Digital Commons Network^™

Tonic Tcr Signaling Inversely Regulates The Basal Metabolism Of Cd4, Ashley A Viehmann Milam, Juliet M Bartleson, Michael D Buck, Chih-Hao Chang, Alexey Sergushichev, David L Donermeyer, Wing Y Lam, Erika L Pearce, Maxim N Artyomov, Paul M Allen

Faculty Research 2020

The contribution of self-peptide-MHC signaling in CD4

Mediastinal Lymphadenopathy, Class-Switched Auto-Antibodies And Myocardial Immune-Complexes During Heart Failure In Rodents And Humans., Amalia Sintou, Catherine Mansfield, Alma Iacob, Rasheda A Chowdhury, Salomon Narodden, Stephen M Rothery, Robert Podovei, Jose L Sanchez-Alonso, Elisa Ferraro, Pamela Swiatlowska, Sian E Harding, Sanjay Prasad, Nadia Rosenthal, Julia Gorelik, Susanne Sattler

Faculty Research 2020

Mediastinal lymphadenopathy and auto-antibodies are clinical phenomena during ischemic heart failure pointing to an autoimmune response against the heart. T and B cells have been convincingly demonstrated to be activated after myocardial infarction, a prerequisite for the generation of mature auto-antibodies. Yet, little is known about the immunoglobulin isotype repertoire thus pathological potential of anti-heart auto-antibodies during heart failure. We obtained human myocardial tissue from ischemic heart failure patients and induced experimental MI in rats. We found that anti-heart autoimmunity persists during heart failure. Rat mediastinal lymph nodes are enlarged and contain active secondary follicles with mature isotype-switched IgG2a B …

Genetic Variants And Functional Pathways Associated With Resilience To Alzheimer's Disease., Logan Dumitrescu, Emily R Mahoney, Shubhabrata Mukherjee, Michael L Lee, William S Bush, Corinne D Engelman, Qiongshi Lu, David W Fardo, Emily H Trittschuh, Jesse Mez, Catherine Kaczorowski, Hector Hernandez Saucedo, Keith F Widaman, Rachel Buckley, Michael Properzi, Elizabeth Mormino, Hyun-Sik Yang, Tessa Harrison, Trey Hedden, Kwangsik Nho, Shea J Andrews, Doug Tommet, Niran Hadad, R Elizabeth Sanders, Douglas M Ruderfer, Katherine A Gifford, Annah M Moore, Francis Cambronero, Xiaoyuan Zhong, Neha S Raghavan, Badri Vardarajan, Margaret A Pericak-Vance, Lindsay A Farrer, Li-San Wang, Carlos Cruchaga, Gerard Schellenberg, Nancy J Cox, Jonathan L Haines, C Dirk Keene, Andrew J Saykin, Eric B Larson, Reisa A Sperling, Richard Mayeux, David A Bennett, Julie A Schneider, Paul K Crane, Angela L Jefferson, Timothy J Hohman

Faculty Research 2020

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run …

Decoding The Mechanisms Underlying Cell-Fate Decision-Making During Stem Cell Differentiation By Random Circuit Perturbation., Bin Huang, Mingyang Lu, Madeline Galbraith, Herbert Levine, Jose N Onuchic, Dongya Jia

Faculty Research 2020

Stem cells can precisely and robustly undergo cellular differentiation and lineage commitment, referred to as stemness. However, how the gene network underlying stemness regulation reliably specifies cell fates is not well understood. To address this question, we applied a recently developed computational method, random circuit perturbation (RACIPE), to a nine-component gene regulatory network (GRN) governing stemness, from which we identified robust gene states. Among them, four out of the five most probable gene states exhibit gene expression patterns observed in single mouse embryonic cells at 32-cell and 64-cell stages. These gene states can be robustly predicted by …

Regulation Of Bmp4/Dpp Retrotranslocation And Signaling By Deglycosylation., Antonio Galeone, Joshua M Adams, Shinya Matsuda, Maximiliano F. Presa, Ashutosh Pandey, Seung Yeop Han, Yuriko Tachida, Hiroto Hirayama, Thomas Vaccari, Tadashi Suzuki, Cathleen M. Lutz, Markus Affolter, Aamir Zuberi, Hamed Jafar-Nejad

Faculty Research 2020

During endoplasmic reticulum-associated degradation (ERAD), the cytoplasmic enzyme N-glycanase 1 (NGLY1) is proposed to remove N-glycans from misfolded N-glycoproteins after their retrotranslocation from the ER to the cytosol. We previously reported that NGLY1 regulates Drosophila BMP signaling in a tissue-specific manner (Galeone et al., 2017). Here, we establish the Drosophila Dpp and its mouse ortholog BMP4 as biologically relevant targets of NGLY1 and find, unexpectedly, that NGLY1-mediated deglycosylation of misfolded BMP4 is required for its retrotranslocation. Accumulation of misfolded BMP4 in the ER results in ER stress and prompts the ER recruitment of NGLY1. The ER-associated NGLY1 …

Bayesian Model Selection Reveals Biological Origins Of Zero Inflation In Single-Cell Transcriptomics., Kwangbom Choi, Yang Chen, Daniel A Skelly, Gary A Churchill

Faculty Research 2020

BACKGROUND: Single-cell RNA sequencing is a powerful tool for characterizing cellular heterogeneity in gene expression. However, high variability and a large number of zero counts present challenges for analysis and interpretation. There is substantial controversy over the origins and proper treatment of zeros and no consensus on whether zero-inflated count distributions are necessary or even useful. While some studies assume the existence of zero inflation due to technical artifacts and attempt to impute the missing information, other recent studies argue that there is no zero inflation in scRNA-seq data.

RESULTS: We apply a Bayesian model selection approach to unambiguously demonstrate …

Nine Quick Tips For Efficient Bioinformatics Curriculum Development And Training., Susan Mcclatchy, Kristin M Bass, Daniel M. Gatti, Adam Moylan, Gary Churchill

Faculty Research 2020

Biomedical research is becoming increasingly data driven. New technologies that generate large-scale, complex data are continually emerging and evolving. As a result, there is a concurrent need for training researchers to use and understand new computational tools. Here we describe an efficient and effective approach to developing curriculum materials that can be deployed in a research environment to meet this need.

Lipidomic Profiling Of The Epidermis In A Mouse Model Of Dermatitis Reveals Sexual Dimorphism And Changes In Lipid Composition Before The Onset Of Clinical Disease., Jackeline Franco, Bartek Rajwa, Christina R Ferreira, John P Sundberg, Harm Hogenesch

Faculty Research 2020

Atopic dermatitis (AD) is a multifactorial disease associated with alterations in lipid composition and organization in the epidermis. Multiple variants of AD exist with different outcomes in response to therapies. The evaluation of disease progression and response to treatment are observational assessments with poor inter-observer agreement highlighting the need for molecular markers. SHARPIN-deficient mice (Sharpincpdm) spontaneously develop chronic proliferative dermatitis with features similar to AD in humans. To study the changes in the epidermal lipid-content during disease progression, we tested 72 epidermis samples from three groups (5-, 7-, and 10-weeks old) of cpdm mice and their WT littermates. …

Keratinocyte-Specific Deletion Of Sharpin Induces Atopic Dermatitis-Like Inflammation In Mice., John P Sundberg, C Herbert Pratt, Leslie P. Goodwin, Kathleen A Silva, Victoria E. Kennedy, Christopher S Potter, Anisa Dunham, Beth A. Sundberg, Harm Hogenesch

Faculty Research 2020

Spontaneous mutations in the SHANK-associated RH domain interacting protein (Sharpin) resulted in a severe autoinflammatory type of chronic proliferative dermatitis, inflammation in other organs, and lymphoid organ defects. To determine whether cell-type restricted loss of Sharpin causes similar lesions, a conditional null mutant was created. Ubiquitously expressing cre-recombinase recapitulated the phenotype seen in spontaneous mutant mice. Limiting expression to keratinocytes (using a Krt14-cre) induced a chronic eosinophilic dermatitis, but no inflammation in other organs or lymphoid organ defects. The dermatitis was associated with a markedly increased concentration of serum IgE and IL18. Crosses with S100a4-cre resulted in milder skin lesions …

Adad1 And Adad2, Testis-Specific Adenosine Deaminase Domain-Containing Proteins, Are Required For Male Fertility., Elizabeth Snyder, Lauren Chukrallah, Kelly Seltzer, Leslie Goodwin, Robert E Braun

Faculty Research 2020

Adenosine-to-inosine RNA editing, a fundamental RNA modification, is regulated by adenosine deaminase (AD) domain containing proteins. Within the testis, RNA editing is catalyzed by ADARB1 and is regulated in a cell-type dependent manner. This study examined the role of two testis-specific AD domain proteins, ADAD1 and ADAD2, on testis RNA editing and male germ cell differentiation. ADAD1, previously shown to localize to round spermatids, and ADAD2 had distinct localization patterns with ADAD2 expressed predominantly in mid- to late-pachytene spermatocytes suggesting a role for both in meiotic and post-meiotic germ cell RNA editing. AD domain analysis showed the AD domain of …

Meta-Analysis Of The Alzheimer's Disease Human Brain Transcriptome And Functional Dissection In Mouse Models., Ying-Wooi Wan, Rami Al-Ouran, Carl G Mangleburg, Thanneer M Perumal, Tom V Lee, Katherine Allison, Vivek Swarup, Cory C Funk, Chris Gaiteri, Mariet Allen, Minghui Wang, Sarah M Neuner, Catherine Kaczorowski, Vivek M. Philip, Gareth R Howell, Heidi Martini-Stoica, Hui Zheng, Hongkang Mei, Xiaoyan Zhong, Jungwoo Wren Kim, Valina L Dawson, Ted M Dawson, Ping-Chieh Pao, Li-Huei Tsai, Jean-Vianney Haure-Mirande, Michelle E Ehrlich, Paramita Chakrabarty, Yona Levites, Xue Wang, Eric B Dammer, Gyan Srivastava, Sumit Mukherjee, Solveig K Sieberts, Larsson Omberg, Kristen D Dang, James A Eddy, Phil Snyder, Yooree Chae, Sandeep Amberkar, Wenbin Wei, Winston Hide, Christoph Preuss, Ayla Ergun, Phillip J Ebert, David C Airey, Sara Mostafavi, Lei Yu, Hans-Ulrich Klein, Gregory W. Carter, David A Collier, Todd E Golde, Allan I Levey, David A Bennett, Karol Estrada, T Matthew Townsend, Bin Zhang, Eric Schadt, Philip L De Jager, Nathan D Price, Nilüfer Ertekin-Taner, Zhandong Liu, Joshua M Shulman, Lara M Mangravite, Benjamin A Logsdon

Faculty Research 2020

We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic …

Anti-Integrin Αv Therapy Improves Cardiac Fibrosis After Myocardial Infarction By Blunting Cardiac Pw1+ Stromal Cells., Marion Bouvet, Olivier Claude, Maguelonne Roux, Daniel A Skelly, Nihar Masurkar, Nathalie Mougenot, Sophie Nadaud, Catherine Blanc, Clément Delacroix, Solenne Chardonnet, Cédric Pionneau, Claire Perret, Elisa Yaniz-Galende, Nadia Rosenthal, David-Alexandre Trégouët, Giovanna Marazzi, Jean-Sébastien Silvestre, David Sassoon, Jean-Sébastien Hulot

Faculty Research 2020

There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. We have recently shown that cardiac fibrosis post-myocardial infarction (MI) can be regulated by resident cardiac cells with a fibrogenic signature and identified by the expression of PW1 (Peg3). Here we identify αV-integrin (CD51) as an essential regulator of cardiac PW1+ cells fibrogenic behavior. We used transcriptomic and proteomic approaches to identify specific cell-surface markers for cardiac PW1+ cells and found that αV-integrin (CD51) was expressed in almost all cardiac PW1+ cells (93% ± 1%), predominantly as the αVβ1 complex. αV-integrin is a subunit …

Discovery Of A Role For Rab3b In Habituation And Cocaine Induced Locomotor Activation In Mice Using Heterogeneous Functional Genomic Analysis, Jason A. Bubier, Vivek M. Philip, Price E. Dickson, Guy Mittleman, Elissa J Chesler

Faculty Research 2020

Substance use disorders are prevalent and present a tremendous societal cost but the mechanisms underlying addiction behavior are poorly understood and few biological treatments exist. One strategy to identify novel molecular mechanisms of addiction is through functional genomic experimentation. However, results from individual experiments are often noisy. To address this problem, the convergent analysis of multiple genomic experiments can discern signal from these studies. In the present study, we examine genetic loci that modulate the locomotor response to cocaine identified in the recombinant inbred (BXD RI) genetic reference population. We then applied the GeneWeaver software system for heterogeneous functional genomic …

The Membrane Protein Ankh Is Crucial For Bone Mechanical Performance By Mediating Cellular Export Of Citrate And Atp., Flora Szeri, Stefan Lundkvist, Sylvia Donnelly, Udo F H Engelke, Kyu Rhee, Charlene J Williams, John P Sundberg, Ron A Wevers, Ryan E Tomlinson, Robert S Jansen, Koen Van De Wetering

Faculty Research 2020

The membrane protein ANKH was known to prevent pathological mineralization of joints and was thought to export pyrophosphate (PPi) from cells. This did not explain, however, the presence of ANKH in tissues, such as brain, blood vessels and muscle. We now report that in cultured cells ANKH exports ATP, rather than PPi, and, unexpectedly, also citrate as a prominent metabolite. The extracellular ATP is rapidly converted into PPi, explaining the role of ANKH in preventing ankylosis. Mice lacking functional Ank (Ankank/ank mice) had plasma citrate concentrations that were 65% lower than those detected in wild type control animals. Consequently, citrate …

Innovations, Challenges, And Minimal Information For Standardization Of Humanized Mice., Renata Stripecke, Christian Münz, Jan Jacob Schuringa, Karl-Dimiter Bissig, Brian Soper, Terrence Meeham, Li-Chin Yao, James P Di Santo, Michael Brehm, Estefania Rodriguez, Anja Kathrin Wege, Dominique Bonnet, Silvia Guionaud, Kristina E Howard, Scott Kitchen, Florian Klein, Kourosh Saeb-Parsy, Johannes Sam, Amar Deep Sharma, Andreas Trumpp, Livio Trusolino, Carol J Bult, Leonard D. Shultz

Faculty Research 2020

Mice xenotransplanted with human cells and/or expressing human gene products (also known as "humanized mice") recapitulate the human evolutionary specialization and diversity of genotypic and phenotypic traits. These models can provide a relevant in vivo context for understanding of human-specific physiology and pathologies. Humanized mice have advanced toward mainstream preclinical models and are now at the forefront of biomedical research. Here, we considered innovations and challenges regarding the reconstitution of human immunity and human tissues, modeling of human infections and cancer, and the use of humanized mice for testing drugs or regenerative therapy products. As the number of publications exploring …

The Occurrence Of Tarsal Injuries In Male Mice Of C57bl/6n Substrains In Multiple International Mouse Facilities., Eleanor Herbert, Michelle Stewart, Marie Hutchison, Ann M Flenniken, Dawei Qu, Lauryl M J Nutter, Colin Mckerlie, Liane Hobson, Brenda Kick, Bonnie L. Lyons, Jean-Paul Wiegand, Rosalinda A. Doty, Juan Antonio Aguilar-Pimentel, Martin Hrabe De Angelis, Mary Dickinson, John Seavitt, Jacqueline K White, Cheryl L Scudamore, Sara Wells

Faculty Research 2020

Dislocation in hindlimb tarsals are being observed at a low, but persistent frequency in group-housed adult male mice from C57BL/6N substrains. Clinical signs included a sudden onset of mild to severe unilateral or bilateral tarsal abduction, swelling, abnormal hindlimb morphology and lameness. Contraction of digits and gait abnormalities were noted in multiple cases. Radiographical and histological examination revealed caudal dislocation of the calcaneus and partial dislocation of the calcaneoquartal (calcaneus-tarsal bone IV) joint. The detection, frequency, and cause of this pathology in five large mouse production and phenotyping centres (MRC Harwell, UK; The Jackson Laboratory, USA; The Centre for Phenogenomics, …

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 …

Gdnf Promotes Hair Formation And Cutaneous Wound Healing By Targeting Bulge Stem Cells., Thomas S Lisse, Manju Sharma, Neda Vishlaghi, Sri Ramulu N Pullagura, Robert E Braun

Faculty Research 2020

Glial-cell-derived neurotrophic factor (GDNF) is a well-studied neuroregenerative factor; however, the degree to which it supports hair formation and skin wound repair is not known. By using a Gfra1 (GDNF family receptor alpha 1) knock-in reporter mouse line, GDNF signaling was found to occur within hair bulge stem cells (BSCs) during the initiation of the hair cycle and early stages of hair formation after depilation. Both recombinant and transgene overexpression of GDNF promoted BSC colony growth, hair formation, and skin repair after wounding through enhanced self-renewal of BSCs and commitment of BSC-derived progenitors into becoming epidermal cells at the injury …

Facial Shape And Allometry Quantitative Trait Locus Intervals In The Diversity Outbred Mouse Are Enriched For Known Skeletal And Facial Development Genes., David C Katz, J David Aponte, Wei Liu, Rebecca M Green, Jessica M Mayeux, K Michael Pollard, Daniel Pomp, Steven C. Munger, Stephen A Murray, Charles C Roseman, Christopher J Percival, James Cheverud, Ralph S Marcucio, Benedikt Hallgrímsson

Faculty Research 2020

The biology of how faces are built and come to differ from one another is complex. Discovering normal variants that contribute to differences in facial morphology is one key to untangling this complexity, with important implications for medicine and evolutionary biology. This study maps quantitative trait loci (QTL) for skeletal facial shape using Diversity Outbred (DO) mice. The DO is a randomly outcrossed population with high heterozygosity that captures the allelic diversity of eight inbred mouse lines from three subspecies. The study uses a sample of 1147 DO animals (the largest sample yet employed for a shape QTL study in …

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 …

Integrated Analysis Of The Molecular Pathogenesis Of Fdxr-Associated Disease., Jesse D Slone, Li Yang, Yanyan Peng, Luis F Queme, Belinda S. Harris, Stacey J Sukoff Rizzo, Torrian Green, Jennifer L Ryan, Michael P Jankowski, Laura G Reinholdt, Taosheng Huang

Faculty Research 2020

The mitochondrial flavoprotein ferredoxin reductase (FDXR) is required for biogenesis of iron-sulfur clusters and for steroidogenesis. Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, and an increasing number of disorders are associated with disruptions in the synthesis of Fe-S clusters. Our previous studies have demonstrated that hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans and mice, attributed in part to reduced function of the electron transport chain (ETC) as well as elevated production of reactive oxygen species (ROS). Inflammation and peripheral neuropathy are also hallmarks of this disease. In this paper, we …

Ocular Hypertension Suppresses Homeostatic Gene Expression In Optic Nerve Head Microglia Of Dba/2 J Mice., James R Tribble, Jeffrey M. Harder, Pete A Williams, Simon W M John

Faculty Research 2020

Glaucoma is the leading cause of irreversible vision loss. Ocular hypertension is a major risk factor for glaucoma and recent work has demonstrated critical early neuroinflammatory insults occur in the optic nerve head following ocular hypertension. Microglia and infiltrating monocytes are likely candidates to drive these neuroinflammatory insults. However, the exact molecular identity / transcriptomic profile of microglia following ocular hypertensive insults is unknown. To elucidate the molecular identity of microglia after long-term exposure to ocular hypertension, we used a mouse model of glaucoma (DBA/2 J). We performed RNA-sequencing of microglia mRNA from the optic nerve head at a time …

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 …

Diverse Dystonin Gene Mutations Cause Distinct Patterns Of, Nozomu Yoshioka, Yudai Kabata, Momona Kuriyama, Norihisa Bizen, Li Zhou, Dang M Tran, Masato Yano, Atsushi Yoshiki, Tatsuo Ushiki, Thomas J. Sproule, Riichiro Abe, Hirohide Takebayashi

Faculty Research 2020

Loss-of-function mutations in dystonin (DST) can cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) or epidermolysis bullosa simplex (EBS). Recently, DST-related diseases were recognized to be more complex than previously thought because a patient exhibited both neurological and skin manifestations, whereas others display only one or the other. A single DST locus produces at least three major DST isoforms: DST-a (neuronal isoform), DST-b (muscular isoform) and DST-e (epithelial isoform). Dystonia musculorum (dt) mice, which have mutations in Dst, were originally identified as spontaneous mutants displaying neurological phenotypes. To reveal the mechanisms underlying the …

Unique Properties Of A Subset Of Human Pluripotent Stem Cells With High Capacity For Self-Renewal., Kevin X Lau, Elizabeth A Mason, Joshua Kie, David P De Souza, Joachim Kloehn, Dedreia Tull, Malcolm J Mcconville, Andrew Keniry, Tamara Beck, Marnie E Blewitt, Matthew E Ritchie, Shalin H Naik, Daniela Zalcenstein, Othmar Korn, Shian Su, Irene Gallego Romero, Catrina Spruce, Christopher L. Baker, Tracy C. Mcgarr, Christine A Wells, Martin Pera

Faculty Research 2020

Archetypal human pluripotent stem cells (hPSC) are widely considered to be equivalent in developmental status to mouse epiblast stem cells, which correspond to pluripotent cells at a late post-implantation stage of embryogenesis. Heterogeneity within hPSC cultures complicates this interspecies comparison. Here we show that a subpopulation of archetypal hPSC enriched for high self-renewal capacity (ESR) has distinct properties relative to the bulk of the population, including a cell cycle with a very low G1 fraction and a metabolomic profile that reflects a combination of oxidative phosphorylation and glycolysis. ESR cells are pluripotent and capable of differentiation into primordial germ cell-like …

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 …

Rapamycin Rejuvenates Oral Health In Aging Mice., Jonathan Y An, Kristopher A Kerns, Andrew R Ouellette, Laura Robinson, H Douglas Morris, Catherine Kaczorowski, So-Il Park, Title Mekvanich, Alex Kang, Jeffrey S Mclean, Timothy C Cox, Matt Kaeberlein

Faculty Research 2020

Periodontal disease is an age-associated disorder clinically defined by periodontal bone loss, inflammation of the specialized tissues that surround and support the tooth, and microbiome dysbiosis. Currently, there is no therapy for reversing periodontal disease, and treatment is generally restricted to preventive measures or tooth extraction. The FDA-approved drug rapamycin slows aging and extends lifespan in multiple organisms, including mice. Here, we demonstrate that short-term treatment with rapamycin rejuvenates the aged oral cavity of elderly mice, including regeneration of periodontal bone, attenuation of gingival and periodontal bone inflammation, and revertive shift of the oral microbiome toward a more youthful composition. …

Interaction Between Mas1 And At1ra Contributes To Enhancement Of Skeletal Muscle Angiogenesis By Angiotensin-(1-7) In Dahl Salt-Sensitive Rats., Eric C Exner, Aron M Geurts, Brian R Hoffmann, Marc Casati, Timothy Stodola, Nikita R Dsouza, Michael Zimmermann, Julian H Lombard, Andrew S Greene

Faculty Research 2020

The heptapeptide angiotensin-(1-7) (Ang-(1-7)) is protective in the cardiovascular system through its induction of vasodilator production and angiogenesis. Despite acting antagonistically to the effects of elevated, pathophysiological levels of angiotensin II (AngII), recent evidence has identified convergent and beneficial effects of low levels of both Ang-(1-7) and AngII. Previous work identified the AngII receptor type I (AT1R) as a component of the protein complex formed when Ang-(1-7) binds its receptor, Mas1. Importantly, pharmacological blockade of AT1R did not alter the effects of Ang-(1-7). Here, we use a novel mutation of AT1RA in the Dahl salt-sensitive (SS) rat to test the …

Toward Modeling Context-Specific Emt Regulatory Networks Using Temporal Single Cell Rna-Seq Data., Daniel Ramirez, Vivek Kohar, Mingyang Lu

Faculty Research 2020

Epithelial-mesenchymal transition (EMT) is well established as playing a crucial role in cancer progression and being a potential therapeutic target. To elucidate the gene regulation that drives the decision making of EMT, many previous studies have been conducted to model EMT gene regulatory circuits (GRCs) using interactions from the literature. While this approach can depict the generic regulatory interactions, it falls short of capturing context-specific features. Here, we explore the effectiveness of a combined bioinformatics and mathematical modeling approach to construct context-specific EMT GRCs directly from transcriptomics data. Using time-series single cell RNA-sequencing data from four different cancer cell lines …

An Intact C-Terminal End Of Albumin Is Required For Its Long Half-Life In Humans., Jeannette Nilsen, Esben Trabjerg, Algirdas Grevys, Claudia Azevedo, Stephen O Brennan, Maria Stensland, John J Wilson, Kine Marita Knudsen Sand, Malin Bern, Bjørn Dalhus, Derry C. Roopenian, Inger Sandlie, Kasper Dyrberg Rand, Jan Terje Andersen

Faculty Research 2020

Albumin has an average plasma half-life of three weeks and is thus an attractive carrier to improve the pharmacokinetics of fused therapeutics. The half-life is regulated by FcRn, a cellular receptor that protects against intracellular degradation. To tailor-design the therapeutic use of albumin, it is crucial to understand how structural alterations in albumin affect FcRn binding and transport properties. In the blood, the last C-terminal residue (L585) of albumin may be enzymatically cleaved. Here we demonstrate that removal of the L585 residue causes structural stabilization in regions of the principal FcRn binding domain and reduces receptor binding. In line with …