and SVs data are sourced from the population-scale catalogue of SVs identified by the 1000 Genomes Consortium. However, users may …

Crispr Artificial Splicing Factors., Menghan Du, Nathaniel L. Jillette, Jacqueline Jufen Zhu, Sheng Li, Albert Wu Cheng

Faculty Research 2020

Alternative splicing allows expression of mRNA isoforms from a single gene, expanding the diversity of the proteome. Its prevalence in normal biological and disease processes warrant precise tools for modulation. Here we report the engineering of CRISPR Artificial Splicing Factors (CASFx) based on RNA-targeting CRISPR-Cas systems. We show that simultaneous exon inclusion and exclusion can be induced at distinct targets by differential positioning of CASFx. We also create inducible CASFx (iCASFx) using the FKBP-FRB chemical-inducible dimerization domain, allowing small molecule control of alternative splicing. Finally, we demonstrate the activation of SMN2 exon 7 splicing in spinal muscular atrophy (SMA) patient …

A Cancer Drug Atlas Enables Synergistic Targeting Of Independent Drug Vulnerabilities., Ravi S Narayan, Piet Molenaar, Jian Teng, Fleur M G Cornelissen, Irene Roelofs, Renee Menezes, Rogier Dik, Tonny Lagerweij, Yoran Broersma, Naomi Petersen, Jhon Alexander Marin Soto, Eelke Brands, Philip Van Kuiken, Maria C Lecca, Kristiaan J Lenos, Sjors G J G In 'T Veld, Wessel Van Wieringen, Frederick F Lang, Erik Sulman, Roel G W Verhaak, Brigitta G Baumert, Lucas J A Stalpers, Louis Vermeulen, Colin Watts, David Bailey, Ben J Slotman, Rogier Versteeg, David Noske, Peter Sminia, Bakhos A Tannous, Tom Wurdinger, Jan Koster, Bart A Westerman

Faculty Research 2020

Personalized cancer treatments using combinations of drugs with a synergistic effect is attractive but proves to be highly challenging. Here we present an approach to uncover the efficacy of drug combinations based on the analysis of mono-drug effects. For this we used dose-response data from pharmacogenomic encyclopedias and represent these as a drug atlas. The drug atlas represents the relations between drug effects and allows to identify independent processes for which the tumor might be particularly vulnerable when attacked by two drugs. Our approach enables the prediction of combination-therapy which can be linked to tumor-driving mutations. By using this strategy, …

Controlling The Growth Of The Skin Commensal Staphylococcus Epidermidis Using D-Alanine Auxotrophy., David Dodds, Jeffrey L Bose, Ming-De Deng, Gilles R Dubé, Trudy H Grossman, Alaina Kaiser, Kashmira Kulkarni, Roger Leger, Sara Mootien-Boyd, Azim Munivar, Julia Oh, Matthew Pestrak, Komal Rajpura, Alexander P Tikhonov, Traci Turecek, Travis Whitfill

Faculty Research 2020

Using live microbes as therapeutic candidates is a strategy that has gained traction across multiple therapeutic areas. In the skin, commensal microorganisms play a crucial role in maintaining skin barrier function, homeostasis, and cutaneous immunity. Alterations of the homeostatic skin microbiome are associated with a number of skin diseases. Here, we present the design of an engineered commensal organism, Staphylococcus epidermidis, for use as a live biotherapeutic product (LBP) candidate for skin diseases. The development of novel bacterial strains whose growth can be controlled without the use of antibiotics or genetic elements conferring antibiotic resistance enables modulation of therapeutic …

A Novel Chemically Differentiated Mouse Embryonic Stem Cell-Based Model To Study Liver Stages Of Plasmodium Berghei., Jaishree Tripathi, Charis-Patricia Segeritz, Gareth Griffiths, Wendy Bushell, Ludovic Vallier, William C Skarnes, Maria M Mota, Oliver Billker

Faculty Research 2020

Asymptomatic and obligatory liver stage (LS) infection of Plasmodium parasites presents an attractive target for antimalarial vaccine and drug development. Lack of robust cellular models to study LS infection has hindered the discovery and validation of host genes essential for intrahepatic parasite development. Here, we present a chemically differentiated mouse embryonic stem cell (ESC)-based LS model, which supports complete development of Plasmodium berghei exoerythrocytic forms (EEFs) and can be used to define new host-parasite interactions. Using our model, we established that host Pnpla2, coding for adipose triglyceride lipase, is dispensable for P. berghei EEF development. In addition, we also evaluated …

Covid-19 Preclinical Models: Human Angiotensin-Converting Enzyme 2 Transgenic Mice., Cathleen Lutz, Leigh Maher, Charles Lee, Wonyoung Kang

Faculty Research 2020

Coronavirus disease 2019 (COVID-19) is a declared pandemic that is spreading all over the world at a dreadfully fast rate. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the pathogen of COVID-19, infects the human body using angiotensin-converting enzyme 2 (ACE2) as a receptor identical to the severe acute respiratory syndrome (SARS) pandemic that occurred in 2002-2003. SARS-CoV-2 has a higher binding affinity to human ACE2 than to that of other species. Animal models that mimic the human disease are highly essential to develop therapeutics and vaccines against COVID-19. Here, we review transgenic mice that express human ACE2 in the airway and …

V-Sva: An R Shiny Application For Detecting And Annotating Hidden Sources Of Variation In Single-Cell Rna-Seq Data., Nathan Lawlor, Eladio J Marquez, Donghyung Lee, Duygu Ucar

Faculty Research 2020

SUMMARY: Single-cell RNA-sequencing (scRNA-seq) technology enables studying gene expression programs from individual cells. However, these data are subject to diverse sources of variation, including 'unwanted' variation that needs to be removed in downstream analyses (e.g. batch effects) and 'wanted' or biological sources of variation (e.g. variation associated with a cell type) that needs to be precisely described. Surrogate variable analysis (SVA)-based algorithms, are commonly used for batch correction and more recently for studying 'wanted' variation in scRNA-seq data. However, interpreting whether these variables are biologically meaningful or stemming from technical reasons remains a challenge. To facilitate the interpretation of surrogate …

The Lethal Sex Gap: Covid-19., Eladio J Márquez, Jennifer J. Trowbridge, George A Kuchel, Jacques Banchereau, Duygu Ucar

Faculty Research 2020

While Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is disrupting lives across the globe for everyone, it has a more devastating impact on the health of older adults, especially that of older men. This pandemic has highlighted the crucial importance of considering an individual's age and biological sex in the clinic in addition to other confounding diseases (Kuchel, G.A, J Am Geriatr Soc, 67, 203, 2019, Tannenbaum, C., Nature, 575 451-458, 2009) As an interdisciplinary team of scientists in immunology, hematology, genomics, bioinformatics, and geriatrics, we have been studying how age and sex shape …

Chromatin Topology Reorganization And Transcription Repression By Pml-Rarα In Acute Promyeloid Leukemia., Ping Wang, Zhonghui Tang, Byoungkoo Lee, Jacqueline Jufen Zhu, Liuyang Cai, Przemyslaw Szalaj, Simon Zhongyuan Tian, Meizhen Zheng, Dariusz Plewczynski, Xiaoan Ruan, Edison T Liu, Chia-Lin Wei, Yijun Ruan

Faculty Research 2020

BACKGROUND: Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML-RARα, a major etiological agent in APL. However, the molecular mechanisms underlying the role of PML-RARα in leukemogenesis remain largely unknown.

RESULTS: Using an inducible system, we comprehensively analyze the 3D genome organization in myeloid cells and its reorganization after PML-RARα induction and perform additional analyses in patient-derived APL cells with native PML-RARα. We discover that PML-RARα mediates extensive chromatin interactions genome-wide. Globally, it redefines the chromatin topology of the myeloid genome toward a more condensed configuration in APL cells; locally, it intrudes RNAPII-associated interaction domains, interrupts myeloid-specific …

Metaboanalystr 3.0: Toward An Optimized Workflow For Global Metabolomics., Zhiqiang Pang, Jasmine Chong, Shuzhao Li, Jianguo Xia

Faculty Research 2020

Liquid chromatography coupled to high-resolution mass spectrometry platforms are increasingly employed to comprehensively measure metabolome changes in systems biology and complex diseases. Over the past decade, several powerful computational pipelines have been developed for spectral processing, annotation, and analysis. However, significant obstacles remain with regard to parameter settings, computational efficiencies, batch effects, and functional interpretations. Here, we introduce MetaboAnalystR 3.0, a significantly improved pipeline with three key new features: (1) efficient parameter optimization for peak picking; (2) automated batch effect correction; and 3) more accurate pathway activity prediction. Our benchmark studies showed that this workflow was 20~100X faster compared to …

Ultrastructural Visualization Of 3d Chromatin Folding Using Volume Electron Microscopy And Dna In Situ Hybridization., Paweł Trzaskoma, Błażej Ruszczycki, Byoungkoo Lee, Katarzyna K Pels, Katarzyna Krawczyk, Grzegorz Bokota, Andrzej A Szczepankiewicz, Jesse Aaron, Agnieszka Walczak, Małgorzata A Śliwińska, Adriana Magalska, Michal Kadlof, Artur Wolny, Zofia Parteka, Sebastian Arabasz, Magdalena Kiss-Arabasz, Dariusz Plewczyński, Yijun Ruan, Grzegorz M Wilczyński

Faculty Research 2020

The human genome is extensively folded into 3-dimensional organization. However, the detailed 3D chromatin folding structures have not been fully visualized due to the lack of robust and ultra-resolution imaging capability. Here, we report the development of an electron microscopy method that combines serial block-face scanning electron microscopy with in situ hybridization (3D-EMISH) to visualize 3D chromatin folding at targeted genomic regions with ultra-resolution (5 × 5 × 30 nm in xyz dimensions) that is superior to the current super-resolution by fluorescence light microscopy. We apply 3D-EMISH to human lymphoblastoid cells at a 1.7 Mb segment of the genome and …

Parsmurf, A High-Performance Computing Tool For The Genome-Wide Detection Of Pathogenic Variants., Alessandro Petrini, Marco Mesiti, Max Schubach, Marco Frasca, Daniel Danis, Matteo Re, Giuliano Grossi, Luca Cappelletti, Tiziana Castrignanò, Peter N Robinson, Giorgio Valentini

Faculty Research 2020

BACKGROUND: Several prediction problems in computational biology and genomic medicine are characterized by both big data as well as a high imbalance between examples to be learned, whereby positive examples can represent a tiny minority with respect to negative examples. For instance, deleterious or pathogenic variants are overwhelmed by the sea of neutral variants in the non-coding regions of the genome: thus, the prediction of deleterious variants is a challenging, highly imbalanced classification problem, and classical prediction tools fail to detect the rare pathogenic examples among the huge amount of neutral variants or undergo severe restrictions in managing big genomic …

Pybedgraph: A Python Package For Fast Operations On 1d Genomic Signal Tracks., Henry B Zhang, Minji Kim, Jeffrey Chuang, Yijun Ruan

Faculty Research 2020

MOTIVATION: Modern genomic research is driven by next-generation sequencing experiments such as ChIP-seq and ChIA-PET that generate coverage files for transcription factor binding, as well as DHS and ATAC-seq that yield coverage files for chromatin accessibility. Such files are in a bedGraph text format or a bigWig binary format. Obtaining summary statistics in a given region is a fundamental task in analyzing protein binding intensity or chromatin accessibility. However, the existing Python package for operating on coverage files is not optimized for speed.

RESULTS: We developed pyBedGraph, a Python package to quickly obtain summary statistics for a given interval in …

An Improved Phenotype-Driven Tool For Rare Mendelian Variant Prioritization: Benchmarking Exomiser On Real Patient Whole-Exome Data., Valentina Cipriani, Nikolas Pontikos, Gavin Arno, Panagiotis I Sergouniotis, Eva Lenassi, Penpitcha Thawong, Daniel Danis, Michel Michaelides, Andrew R Webster, Anthony T Moore, Peter N Robinson, Julius O B Jacobsen, Damian Smedley

Faculty Research 2020

Next-generation sequencing has revolutionized rare disease diagnostics, but many patients remain without a molecular diagnosis, particularly because many candidate variants usually survive despite strict filtering. Exomiser was launched in 2014 as a Java tool that performs an integrative analysis of patients' sequencing data and their phenotypes encoded with Human Phenotype Ontology (HPO) terms. It prioritizes variants by leveraging information on variant frequency, predicted pathogenicity, and gene-phenotype associations derived from human diseases, model organisms, and protein-protein interactions. Early published releases of Exomiser were able to prioritize disease-causative variants as top candidates in up to 97% of simulated whole-exomes. The size of …

Antibody Targeting Of B7-H4 Enhances The Immune Response In Urothelial Carcinoma., Joseph R Podojil, Alexander P Glaser, Dylan Baker, Elise T Courtois, Damiano Fantini, Yanni Yu, Valerie Eaton, Santhosh Sivajothi, Mingyi Chiang, Arighno Das, Kimberly A Mclaughlin, Paul Robson, Stephen D Miller, Joshua J Meeks

Faculty Research 2020

Patients with locally advanced and metastatic urothelial carcinoma have a low survival rate (median 15.7 months, 13.1-17.8), with only a 23% response rate to monotherapy treatment with anti-PDL1 checkpoint immunotherapy. To identify new therapeutic targets, we profiled the immune regulatory signatures during murine cancer development using the BBN carcinogen and identified an increase in the expression of the T cell inhibitory protein B7-H4 (VTCN1, B7S1, B7X). B7-H4 expression temporally correlated with decreased lymphocyte infiltration. While the increase in B7-H4 expression within the bladder by CD11b

Sensitivity Of Comorbidity Network Analysis., Jason Cory Brunson, Thomas P Agresta, Reinhard Laubenbacher

Faculty Research 2020

Objectives: Comorbidity network analysis (CNA) is a graph-theoretic approach to systems medicine based on associations revealed from disease co-occurrence data. Researchers have used CNA to explore epidemiological patterns, differentiate populations, characterize disorders, and more; but these techniques have not been comprehensively evaluated. Our objectives were to assess the stability of common CNA techniques.

Materials and Methods: We obtained seven co-occurrence data sets, most from previous CNAs, coded using several ontologies. We constructed comorbidity networks under various modeling procedures and calculated summary statistics and centrality rankings. We used regression, ordination, and rank correlation to assess these properties' sensitivity to the source …

Genome-Wide Characterization Of Cytosine-Specific 5-Hydroxymethylation In Normal Breast Tissue., Owen M Wilkins, Kevin C Johnson, E Andres Houseman, Jessica E King, Carmen J Marsit, Brock C Christensen

Faculty Research 2020

Despite recent evidence that 5-hydroxymethylcytosine (5hmC) possesses roles in gene regulation distinct from 5-methylcytosine (5mC), relatively little is known regarding the functions of 5hmC in mammalian tissues. To address this issue, we utilized an approach combining both paired bisulfite (BS) and oxidative bisulfite (oxBS) DNA treatment, to resolve genome-wide patterns of 5hmC and 5mC in normal breast tissue from disease-free women. Although less abundant than 5mC, 5hmC was differentially distributed, and consistently enriched among breast-specific enhancers and transcriptionally active chromatin. In contrast, regulatory regions associated with transcriptional inactivity, such as heterochromatin and repressed Polycomb regions, were relatively depleted of 5hmC. …

Systems Biology Of Ferroptosis: A Modeling Approach., Anna Konstorum, Lia Tesfay, Bibbin T Paul, Frank M Torti, Reinhard Laubenbacher, Suzy V Torti

Faculty Research 2020

Ferroptosis is a recently discovered form of iron-dependent regulated cell death (RCD) that occurs via peroxidation of phospholipids containing polyunsaturated fatty acid (PUFA) moieties. Activating this form of cell death is an emerging strategy in cancer treatment. Because multiple pathways and molecular species contribute to the ferroptotic process, predicting which tumors will be sensitive to ferroptosis is a challenge. We thus develop a mathematical model of several critical pathways to ferroptosis in order to perform a systems-level analysis of the process. We show that sensitivity to ferroptosis depends on the activity of multiple upstream cascades, including PUFA incorporation into the …

Lats Kinase-Mediated Ctcf Phosphorylation And Selective Loss Of Genomic Binding., Huacheng Luo, Qin Yu, Yang Liu, Ming Tang, Mingwei Liang, Dingpeng Zhang, Tsan Sam Xiao, Lizi Wu, Ming Tan, Yijun Ruan, Jörg Bungert, Jianrong Lu

Faculty Research 2020

Chromatin topological organization is instrumental in gene transcription. Gene-enhancer interactions are accommodated in the same CTCF-mediated insulated neighborhoods. However, it remains poorly understood whether and how the 3D genome architecture is dynamically restructured by external signals. Here, we report that LATS kinases phosphorylated CTCF in the zinc finger (ZF) linkers and disabled its DNA-binding activity. Cellular stress induced LATS nuclear translocation and CTCF ZF linker phosphorylation, and altered the landscape of CTCF genomic binding partly by dissociating it selectively from a small subset of its genomic binding sites. These sites were highly enriched for the boundaries of chromatin domains containing …

A Universal, Genomewide Guidefinder For Crispr/Cas9 Targeting In Microbial Genomes., Michelle Spoto, Changhui Guan, Elizabeth Fleming, Julia Oh

Faculty Research 2020

The CRISPR/Cas system has significant potential to facilitate gene editing in a variety of bacterial species. CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) represent modifications of the CRISPR/Cas9 system utilizing a catalytically inactive Cas9 protein for transcription repression and activation, respectively. While CRISPRi and CRISPRa have tremendous potential to systematically investigate gene function in bacteria, few programs are specifically tailored to identify guides in draft bacterial genomes genomewide. Furthermore, few programs offer open-source code with flexible design parameters for bacterial targeting. To address these limitations, we created GuideFinder, a customizable, user-friendly program that can design guides for any annotated bacterial …

Sexual-Dimorphism In Human Immune System Aging., Eladio J Márquez, Cheng-Han Chung, Radu Marches, Robert J Rossi, Djamel Nehar-Belaid, Alper Eroglu, David J Mellert, George A Kuchel, Jacques Banchereau, Duygu Ucar

Faculty Research 2020

Differences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22-93 years of age using ATAC-seq, RNA-seq, and flow cytometry. These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte and cytotoxic cell functions. These changes are greater in magnitude in men and accompanied by a male-specific decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between …

Significantly Different Clinical Phenotypes Associated With Mutations In Synthesis And Transamidase+Remodeling Glycosylphosphatidylinositol (Gpi)-Anchor Biosynthesis Genes., Leigh Carmody, Hannah Blau, Daniel Danis, Xingman A Zhang, Jean-Philippe Gourdine, Nicole Vasilevsky, Peter Krawitz, Miles D Thompson, Peter N Robinson

Faculty Research 2020

BACKGROUND: Defects in the glycosylphosphatidylinositol (GPI) biosynthesis pathway can result in a group of congenital disorders of glycosylation known as the inherited GPI deficiencies (IGDs). To date, defects in 22 of the 29 genes in the GPI biosynthesis pathway have been identified in IGDs. The early phase of the biosynthetic pathway assembles the GPI anchor (Synthesis stage) and the late phase transfers the GPI anchor to a nascent peptide in the endoplasmic reticulum (ER) (Transamidase stage), stabilizes the anchor in the ER membrane using fatty acid remodeling and then traffics the GPI-anchored protein to the cell surface (Remodeling stage).

RESULTS: …

Molecular And Clonal Evolution In Recurrent Metastatic Gliosarcoma., Kevin J Anderson, Aaron C Tan, Jonathon Parkinson, Michael Back, Marina Kastelan, Allison Newey, Janice Brewer, Helen Wheeler, Amanda L Hudson, Samirkumar B Amin, Kevin C Johnson, Floris P Barthel, Roel G W Verhaak, Mustafa Khasraw

Faculty Research 2020

We discuss the molecular evolution of gliosarcoma, a mesenchymal type of glioblastoma (GBM), using the case of a 37-yr-old woman who developed two recurrences and an extracranial metastasis. She was initially diagnosed with isocitrate dehydrogenase (IDH) wild-type gliosarcoma in the frontal lobe and treated with surgery followed by concurrent radiotherapy with temozolomide. Five months later the tumor recurred in the left frontal lobe, outside the initially resected area, and was treated with further surgery and radiotherapy. Six months later the patient developed a second left frontal recurrence and was again treated with surgery and radiotherapy. Six weeks later, further recurrence …

Transplanting Cells From Old But Not Young Donors Causes Physical Dysfunction In Older Recipients., Binsheng Wang, Zukai Liu, Vicky P Chen, Lichao Wang, Christina L Inman, Yueying Zhou, Chun Guo, Tamar Tchkonia, David W Rowe, George A Kuchel, Paul Robson, James L Kirkland, Ming Xu

Faculty Research 2020

Adipose-derived mesenchymal stem cell (ADSC)-based regenerative therapies have shown potential for use in many chronic diseases. Aging diminishes stem cell regenerative potential, yet it is unknown whether stem cells from aged donors cause adverse effects in recipients. ADSCs can be obtained using minimally invasive approaches and possess low immunogenicity. Nevertheless, we found that transplanting ADSCs from old donors, but not those from young donors, induces physical dysfunction in older recipient mice. Using single-cell transcriptomic analysis, we identified a naturally occurring senescent cell-like population in ADSCs primarily from old donors that resembles in vitro-generated senescent cells with regard to a number …

Discovery Of A New Predominant Cytosine Dna Modification That Is Linked To Gene Expression In Malaria Parasites., Elie Hammam, Guruprasad Ananda, Ameya Sinha, Christine Scheidig-Benatar, Mylene Bohec, Peter R Preiser, Peter C Dedon, Artur Scherf, Shruthi S Vembar

Faculty Research 2020

DNA cytosine modifications are key epigenetic regulators of cellular processes in mammalian cells, with their misregulation leading to varied disease states. In the human malaria parasite Plasmodium falciparum, a unicellular eukaryotic pathogen, little is known about the predominant cytosine modifications, cytosine methylation (5mC) and hydroxymethylation (5hmC). Here, we report the first identification of a hydroxymethylcytosine-like (5hmC-like) modification in P. falciparum asexual blood stages using a suite of biochemical methods. In contrast to mammalian cells, we report 5hmC-like levels in the P. falciparum genome of 0.2-0.4%, which are significantly higher than the methylated cytosine (mC) levels of 0.01-0.05%. Immunoprecipitation of hydroxymethylated …

The Monarch Initiative In 2019: An Integrative Data And Analytic Platform Connecting Phenotypes To Genotypes Across Species., Kent A Shefchek, Nomi L Harris, Michael Gargano, Nicolas Matentzoglu, Deepak Unni, Matthew Brush, Daniel Keith, Tom Conlin, Nicole Vasilevsky, Xingmin Aaron Zhang, James P Balhoff, Larry Babb, Susan M. Bello, Hannah Blau, Yvonne Bradford, Seth Carbon, Leigh Carmody, Lauren E Chan, Valentina Cipriani, Alayne Cuzick, Maria D Rocca, Nathan Dunn, Shahim Essaid, Petra Fey, Chris Grove, Jean-Phillipe Gourdine, Ada Hamosh, Midori Harris, Ingo Helbig, Maureen Hoatlin, Marcin Joachimiak, Simon Jupp, Kenneth B Lett, Suzanna E Lewis, Craig Mcnamara, Zoë M Pendlington, Clare Pilgrim, Tim Putman, Vida Ravanmehr, Justin Reese, Erin Riggs, Sofia Robb, Paola Roncaglia, James Seager, Erik Segerdell, Morgan Similuk, Andrea L Storm, Courtney Thaxon, Anne Thessen, Julius O B Jacobsen, Julie A Mcmurry, Tudor Groza, Sebastian Köhler, Damian Smedley, Peter N Robinson, Christopher J Mungall, Melissa A Haendel, Monica C Munoz-Torres, David Osumi-Sutherland

Faculty Research 2020

In biology and biomedicine, relating phenotypic outcomes with genetic variation and environmental factors remains a challenge: patient phenotypes may not match known diseases, candidate variants may be in genes that haven't been characterized, research organisms may not recapitulate human or veterinary diseases, environmental factors affecting disease outcomes are unknown or undocumented, and many resources must be queried to find potentially significant phenotypic associations. The Monarch Initiative (https://monarchinitiative.org) integrates information on genes, variants, genotypes, phenotypes and diseases in a variety of species, and allows powerful ontology-based search. We develop many widely adopted ontologies that together enable sophisticated computational analysis, mechanistic discovery …

Methods For Comparative Chia-Pet And Hi-C Data Analysis., Dan Capurso, Zhonghui Tang, Yijun Ruan

Faculty Research 2020

The three-dimensional architecture of chromatin in the nucleus is important for genome regulation and function. Advanced high-throughput sequencing-based methods have been developed for capturing chromatin interactions (Hi-C, genome-wide chromosome conformation capture) or enriching for those involving a specific protein (ChIA-PET, chromatin interaction analysis with paired-end tag sequencing). There is widespread interest in utilizing and interpreting ChIA-PET and Hi-C. We review methods for comparative ChIA-PET and Hi-C data analysis and visualization. The topics reviewed include: downloading ChIA-PET and Hi-C data from the ENCODE and 4DN portals; processing ChIA-PET data using ChIA-PIPE; processing Hi-C data using Juicer or distiller and cooler; viewing …

Proceedings Of The Comprehensive Oncology Network Evaluating Rare Cns Tumors (Nci-Connect) Oligodendroglioma Workshop., Marta Penas-Prado, Jing Wu, Daniel P Cahill, Daniel J Brat, Joseph F Costello, Paul G Kluetz, J Gregory Cairncross, Martin Van Den Bent, Roel G W Verhaak, Orwa Aboud, Peter Burger, Susan M Chang, Christine Cordova, Raymond Y Huang, Lindsay S Rowe, Martin J B Taphoorn, Mark R Gilbert, Terri S Armstrong, Nci-Connect Oligodendr0glioma Worhshop

Faculty Research 2020

Background: Oligodendroglioma is a rare primary central nervous system (CNS) tumor with highly variable outcome and for which therapy is usually not curative. At present, little is known regarding the pathways involved with progression of oligodendrogliomas or optimal biomarkers for stratifying risk. Developing new therapies for this rare cancer is especially challenging. To overcome these challenges, the neuro-oncology community must be particularly innovative, seeking multi-institutional and international collaborations, and establishing partnerships with patients and advocacy groups thereby ensuring that each patient enrolled in a study is as informative as possible.

Methods: The mission of the National Cancer Institute's NCI-CONNECT program …