Polymorphisms at PRSS1–PRSS2 and CLDN2–MORC4 Loci Associate
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PARSANA-DISSERTATION-2020.Pdf
DECIPHERING TRANSCRIPTIONAL PATTERNS OF GENE REGULATION: A COMPUTATIONAL APPROACH by Princy Parsana A dissertation submitted to The Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland July, 2020 © 2020 Princy Parsana All rights reserved Abstract With rapid advancements in sequencing technology, we now have the ability to sequence the entire human genome, and to quantify expression of tens of thousands of genes from hundreds of individuals. This provides an extraordinary opportunity to learn phenotype relevant genomic patterns that can improve our understanding of molecular and cellular processes underlying a trait. The high dimensional nature of genomic data presents a range of computational and statistical challenges. This dissertation presents a compilation of projects that were driven by the motivation to efficiently capture gene regulatory patterns in the human transcriptome, while addressing statistical and computational challenges that accompany this data. We attempt to address two major difficulties in this domain: a) artifacts and noise in transcriptomic data, andb) limited statistical power. First, we present our work on investigating the effect of artifactual variation in gene expression data and its impact on trans-eQTL discovery. Here we performed an in-depth analysis of diverse pre-recorded covariates and latent confounders to understand their contribution to heterogeneity in gene expression measurements. Next, we discovered 673 trans-eQTLs across 16 human tissues using v6 data from the Genotype Tissue Expression (GTEx) project. Finally, we characterized two trait-associated trans-eQTLs; one in Skeletal Muscle and another in Thyroid. Second, we present a principal component based residualization method to correct gene expression measurements prior to reconstruction of co-expression networks. -
HHS Public Access Author Manuscript
HHS Public Access Author manuscript Author Manuscript Author ManuscriptNat Genet Author Manuscript. Author manuscript; Author Manuscript available in PMC 2013 June 01. Published in final edited form as: Nat Genet. 2012 December ; 44(12): 1349–1354. doi:10.1038/ng.2466. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis A full list of authors and affiliations appears at the end of the article. Abstract Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol- related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07. The exocrine pancreas is a simple digestive gland of only two primary cell types, each with a single function (Supplementary Figure 1). Recurrent acute pancreatic inflammation can, but does not always, progress to irreversible damage of the gland, including fibrosis, atrophy, pain, and exocrine and endocrine insufficiency,1-3 known as chronic pancreatitis Different genetic and environmental factors produce the same clinical phenotype4. -
Age-Associated DNA Methylation Changes in Immune Genes, Histone Modifiers and Chromatin Remodeling Factors Within 5 Years After Birth in Human Blood Leukocytes
Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes Acevedo, Nathalie; Reinius, Lovisa E; Vitezic, Morana; Fortino, Vittorio; Söderhäll, Cilla; Honkanen, Hanna; Veijola, Riitta; Simell, Olli; Toppari, Jorma; Ilonen, Jorma; Knip, Mikael; Scheynius, Annika; Hyöty, Heikki; Greco, Dario; Kere, Juha Published in: Clinical Epigenetics DOI: 10.1186/s13148-015-0064-6 Publication date: 2015 Document version Publisher's PDF, also known as Version of record Citation for published version (APA): Acevedo, N., Reinius, L. E., Vitezic, M., Fortino, V., Söderhäll, C., Honkanen, H., Veijola, R., Simell, O., Toppari, J., Ilonen, J., Knip, M., Scheynius, A., Hyöty, H., Greco, D., & Kere, J. (2015). Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes. Clinical Epigenetics, 7, [34]. https://doi.org/10.1186/s13148-015-0064-6 Download date: 30. Sep. 2021 Acevedo et al. Clinical Epigenetics (2015) 7:34 DOI 10.1186/s13148-015-0064-6 RESEARCH Open Access Age-associated DNA methylation changes in immune genes, histone modifiers and chromatin remodeling factors within 5 years after birth in human blood leukocytes Nathalie Acevedo1,2, Lovisa E Reinius2, Morana Vitezic3, Vittorio Fortino4, Cilla Söderhäll2, Hanna Honkanen5, Riitta Veijola6, Olli Simell7, Jorma Toppari8, Jorma Ilonen9, Mikael Knip10,11,13, Annika Scheynius1, Heikki Hyöty5,12, Dario Greco4 and Juha Kere2,13* Abstract Background: Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate the dynamics of DNA methylation. -
Prognostic Significance of Autophagy-Relevant Gene Markers in Colorectal Cancer
ORIGINAL RESEARCH published: 15 April 2021 doi: 10.3389/fonc.2021.566539 Prognostic Significance of Autophagy-Relevant Gene Markers in Colorectal Cancer Qinglian He 1, Ziqi Li 1, Jinbao Yin 1, Yuling Li 2, Yuting Yin 1, Xue Lei 1 and Wei Zhu 1* 1 Department of Pathology, Guangdong Medical University, Dongguan, China, 2 Department of Pathology, Dongguan People’s Hospital, Southern Medical University, Dongguan, China Background: Colorectal cancer (CRC) is a common malignant solid tumor with an extremely low survival rate after relapse. Previous investigations have shown that autophagy possesses a crucial function in tumors. However, there is no consensus on the value of autophagy-associated genes in predicting the prognosis of CRC patients. Edited by: This work screens autophagy-related markers and signaling pathways that may Fenglin Liu, Fudan University, China participate in the development of CRC, and establishes a prognostic model of CRC Reviewed by: based on autophagy-associated genes. Brian M. Olson, Emory University, United States Methods: Gene transcripts from the TCGA database and autophagy-associated gene Zhengzhi Zou, data from the GeneCards database were used to obtain expression levels of autophagy- South China Normal University, China associated genes, followed by Wilcox tests to screen for autophagy-related differentially Faqing Tian, Longgang District People's expressed genes. Then, 11 key autophagy-associated genes were identified through Hospital of Shenzhen, China univariate and multivariate Cox proportional hazard regression analysis and used to Yibing Chen, Zhengzhou University, China establish prognostic models. Additionally, immunohistochemical and CRC cell line data Jian Tu, were used to evaluate the results of our three autophagy-associated genes EPHB2, University of South China, China NOL3, and SNAI1 in TCGA. -
Identification of Pancreatic Juice Proteins As Biomarkers of Pancreatic Cancer
1683-1692.qxd 23/4/2010 10:57 Ì ™ÂÏ›‰·1683 ONCOLOGY REPORTS 23: 1683-1692, 2010 Identification of pancreatic juice proteins as biomarkers of pancreatic cancer JUN GAO1*, FENG ZHU1*, SHUNLI LV1*, ZHAOSHEN LI1, ZHANG LING1, YANFANG GONG1, CHEN JIE1 and LIE MA2 1Department of Gastroenterology, Changhai Hospital, 2Department of Biochemistry, Basic Medicine, Second Military Medical University, Shanghai 200433, P.R. China Received December 17, 2009; Accepted February 4, 2010 DOI: 10.3892/or_00000812 Abstract. Pancreatic juice is a potential source of proteins analysis of pancreatic juice from PC patients is a powerful associated with pancreatic cancer (PC) due to the proximity of method to find new PC biomarkers. Hyperexpression of the ducts to tumor tissue. Therefore, screening of proteins in PRSS2 gene and hypermethylation of ELA3B gene promoter pancreatic juice from PC patients may identify new PC were associated with PC, raising the possibility of their biomarkers. We analyzed pancreatic juice from patients with application as new biomarkers in PC diagnosis and screening. pancreatic diseases including PC, chronic pancreatitis (CP) and simple choledocholithiasis (CDS) by 2-DE. Protein spots Introduction from PC patients that changed >2-fold compared with both CP and CDS were selected and identified by mass spectro- Pancreatic cancer (PC) is an almost uniformly fatal disease, metry (MS). mRNA levels were measured by QRT-PCR in with a 5-year survival rate of less than 4%. In the United PC cell lines, PC tissues and adjacent pancreatic normal (PN) States, PC is the 4th leading cause of cancer death, while in tissues. Relationships between mRNA levels in PC tissues Europe it is the 6th (1). -
Regulation of Claudin-3 Expression in Kidney Tubular Epithelial Cells
Regulation of Claudin-3 Expression in Kidney Tubular Epithelial Cells by Shaista Anwer A thesis submitted in conformity with the requirements for the degree of Master of Science Institute of Medical Science University of Toronto © Copyright by Shaista Anwer 2020 Regulation of Claudin-3 Expression in Kidney Tubular Epithelial Cells Shaista Anwer Master of Science Institute of Medical Science University of Toronto 2020 Abstract The overall objective of my studies was to gain insight into the regulation of the tight junction protein, claudin-3, upon inflammatory stimuli in kidney tubular epithelial cells. Claudins mediate paracellular transport and modulate key cellular events like proliferation, migration and differentiation. The inflammatory cytokine Tumor Necrosis Factor-α (TNFα) is a pathogenic factor in kidney disease and alters epithelial permeability. However, the effect of TNFα on claudin-3 expression in the tubules and the mechanisms are not defined. My studies showed that TNFα elevated claudin-3 expression in kidney tubular cells. This effect was due to increased claudin-3 synthesis and mediated by two signaling pathways: extracellular signal regulated kinase- dependent activation of NFκB and protein kinase A-induced CREB1 activation. Claudin-3 overexpression elevated transepithelial resistance in tubular cells and it may play a role in regulating tubular epithelial permeability. Claudin-3 downregulation also affected cell cycle proteins; thus, claudin-3 may also affect cell proliferation. ii Acknowledgements I would like to dedicate this thesis to two important people in my life: my mother, Tahniyat Anwer and my supervisor, Dr. Katalin Szászi. My mom has been a great source of inspiration and a pillar of strength in my life and has always supported me in my endeavours. -
B Inhibition in a Mouse Model of Chronic Colitis1
The Journal of Immunology Differential Expression of Inflammatory and Fibrogenic Genes and Their Regulation by NF-B Inhibition in a Mouse Model of Chronic Colitis1 Feng Wu and Shukti Chakravarti2 Fibrosis is a major complication of chronic inflammation, as seen in Crohn’s disease and ulcerative colitis, two forms of inflam- matory bowel diseases. To elucidate inflammatory signals that regulate fibrosis, we investigated gene expression changes under- lying chronic inflammation and fibrosis in trinitrobenzene sulfonic acid-induced murine colitis. Six weekly 2,4,6-trinitrobenzene sulfonic acid enemas were given to establish colitis and temporal gene expression patterns were obtained at 6-, 8-, 10-, and 12-wk time points. The 6-wk point, TNBS-w6, was the active, chronic inflammatory stage of the model marked by macrophage, neu- trophil, and CD3؉ and CD4؉ T cell infiltrates in the colon, consistent with the idea that this model is T cell immune response driven. Proinflammatory genes Cxcl1, Ccl2, Il1b, Lcn2, Pla2g2a, Saa3, S100a9, Nos2, Reg2, and Reg3g, and profibrogenic extra- cellular matrix genes Col1a1, Col1a2, Col3a1, and Lum (lumican), encoding a collagen-associated proteoglycan, were up-regulated at the active/chronic inflammatory stages. Rectal administration of the NF-B p65 antisense oligonucleotide reduced but did not abrogate inflammation and fibrosis completely. The antisense oligonucleotide treatment reduced total NF-B by 60% and down- regulated most proinflammatory genes. However, Ccl2, a proinflammatory chemokine known to promote fibrosis, was not down- regulated. Among extracellular matrix gene expressions Lum was suppressed while Col1a1 and Col3a1 were not. Thus, effective treatment of fibrosis in inflammatory bowel disease may require early and complete blockade of NF-B with particular attention to specific proinflammatory and profibrogenic genes that remain active at low levels of NF-B. -
PRSS2 Polyclonal Antibody
PRODUCT DATA SHEET Bioworld Technology,Inc. PRSS2 polyclonal antibody Catalog: BS61619 Host: Rabbit Reactivity: Human,Mouse,Rat BackGround: Applications: This gene belongs to the trypsin family of serine proteas- WB: 1:500~1:1000 es and encodes anionic trypsinogen. It is part of a cluster Storage&Stability: of trypsinogen genes that are located within the T cell re- Store at 4°C short term. Aliquot and store at -20°C long ceptor beta locus. Enzymes of this family cleave peptide term. Avoid freeze-thaw cycles. bonds that follow lysine or arginine residues. This protein Specificity: is found at high levels in pancreatic juice and its upregu- PRSS2 polyclonal antibody detects endogenous levels of lation is a characteristic feature of pancreatitis. This pro- PRSS2 protein. tein has also been found to activate pro-urokinase in DATA: ovarian tumors, suggesting a function in tumor invasion. In addition, this enzyme is able to cleave across the type II collagen triple helix in rheumatoid arthritis synovitis tissue, potentially participating in the degradation of type II collagen-rich cartilage matrix. Alternative splicing re- sults in multiple transcript variants. Product: Western blot (WB) analysis of PRSS2 polyclonal antibody at 1:500 Rabbit IgG, 1mg/ml in PBS with 0.02% sodium azide, dilution 50% glycerol, pH7.2 Lane1:HT102 whole cell lysate(40ug) Molecular Weight: Lane2:SW620 whole cell lysate(40ug) ~ 26 kDa Lane3:CT26 whole cell lysate(40ug) Swiss-Prot: Lane4:PC12 whole cell lysate(40ug) P07478 Note: Purification&Purity: For research use only, not for use in diagnostic procedure. The antibody was affinity-purified from rabbit antiserum by affinity-chromatography using epitope-specific im- munogen and the purity is > 95% (by SDS-PAGE). -
Trypsin-Encoding PRSS1-PRSS2 Variations
ARTICLE Acute Lymphoblastic Leukemia Ferrata Storti Foundation Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report Haematologica 2019 Benjamin O. Wolthers,1 Thomas L. Frandsen,1 Chirag J. Patel,2 Rachid Abaji,3 Volume 104(3):556-563 Andishe Attarbaschi,4 Shlomit Barzilai,5 Antonella Colombini,6 Gabriele Escherich,7 Marie Grosjean,8 Maja Krajinovic,3,9 Eric Larsen,10 Der-Cherng Liang,11 Anja Möricke,12 Kirsten K. Rasmussen,1 Sujith Samarasinghe,13 Lewis B. Silverman,14 Inge M. van der Sluis,15 Martin Stanulla,16 Morten Tulstrup,1 Rachita Yadav,8,17 Wenjian Yang,18 Ester Zapotocka,19 Ramneek Gupta8 and Kjeld Schmiegelow1,20 on behalf of the Ponte di Legno toxicity working group 1Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark; 2Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; 3CHU Sainte-Justine Research Center and Department of Pharmacology, University of Montreal, QC, Canada; 4Department of Pediatric Hematology and Oncology, St Anna Children's Hospital and Department of Pediatric and Adolescent Medicine, Medical University of Vienna, Austria; 5Pediatric Hematology and Oncology, Schneider Children's Medical Center of Israel, Petah-Tikva, Israel and Sackler Faculty of Medicine, Tel Aviv University, Israel; 6Department of Pediatrics, Ospedale San Gerardo, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy; -
Irf2)Intrypsinogen5 Gene Transcription
Characterization of dsRNA-induced pancreatitis model reveals the regulatory role of IFN regulatory factor 2 (Irf2)intrypsinogen5 gene transcription Hideki Hayashia, Tomoko Kohnoa, Kiyoshi Yasuia, Hiroyuki Murotab, Tohru Kimurac, Gordon S. Duncand, Tomoki Nakashimae, Kazuo Yamamotod, Ichiro Katayamab, Yuhua Maa, Koon Jiew Chuaa, Takashi Suematsua, Isao Shimokawaf, Shizuo Akirag, Yoshinao Kuboa, Tak Wah Makd,1, and Toshifumi Matsuyamaa,h,1 aDivision of Cytokine Signaling, Department of Molecular Biology and Immunology and fDepartment of Investigative Pathology, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8523, Japan; Departments of bDermatology and cPathology, Graduate School of Medicine and gDepartment of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; dCampbell Family Cancer Research Institute, Princess Margaret Hospital, Toronto, ON, Canada M5G 2M9; eDepartment of Cell Signaling, Tokyo Medical and Dental University, Tokyo 113-8549, Japan; and hGlobal Center of Excellence Program, Nagasaki University, Nagasaki 852-8523, Japan Contributed by Tak Wah Mak, October 5, 2011 (sent for review September 8, 2011) − − Mice deficient for interferon regulatory factor (Irf)2 (Irf2 / mice) transcriptional activation of dsRNA-sensing PRRs were critical for exhibit immunological abnormalities and cannot survive lympho- the pIC-induced death. cytic choriomeningitis virus infection. The pancreas of these ani- mals is highly inflamed, a phenotype replicated by treatment with Results and Discussion − − poly(I:C), a synthetic double-stranded RNA. Trypsinogen5 mRNA Irf2 / Mice Show IFN-Dependent Poly(I:C)-Induced Pancreatitis and −/− IFN-Independent Secretory Dysfunction in Pancreatic Acinar Cells. was constitutively up-regulated about 1,000-fold in Irf2 mice − − LCMV-infected Irf2 / mice die within 4 wk postinfection (3), compared with controls as assessed by quantitative RT-PCR. -
Claudin 2 and Hypercalciuria—Of Mice And
RESEARCH HIGHLIGHTS Credit: Image courtesy of A. Yu and J. Curry, University of Kansas Medical Center, USA STONES Claudin 2 and hyper calciuria — of mice and men Claudin 2 is a regulator of calcium and glomerular calcium filtration with kidney stones and 187,639 excretion and could be a treatment were comparable between Cldn2–/y controls and identifying 9 SNPs that They began target for patients with urolithiasis, mice and wild-type littermates, were significantly associated with by studying according to new data published in suggesting that this difference is risk of nephrocalcinosis (P < 0.05). the Journal of Clinical Investigation. due to a decrease in renal calcium These data were further supported by claudin Hypercalciuria is integral to the reabsorption in Cldn2–/y mice as a genome analysis of an Iranian family, 2- knockout pathogenesis of stone formation, result of impaired proximal tubule who had previously been shown to (Cldn2–/y) which is likely to arise via calcium paracellular calcium transport. harbour a rare missense mutation mice deposition in the renal papilla. The Leading on from the observation in CLDN2 that led to obstructive … aetiology of hypercalciuria is somewhat of hypercalciuria, the team then azoospermia. Both male and female confirming uncertain but is thought to include investigated whether Cldn2–/y mice members of this family also had that they increased bone resorption, calcium were prone to nephrocalcinosis. marked hypercalciuria. are indeed hyperabsorption in the intestine and Accordingly, they observed abundant “Our premise — that defects in hypercalciuric reduced renal reabsorption. Calcium mineral deposits in the renal papillae proximal tubule calcium handling reabsorption occurs largely in the of 6- month- old and 1- year- old lead to papillary calcification and, proximal tubule, where ~60% of Cldn2–/y mice. -
Mouse Trypsin 2 / PRSS2 Protein (His Tag)
Mouse Trypsin 2 / PRSS2 Protein (His Tag) Catalog Number: 50383-M08H General Information SDS-PAGE: Gene Name Synonym: Prss2; Ta; Tesp4; Try2; TRY8; TRYP Protein Construction: A DNA sequence encoding the mouse PRSS2 (NP_033456.1) precursor (Met 1-Asn 246) was expressed, with a C-terminal polyhistidine tag. Source: Mouse Expression Host: HEK293 Cells QC Testing Purity: > 92 % as determined by SDS-PAGE Bio Activity: Protein Description Measured by its ability to cleave the fluorogenic peptide substrate, Mca- RPKPVE-Nval-WRK(Dnp)-NH2 (Anaspec, Catalog #27096) . The specific Trypsin-2, also known as Trypsin II, Anionic trypsinogen, Serine protease 2, activity is >1500 pmoles/min/μg . (Activation description: The proenzyme PRSS2 and TRY2, is a secreted protein which belongs to the trypsin serine needs to be activated by enteropeptidase for an activated form) protease family including Trypsin, PRSS1, PRSS2 and PRSS3. It consists of a signal peptide (residues 1-15), a pro region (residues 16-23), and a Endotoxin: proteolytically active mature chain (residues 24-247). PRSS2 contains onepeptidase S1 domain. It is secreted into theduodenum,hydrolysing < 1.0 EU per μg of the protein as determined by the LAL method peptides into their smaller building blocks, which is necessary for the uptake of protein in the food. It is secreted by the pancreas in the form of Stability: inactivezymogen,trypsinogen and cleaved to its active form in the small Samples are stable for up to twelve months from date of receipt at -70 ℃ intestine when the pancreas is stimulated bycholecystokinin through the common activation mechanism. Predicted N terminal: Phe 16 References Molecular Mass: 1.Rawlings, N.D.