Genetics and Genomics Commons^™

Als Mutations Of Fus Suppress Protein Translation And Disrupt The Regulation Of Nonsense-Mediated Decay, Marisa Kamelgarn, Jing Chen, Lisha Kuang, Huan Jin, Edward J. Kasarskis, Haining Zhu

Toxicology and Cancer Biology Faculty Publications

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by preferential motor neuron death. Approximately 15% of ALS cases are familial, and mutations in the fused in sarcoma (FUS) gene contribute to a subset of familial ALS cases. FUS is a multifunctional protein participating in many RNA metabolism pathways. ALS-linked mutations cause a liquid–liquid phase separation of FUS protein in vitro, inducing the formation of cytoplasmic granules and inclusions. However, it remains elusive what other proteins are sequestered into the inclusions and how such a process leads to neuronal dysfunction and degeneration. In this study, we developed …

Dna Methylation By Restriction Modification Systems Affects The Global Transcriptome Profile In Borrelia Burgdorferi, Timothey Casselli, Yvonne Tourand, Adam Scheidegger, William K. Arnold, Anna Proulx, Brian Stevenson, Catherine A. Brissette

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Prokaryote restriction modification (RM) systems serve to protect bacteria from potentially detrimental foreign DNA. Recent evidence suggests that DNA methylation by the methyltransferase (MTase) components of RM systems can also have effects on transcriptome profiles. The type strain of the causative agent of Lyme disease, Borrelia burgdorferi B31, possesses two RM systems with N6-methyladenosine (m6A) MTase activity, which are encoded by the bbe02 gene located on linear plasmid lp25 and bbq67 on lp56. The specific recognition and/or methylation sequences had not been identified for either of these B. burgdorferi MTases, and it was not previously known whether these RM …

8th Annual Postdoctoral Science Symposium, University Of Texas Md Anderson Cancer Center Postdoctoral Association

Annual Postdoctoral Science Symposium Abstracts

The mission of the Annual Postdoctoral Science Symposium (APSS) is to provide a platform for talented postdoctoral fellows throughout the Texas Medical Center to present their work to a wider audience. The MD Anderson Postdoctoral Association convened its inaugural Annual Postdoctoral Science Symposium (APSS) on August 4, 2011.

The APSS provides a professional venue for postdoctoral scientists to develop, clarify, and refine their research as a result of formal reviews and critiques of faculty and other postdoctoral scientists. Additionally, attendees discuss current research on a broad range of subjects while promoting academic interactions and enrichment and developing new collaborations.

Genetic Determinants Of Telomere Length In African American Youth, Andrew M. Zeiger, Marquitta J. White, Celeste Eng, Sam S. Oh, Jonathan Witonsky, Pagé C. Goddard, Maria G. Contreras, Jennifer R. Elhawary, Donglei Hu, Angel C. Y. Mak, Eunice Y. Lee, Kevin L. Keys, Lesly-Anne Samedy, Oona Risse Adams, Joaquín Magaña, Scott Huntsman, Sandra Salazar, Adam Davis, Kelley Meade, Emerita Brigino-Buenaventura, Michael A. Lenoir, Harold J. Farber, Kirsten Bibbins-Domingo, Luisa N. Borrell, Esteban G. Burchard

Publications and Research

Telomere length (TL) is associated with numerous disease states and is affected by genetic and environmental factors. However, TL has been mostly studied in adult populations of European or Asian ancestry. These studies have identified 34 TL-associated genetic variants recently used as genetic proxies for TL. The generalizability of these associations to pediatric populations and racially diverse populations, specifically of African ancestry, remains unclear. Furthermore, six novel variants associated with TL in a population of European children have been identified but not validated. We measured TL from whole blood samples of 492 healthy African American youth (children and adolescents between …

Hypermethylation Of Mir21 In Cd4+ T Cells From Patients With Relapsing-Remitting Multiple Sclerosis Associates With Lower Mirna-21 Levels And Concomitant Up-Regulation Of Its Target Genes, Sabrina Ruhrmann, Ewoud Ewing, Eliane Piket, Lara Kular, Julio Cesar Cetrulo Lorenzi, Sunjay Jude Fernandes, Hiromasa Morikawa, Shahin Aeinehband, Sergi Sayols-Baixeras, Stella Aslibekyan, Devin M. Absher, Donna K. Arnett, Jesper Tegner, David Gomez-Cabrero, Fredrik Piehl, Maja Jagodic

Epidemiology and Environmental Health Faculty Publications

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system caused by genetic and environmental factors. DNA methylation, an epigenetic mechanism that controls genome activity, may provide a link between genetic and environmental risk factors.

Objective: We sought to identify DNA methylation changes in CD4+ T cells in patients with relapsing-remitting (RR-MS) and secondary-progressive (SP-MS) disease and healthy controls (HC).

Methods: We performed DNA methylation analysis in CD4+ T cells from RR-MS, SP-MS, and HC and associated identified changes with the nearby risk allele, smoking, age, and gene expression.

Results: We observed significant methylation differences in …

Identifying Kif Subtype That Mediates Axonal Targeting Of Kv7 Channels, Allison Houghton, Jennifer Walters, Mary Hong, Dhruv Joshi, Hee Jung Chung

PRECS 2018

Early-onset Benign Familial Neonatal Epilepsy (BFNE) and Epileptic Encephalopathy (EE), are associated with mutations in neuronal KCNQ/Kv7 channel subunits Kv7.2 and Kv7.3. Kv7 channels are voltage-dependent potassium channels. Enriched at the axonal plasma membrane, they pump potassium ions out of the neurons and inhibit repetitive or burst firing of action potentials. A single neuronal Kv7 channel is a heterotetramer composed of two Kv7.2 and two Kv7.3 subunits. BFNE and EE mutations in Kv7.2 and Kv7.3 lead to decreased surface expression along the axon, which means less potassium ions are moved across the axonal membrane where action potentials are generated and …

Epigenetic Alterations Mediate Ipsc Normalization Of Dna-Repair Expression And Tnr Stability In Huntington's Disease, Peter A. Mollica, Martina Zamponi, John Reid, Deepak Sharma, Alyson E. White, Roy C. Ogle, Robert D. Bruno, Patrick C. Sachs

School of Medical Diagnostics & Translational Sciences Faculty Publications

Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat (TNR) expansion within the HTT gene. The mechanisms underlying HD-associated cellular dysfunction in pluripotency and neurodevelopment are poorly understood. We had previously identified downregulation of selected DNA repair genes in HD fibroblasts relative to wild-type fibroblasts, as a result of promoter hypermethylation. Here, we tested the hypothesis that hypomethylation during cellular reprogramming to the induced pluripotent stem cell (iPSC) state leads to upregulation of DNA repair genes and stabilization of TNRs in HD cells. We sought to determine how the HD TNR region …

Sources And Fates Of Carbamyl Phosphate: A Labile Energy-Rich Molecule With Multiple Facets., Dashuang Shi, Ljubica Caldovic, Mendel Tuchman

Genomics and Precision Medicine Faculty Publications

Carbamyl phosphate (CP) is well-known as an essential intermediate of pyrimidine and arginine/urea biosynthesis. Chemically, CP can be easily synthesized from dihydrogen phosphate and cyanate. Enzymatically, CP can be synthesized using three different classes of enzymes: (1) ATP-grasp fold protein based carbamyl phosphate synthetase (CPS); (2) Amino-acid kinase fold carbamate kinase (CK)-like CPS (anabolic CK or aCK); and (3) Catabolic transcarbamylase. The first class of CPS can be further divided into three different types of CPS as CPS I, CPS II, and CPS III depending on the usage of ammonium or glutamine as its nitrogen source, and whether

Borrelia Burgdorferi Spovg Dna- And Rna-Binding Protein Modulates The Physiology Of The Lyme Disease Spirochete, Christina R. Savage, Brandon L. Jutras, Aaron Bestor, Kit Tilly, Patricia A. Rosa, Yvonne Tourand, Philip E. Stewart, Catherine A. Brissette, Brian Stevenson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The SpoVG protein of Borrelia burgdorferi, the Lyme disease spirochete, binds to specific sites of DNA and RNA. The bacterium regulates transcription of spoVG during the natural tick-mammal infectious cycle and in response to some changes in culture conditions. Bacterial levels of spoVG mRNA and SpoVG protein did not necessarily correlate, suggesting that posttranscriptional mechanisms also control protein levels. Consistent with this, SpoVG binds to its own mRNA, adjacent to the ribosome-binding site. SpoVG also binds to two DNA sites in the glpFKD operon and to two RNA sites in glpFKD mRNA; that operon encodes genes necessary for glycerol catabolism …

The Role Of Id3 And Pcb153 In The Hyperproliferation And Dysregulation Of Lung Endothelial Cells, Mayur Arvind Doke

FIU Electronic Theses and Dissertations

Uncontrolled growth of vascular stem cells as a result of endothelial-mesenchymal transition is considered to cause hyper-proliferative vascular remodeling in severe pulmonary arterial hypertension (PAH) patients. Hyperplastic intimal growth is one of the causes of closure of the lumen of pulmonary arterioles. This abnormal vessel remodeling leads to the progressive increase in pressure of the pulmonary arterioles causing severe PAH; and debilitating harm to patients resulting in mortality from right heart failure. Environmental factors, including polychlorinated biphenyls (PCBs), are considered to be involved in hyper-proliferative vascular remodeling because genetic makeup can only explain about 10% of severe PAH cases. PCB …

Epigenome-Wide Association Study Of Metabolic Syndrome In African-American Adults, Tomi Akinyemiju, Anh N. Do, Amit Patki, Stella Aslibekyan, Degui Zhi, Bertha Hidalgo, Hemant K. Tiwari, Devin Absher, Xin Geng, Donna K. Arnett, Marguerite R. Irvin

Epidemiology and Environmental Health Faculty Publications

Background: The high prevalence of obesity among US adults has resulted in significant increases in associated metabolic disorders such as diabetes, dyslipidemia, and high blood pressure. Together, these disorders constitute metabolic syndrome, a clinically defined condition highly prevalent among African-Americans. Identifying epigenetic alterations associated with metabolic syndrome may provide additional information regarding etiology beyond current evidence from genome-wide association studies.

Methods: Data on metabolic syndrome and DNA methylation was assessed on 614 African-Americans from the Hypertension Genetic Epidemiology Network (HyperGEN) study. Metabolic syndrome was defined using the joint harmonized criteria, and DNA methylation was assessed using the Illumina HumanMethylation450K Bead …

Skeletal, Cardiac, And Respiratory Muscle Function And Histopathology In The P448lneo- Mouse Model Of Fkrp-Deficient Muscular Dystrophy., Qing Yu, Melissa Morales, Ning Li, Alexander G Fritz, Ren Ruobing, Anthony Blaeser, Ershia Francois, Qi-Long Lu, Kanneboyina Nagaraju, Christopher F Spurney

Genomics and Precision Medicine Faculty Publications

BACKGROUND: Fukutin-related protein (FKRP) mutations are the most common cause of dystroglycanopathies known to cause both limb girdle and congenital muscular dystrophy. The P448Lneo- mouse model has a knock-in mutation in the FKRP gene and develops skeletal, respiratory, and cardiac muscle disease.

METHODS: We studied the natural history of the P448Lneo- mouse model over 9 months and the effects of twice weekly treadmill running. Forelimb and hindlimb grip strength (Columbus Instruments) and overall activity (Omnitech Electronics) assessed skeletal muscle function. Echocardiography was performed using VisualSonics Vevo 770 (FujiFilm VisualSonics). Plethysmography was performed using whole body system (ADInstruments). Histological evaluations included …

Cross Talk Between Serum Kisspeptin-Leptin During Assisted Reproduction Techniques, Rehana Rehman, Zehra Jamil, Aqsa Khalid, Syeda Sadia Fatima

Department of Biological & Biomedical Sciences

Background & Objective: Leptin facilitates onset of puberty by impact on hypothalamic Kisspeptin, gonadotropin releasing hormone, follicle stimulating and luteinizing hormone. The link of peripheral Leptin-Kisspeptin in regulating the ovarian and endometrial tissue in relation to adiposity is unknown. Therefore, we wanted to identify Kisspeptin-Leptin association with body mass index (BMI) and success of assisted reproductive treatments (ART) in infertile females.
Methods: A cross sectional study was carried from August 2014 till May 2016 after receiving ethical approval at Australian Concept Infertility Medical Centre, and Aga Khan University. The study group comprised of females with an age range …

Repeat-Associated Non-Aug (Ran) Translation And Other Molecular Mechanisms In Fragile X Tremor Ataxia Syndrome, M. Rebecca Glineburg, Peter K. Todd, Nicolas Charlet-Berguerand, Chantal Sellier

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset inherited neurodegenerative disorder characterized by progressive intention tremor, gait ataxia and dementia associated with mild brain atrophy. The cause of FXTAS is a premutation expansion, of 55 to 200 CGG repeats localized within the 5′UTR of FMR1. These repeats are transcribed in the sense and antisense directions into mutants RNAs, which have increased expression in FXTAS. Furthermore, CGG sense and CCG antisense expanded repeats are translated into novel proteins despite their localization in putatively non-coding regions of the transcript. Here we focus on two proposed disease mechanisms for FXTAS: 1) RNA …

The Role Of Tgf-Β/Smad4 Signaling In Cancer, M Zhao, Lopa Mishra, C Deng

Surgery Faculty Publications

Transforming growth factor β (TGF-β) signaling pathway plays important roles in many biological processes, including cell growth, differentiation, apoptosis, migration, as well as cancer initiation and progression. SMAD4, which serves as the central mediator of TGF-β signaling, is specifically inactivated in over half of pancreatic duct adenocarcinoma, and varying degrees in many other types of cancers. In the past two decades, multiple studies have revealed that SMAD4 loss on its own does not initiate tumor formation, but can promote tumor progression initiated by other genes, such as KRAS activation in pancreatic duct adenocarcinoma and APC inactivation in colorectal cancer. In …

Rest Upregulates Gremlin To Modulate Diffuse Intrinsic Pontine Glioma Vasculature, Shavali Shaik, Bridget Kennis, Shinji Maegawa, Keri Schadler, Yang Yanwen, Javad Nazarian, +Several Additional Authors

Genomics and Precision Medicine Faculty Publications

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive glial tumor that occurs in children. The extremely poor median and 5-year survival in children afflicted with DIPG highlights the need for novel biology-driven therapeutics. Here, we have implicated the chromatin remodeler and regulator of brain development called RE1 Silencing Transcription Factor (REST), in DIPG pathology. We show that REST protein is aberrantly elevated in at least 21% of DIPG tumors compared to normal controls. Its knockdown in DIPG cell lines diminished cell growth and decreased their tumorigenicity in mouse intracranial models. DIPGs are vascularized tumors and interestingly, REST loss in …

Qatar: Diabetes, Diangelo Gonzalez

Global Public Health

The State of Qatar is a developed nation that is located in the Middle East and borders the Persian Gulf and Saudi Arabia. The nation is a constitutional monarchy and is currently led by Amir Tamim bin Hamad Al Thani. The 2,300,000+ people of Qatar face many major challenges. Although it is one of the wealthiest nations in the Middle East, Qatar faces issues of human trafficking, migrants willing to work in poor conditions, and Middle Eastern Respiratory Syndrome (MERS). The most critical issue that plagues this county is diabetes, both I and II. Diabetes is a disease that is …

Wild-Type P53 Enhances Endothelial Barrier Function By Mediating Rac1 Signalling And Rhoa Inhibition, Nektarios Barabutis, Christiana Dimitropoulou, Betsy Gregory, John D. Catravas

Bioelectrics Publications

Inflammation is the major cause of endothelial barrier hyper-permeability, associated with acute lung injury and acute respiratory distress syndrome. This study reports that p53 "orchestrates" the defence of vascular endothelium against LPS, by mediating the opposing actions of Rac1 and RhoA in pulmonary tissues. Human lung microvascular endothelial cells treated with HSP90 inhibitors activated both Rac1- and P21-activated kinase, which is an essential element of vascular barrier function. 17AAG increased the phosphorylation of both LIMK and cofilin, in contrast to LPS which counteracted those effects. Mouse lung microvascular endothelial cells exposed to LPS exhibited decreased expression of phospho-cofilin. 17AAG treatment …