DOCSLIB.ORG

DNA Methylation Variants at HIF3A Locus, B-Vitamin Intake, and Long-Term Weight Change: Gene-Diet Interactions in Two U.S

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
DNA Methylation Variants at HIF3A Locus, B-Vitamin Intake, and Long-Term Weight Change: Gene-Diet Interactions in Two U.S 3146 Diabetes Volume 64, September 2015 Tao Huang,1 Yan Zheng,1 Qibin Qi,2 Min Xu,3 Sylvia H. Ley,1 Yanping Li,1 Jae H. Kang,4 Janey Wiggs,5 Louis R. Pasquale,4,5 Andrew T. Chan,6 Eric B. Rimm,1,4,7 David J. Hunter,1,7 JoAnn E. Manson,4,7,8 Walter C. Willett,1,4,7 Frank B. Hu,1,4,7 and Lu Qi1,4 DNA Methylation Variants at HIF3A Locus, B-Vitamin Intake, and Long-term Weight Change: Gene-Diet Interactions in Two U.S. Cohorts Diabetes 2015;64:3146–3154 | DOI: 10.2337/db15-0264 The first epigenome-wide association study of BMI not induced by changes in the DNA sequence (1). Increasing identified DNA methylation at an HIF3A locus associated evidence indicates that DNA methylation plays a pivotal role with BMI. We tested the hypothesis that DNA methylation in regulating body adiposity (2–5). In a recent large-scale variants are associated with BMI according to intake of epigenome-wide association study, Dick et al. (4) found B vitamins. In two large cohorts, we found significant inter- that DNA methylation at HIF3A was associated with BMI. actions between the DNA methylation–associated HIF3A However, genetic variants in this locus were not associated single nucleotide polymorphism (SNP) rs3826795 and in- with BMI, although they were associated with HIF3A meth- take of B vitamins on 10-year changes in BMI. The asso- ylationlevelsinbloodandadiposeandskintissues.The ciation between rs3826795 and BMI changes consistently authors suggested that the association between HIF3A meth- increased across the tertiles of total vitamin B and B 2 12 ylation and BMI might not be operating by the Mendelian intake (all P for interaction <0.01). The differences in the randomization theory (4), but the study did not consider BMI changes per increment of minor allele were 20.10 OBESITY STUDIES potential modifying effects of environmental factors on the (SE 0.06), 20.01 (SE 0.06), and 0.12 (SE 0.07) within sub- genetic associations. Previous evidence supports the impor- groups defined by increasing tertiles of total vitamin B2 intake and 20.10 (SE 0.06), 20.01 (SE 0.06), and 0.10 (SE tance of considering interactions between genetic and diet/ – 0.07) within subgroups defined by increasing tertiles of lifestyle factors in the development of adiposity (6 10). It has long been acknowledged that DNA methylation total vitamin B12 intake. In two independent cohorts, a DNA methylation variant in HIF3A was associated with levels are subject to modulation by environmental factors BMI changes through interactions with total or supple- such as diet and lifestyle. Methylation of DNA is a bio- mental vitamin B2, vitamin B12, and folate. These findings chemical process in which a methyl group is added to suggest a potential causal relation between DNA methyl- DNA nucleotides. Several B vitamins, including folate, ation and adiposity. riboflavin (B2), pyridoxine (B6), and B12, act as key en- zyme cofactors and play essential roles in methyl group metabolism and DNA methylation in particular (11,12). DNA methylation is one of the major epigenetic events Previous studies have associated B-vitamin intake with ad- that affect gene expression through a mechanism that is iposity in humans (13,14). Therefore, we hypothesized that 1Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 8Division of Preventive Medicine, Department of Medicine, Brigham and Women’s 2Department of Epidemiology and Population Health, Albert Einstein College of Hospital and Harvard Medical School, Boston, MA Medicine, Bronx, NY Corresponding author: Lu Qi, [email protected]. 3Shanghai Clinical Center for Endocrine and Metabolic Diseases and Shanghai Received 25 February 2015 and accepted 14 May 2015. Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China This article contains Supplementary Data online at http://diabetes 4Channing Division of Network Medicine, Department of Medicine, Brigham and .diabetesjournals.org/lookup/suppl/doi:10.2337/db15-0264/-/DC1. Women’s Hospital and Harvard Medical School, Boston, MA © 2015 by the American Diabetes Association. Readers may use this article as 5Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and long as the work is properly cited, the use is educational and not for profit, and Ear Infirmary, Boston, MA the work is not altered. 6Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 7Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA diabetes.diabetesjournals.org Huang and Associates 3147 B vitamins modify the relation between the methylation- with a BMI $30 kg/m2 were defined as obese, and those associated genetic variants at HIF3A and BMI. To test this with a BMI $25 kg/m2 were defined as overweight. The hypothesis, we examined interactions between intake of epidemic of obesity occurred during a relatively short pe- B vitamins and DNA methylation variants at the HIF3A riod of time in the U.S. between ;1980 and 2000 (28,29), locus in relation to BMI and 10-year changes in BMI in paralleling a dramatic transition from traditional to obe- two prospective cohorts: the Nurses’ Health Study (NHS) sogenic diet/lifestyle patterns (9,10,30). Obesity traits and the Health Professionals Follow-Up Study (HPFS). measured at a single time point cannot capture the vari- ance in gradual changes, whereas changes in BMI/body RESEARCH DESIGN AND METHODS weight during the period of the obesity epidemic more Study Population likely reflect the long-term, dynamic response to gene- The NHS is a prospective cohort study of 121,700 female environment interactions. Furthermore, considerable in- registered nurses aged 30–55 years at study inception in terindividual variations of weight change in response to 1976 (15). The HPFS is a prospective cohort study of diet interventions have long been noted (10); therefore, 51,529 U.S. male health professionals aged 40–75 years the present study mainly focused on 10-year changes in at study inception in 1986 (16). The human subjects com- BMI. We defined the 10-year period for changes in BMI as mittees at the Harvard School of Public Health and Brigham 1980–1990 in the NHS cohort and 1986–1996 in the and Women’s Hospital approved these studies. Informed HPFS cohort. consent was obtained from all participants. In both cohorts, Single Nucleotide Polymorphism Selection and information about medical history, lifestyle, and health con- Genotyping ditions has been collected by self-administered question- The HIF3A variants rs3826795 and rs8102595 were se- naires every 2 years since inception. The current analysis lected because they had independent associations with baseline was set in 1980 for the NHS and 1986 for the methylation at a specific CpG site (cg22891070) within fi HPFS when the rst data on intake of B vitamins were intron 1 of HIF3A in adipose tissue and skin DNA asso- collected. We included 8,109 women and 6,761 men of ciated with BMI (4). The single nucleotide polymorphisms European ancestry. Both case and control participants (SNPs) were genotyped and had a high imputation quality with genotyping data available based on previous genome- score (r2 $ 0.8) as assessed with the use of MACH version – wide association studies were included (17 22). 1.0.16 software (Center for Statistical Genetics, Univer- Assessment of Dietary Factors and Covariates sity of Michigan). DNA extraction methods, quality con- Questionnaires were sent every 2 years to update in- trol measures, SNP genotyping, and imputations are formation on medical history and lifestyle factors. The described in detail elsewhere (17–22,31). The minor allele cohorts had follow-up rates of .85%. Dietary intake of frequencies (MAFs) of rs3826795 and rs8102595 are 0.09 various nutrients at baseline, including folate and vita- and 0.18, respectively. mins B2,B6, and B12, as well as daily consumption of Statistical Analyses alcohol, sugar-sweetened beverages, fried food, and total We examined the association of genetic variants with meat were assessed by validated semiquantitative food adiposity measures, baseline B-vitamin intake, and 10- frequency questionnaires every 4 years (23,24). All con- year changes in BMI or body weight using general linear tributions, including those from food and supplements, models. Interactions between the genetic variants and were summed to derive the total intake of specific intake of baseline nutrients (e.g., intake of total B vitamins, nutrients (23). The validity and reliability of the food intake of B vitamins from supplements or food frequency questionnaire has been established previously sources) on body weight, BMI, and 10-year changes in (23,24). Physical activity was expressed as metabolic body weight or BMI were tested by including a multi- equivalents per week by incorporating the reported time plicative interaction term in the models. Potential spent on various activities and the intensity level of each confounders considered in multivariable models were age activity. The validity of the self-reported physical activity (years, continuous), baseline physical activity (MET-h/week, data has been described previously (25). The Alternate continuous), baseline television watching (0–1, 2–5, 6–20, Healthy Eating Index was calculated previously in the 21–40, .40 h/week), baseline smoking (never, past, cur- NHS and HPFS (26). rent), baseline alcohol intake (0, 0.1–4.9, 5.0–9.9, 10– Assessment of Adiposity and 10-Year Changes in BMI 14.9, $15 g/day), baseline Alternate Healthy Eating Index Height and body weight were assessed by questionnaire at (in quintiles), and baseline total energy intake (in quin- baseline, and weight was requested on each follow-up tiles). Sugar-sweetened beverage, fried food, and total questionnaire. Body weight at a young age (18 years old in meat consumption were further adjusted in sensitivity the NHS and 21 years old in the HPFS) was also collected analyses.
Load more

Recommended publications
  • Nus a Thesis Submitted
    EPAS1 REGULATION AND FUNCTION IN THE HUMAN TROPHOBLAST NORHAM ERLYANI BTE ABDUL HAMID B.Sc. (Hons.), NUS A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY NUS GRADUATE SCHOOL FOR INTEGRATIVE SCIENCES AND ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2013 ACKNOWLEDGEMENTS Writing this doctoral dissertation has been most challenging and it would not have been possible without the support of many people. First of all, my gratitude goes to A*STAR, NGS, and GIS for giving me the opportunity to pursue the Doctor of Philosophy. I would like to thank A/P Paul Robson for being a tremendous mentor, and for his invaluable guidance. Under his care, I was able to develop and grow into an independent researcher. His unyielding encouragement gave me confidence to pursue the work I have achieved today. For always pointing me in the right direction and having the student’s best interest at heart, I must thank the panel of advisors at GIS as well as my thesis advisory committee; A/P Neil Clarke, Asst. Prof. Tara Huber, Asst. Prof. Thilo Hagen, and Dr. Shyam Prabhakar. I owe special thanks to my co-workers, Dr. Wishva Herath and Dr. Li Juntao. Their indispensable expertise in Bioinformatics is deeply appreciated, without which much of the data would have been rendered unintelligible to me. To my peers Mehran Rahmani, Nani Djunaidi, and Tapan Mistri, I thank you all for the sharing of ideas as well as laboratory material. Together, we can conquer the PhD! Additionally, I would also like to extend my thanks to Sun Lili, Jameelah Sheikh, Woon Chow Thai, and all members of the lab for their support and cooperation, ensuring research in the Robson lab proceeds as smoothly as possible.
    [Show full text]
  • Supplemental Materials ZNF281 Enhances Cardiac Reprogramming
    Supplemental Materials ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression Huanyu Zhou, Maria Gabriela Morales, Hisayuki Hashimoto, Matthew E. Dickson, Kunhua Song, Wenduo Ye, Min S. Kim, Hanspeter Niederstrasser, Zhaoning Wang, Beibei Chen, Bruce A. Posner, Rhonda Bassel-Duby and Eric N. Olson Supplemental Table 1; related to Figure 1. Supplemental Table 2; related to Figure 1. Supplemental Table 3; related to the “quantitative mRNA measurement” in Materials and Methods section. Supplemental Table 4; related to the “ChIP-seq, gene ontology and pathway analysis” and “RNA-seq” and gene ontology analysis” in Materials and Methods section. Supplemental Figure S1; related to Figure 1. Supplemental Figure S2; related to Figure 2. Supplemental Figure S3; related to Figure 3. Supplemental Figure S4; related to Figure 4. Supplemental Figure S5; related to Figure 6. Supplemental Table S1. Genes included in human retroviral ORF cDNA library. Gene Gene Gene Gene Gene Gene Gene Gene Symbol Symbol Symbol Symbol Symbol Symbol Symbol Symbol AATF BMP8A CEBPE CTNNB1 ESR2 GDF3 HOXA5 IL17D ADIPOQ BRPF1 CEBPG CUX1 ESRRA GDF6 HOXA6 IL17F ADNP BRPF3 CERS1 CX3CL1 ETS1 GIN1 HOXA7 IL18 AEBP1 BUD31 CERS2 CXCL10 ETS2 GLIS3 HOXB1 IL19 AFF4 C17ORF77 CERS4 CXCL11 ETV3 GMEB1 HOXB13 IL1A AHR C1QTNF4 CFL2 CXCL12 ETV7 GPBP1 HOXB5 IL1B AIMP1 C21ORF66 CHIA CXCL13 FAM3B GPER HOXB6 IL1F3 ALS2CR8 CBFA2T2 CIR1 CXCL14 FAM3D GPI HOXB7 IL1F5 ALX1 CBFA2T3 CITED1 CXCL16 FASLG GREM1 HOXB9 IL1F6 ARGFX CBFB CITED2 CXCL3 FBLN1 GREM2 HOXC4 IL1F7
    [Show full text]
  • HIF3A Antibody Product Type
    PRODUCT INFORMATION Product name：HIF3A antibody Product type： Primary antibodies Description： Rabbit polyclonal to HIF3A Immunogen：3 synthetic peptides (human) conjugated to KLH Reacts with： Human, Mouse Tested applications： ELISA, WB & IF GENE INFORMATION Gene Symbol：HIF3A Gene Name：hypoxia inducible factor 3, alpha subunit Ensembl ID：ENSG00000124440 Entrez GeneID：64344 GenBank Accession number：AK027725 Omim ID：609976 Swiss­Prot：Q9Y2N7 Molecular weight of HIF3A： 72.4kDa Function：Involved in adaptive response to hypoxia. Suppresses hypoxia­inducible expression of HIF1A and EPAS1. Binds to core DNA sequence 5'­TACGTG­3' within the hypoxia response element (HRE) of target gene promoters. The complex HIF3A­ARNT activates the transcription of reporter genes driven by HRE. Isoform 4 has a dominant­ negative function of inactivating HIF1A­mediated transcription. Isoform 4 attenuates the binding of HIF1A to hypoxia­responsive elements (HRE), thus inhibiting HRE­driven transcription. Hypoxia induces down­regulation of isoform 4, leading to activation of HIF1A in hypoxia. Conversely, upon restoring normoxia, the expression of isoform 4 increases and thereby secure an inhibition of HIF1A activity. Isoform 4 may be a negative regulator of hypoxia­inducible gene expression in the kidney and may be involved in renal tumorigenesis. Functions as an inhibitor of angiogenesis in the cornea Expected subcellular localization：Nucleus. Cytoplasm. Note: In the nuclei of all periportal and perivenous hepatocytes. In the distal perivenous zone, detected in the cytoplasm of the hepatocytes Summary：The protein encoded by this gene is the alpha­3 subunit of one of several alpha/beta­subunit heterodimeric transcription factors that regulate many adaptive responses to low oxygen tension (hypoxia).
    [Show full text]
  • Open Full Page
    Published OnlineFirst January 12, 2016; DOI: 10.1158/0008-5472.CAN-15-1859 Cancer Tumor and Stem Cell Biology Research Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1a and HIF2a Desir ee Schonenberger€ 1, Sabine Harlander1,2, Michal Rajski1, Robert A. Jacobs1,2,3, Anne-Kristine Lundby1,2, Mojca Adlesic1, Tomas Hejhal1, Peter J. Wild4, Carsten Lundby1,2, and Ian J. Frew1,2 Abstract The von Hippel–Lindau (VHL) tumor suppressor gene is inac- chondrial abundance and oxidative capacity, glycogen accu- tivated in the majority of clear cell renal cell carcinomas (ccRCC), mulation, and acquisition of a clear cell phenotype in Vhl- but genetic ablation of Vhl alone in mouse models is insufficient deficient renal epithelial cells. HIF1a, but not HIF2a, induced to recapitulate human tumorigenesis. One function of pVHL is to Warburg-like metabolism characterized by increased glycoly- regulate the stability of the hypoxia-inducible factors (HIF), sis, decreased oxygen consumption, and decreased ATP pro- which become constitutively activated in the absence of pVHL. duction in mouse embryonic fibroblasts, providing insights In established ccRCC, HIF1a has been implicated as a renal tumor into the cellular changes potentially occurring in Vhl mutant suppressor, whereas HIF2a is considered an oncoprotein. In this renal cells before ccRCC formation. Importantly, deletion of study, we investigated the contributions of HIF1a and HIF2a to either Hif1a or Hif2a completely prevented the formation of ccRCC initiation in the context of Vhl deficiency. We found that renal cysts and tumors in Vhl/Trp53 mutant mice. These find- deleting Vhl plus Hif1a or Hif2a specifically in the renal ings argue that both HIF1a and HIF2a exert protumorigenic epithelium did not induce tumor formation.
    [Show full text]
  • Role of RUNX1 in Aberrant Retinal Angiogenesis Jonathan D
    Page 1 of 25 Diabetes Identification of RUNX1 as a mediator of aberrant retinal angiogenesis Short Title: Role of RUNX1 in aberrant retinal angiogenesis Jonathan D. Lam,†1 Daniel J. Oh,†1 Lindsay L. Wong,1 Dhanesh Amarnani,1 Cindy Park- Windhol,1 Angie V. Sanchez,1 Jonathan Cardona-Velez,1,2 Declan McGuone,3 Anat O. Stemmer- Rachamimov,3 Dean Eliott,4 Diane R. Bielenberg,5 Tave van Zyl,4 Lishuang Shen,1 Xiaowu Gai,6 Patricia A. D’Amore*,1,7 Leo A. Kim*,1,4 Joseph F. Arboleda-Velasquez*1 Author affiliations: 1Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, MA 02114 2Universidad Pontificia Bolivariana, Medellin, Colombia, #68- a, Cq. 1 #68305, Medellín, Antioquia, Colombia 3C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114 4Retina Service, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 243 Charles St., Boston, MA 02114 5Vascular Biology Program, Boston Children’s Hospital, Department of Surgery, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115 6Center for Personalized Medicine, Children’s Hospital Los Angeles, Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027, USA 7Department of Pathology, Harvard Medical School, 25 Shattuck St., Boston, MA 02115 Corresponding authors: Joseph F. Arboleda-Velasquez: [email protected] Ph: (617) 912-2517 Leo Kim: [email protected] Ph: (617) 912-2562 Patricia D’Amore: [email protected] Ph: (617) 912-2559 Fax: (617) 912-0128 20 Staniford St. Boston MA, 02114 † These authors contributed equally to this manuscript Word Count: 1905 Tables and Figures: 4 Diabetes Publish Ahead of Print, published online April 11, 2017 Diabetes Page 2 of 25 Abstract Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world’s working adult population, and affects those with type 1 and type 2 diabetes mellitus.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Figure S17 Figure S16
    immune responseregulatingcellsurfacereceptorsignalingpathway ventricular cardiacmuscletissuedevelopment t cellactivationinvolvedinimmuneresponse intrinsic apoptoticsignalingpathway single organismalcelladhesion cholesterol biosyntheticprocess myeloid leukocytedifferentiation determination ofadultlifespan response tointerferongamma muscle organmorphogenesis endothelial celldifferentiation brown fatcelldifferentiation mitochondrion organization myoblast differentiation response toprotozoan amino acidtransport leukocyte migration cytokine production t celldifferentiation protein secretion response tovirus angiogenesis Scrt1 Tcf25 Dpf1 Sap30 Ing2 Zfp654 Sp9 Zfp263 Mxi1 Hes6 Zfp395 Rlf Ppp1r13l Snapc1 C030039L03Rik Hif1a Arrb1 Glis3 Rcor2 Hif3a Fbxo21 Dnajc21 Rest Sirt6 Foxj1 Kdm5b Ankzf1 Sos2 Plscr1 Jdp2 Rbbp8 Etv4 Msh5 Mafg Tsc22d3 Nupr1 Ddit3 Cebpg Zfp790 Atf5 Cebpb Atf3 Trim21 Irf9 Irf2 Tbx21 Stat2 Stat1 Zbp1 Irf1 aGOslimPos Ikzf3 Oasl1 Irf7 Trim30a Dhx58 Txk Rorc Rora Nr1d2 Setdb2 Vdr Vax2 Nr1d1 Foxs1 Eno1 Thap3 Nfkbil1 Edf1 Srebf1 Lbr Tead1 Zfp608 Pcx Ift57 Ssbp4 Stat3 Mxd1 Pml Ssh2 Chd7 Maf Cic Bcl3 Prkdc Mbd5 Ppfibp2 Foxp2 Tal2 Mlf1 Bcl6b Zfp827 Ikzf2 Phtf2 Bmyc Plagl2 Nfkb2 Nfkb1 Tox Nrip1 Utf1 Klf3 Plagl1 Nfkbib Spib Nfkbie Akna Rbpj Ncoa3 Id1 Tnp2 Gata3 Gata1 Pparg Id2 Epas1 Zfp280b Commons Pathway Erg GO MSigDB KEGG Hhex WikiPathways SetGene Databases Batf Aff3 Zfp266 gene modules other (hypergeometric TF, from Figure Trim24 Zbtb5 Foxo3 Aebp2 XPodNet -protein-proteininteractionsinthepodocyteexpandedbySTRING Ppp1r10 Dffb Trp53 Enrichment
    [Show full text]
  • Metabolic Profiling of Cancer Cells Reveals Genome-Wide
    ARTICLE https://doi.org/10.1038/s41467-019-09695-9 OPEN Metabolic profiling of cancer cells reveals genome- wide crosstalk between transcriptional regulators and metabolism Karin Ortmayr 1, Sébastien Dubuis1 & Mattia Zampieri 1 Transcriptional reprogramming of cellular metabolism is a hallmark of cancer. However, systematic approaches to study the role of transcriptional regulators (TRs) in mediating 1234567890():,; cancer metabolic rewiring are missing. Here, we chart a genome-scale map of TR-metabolite associations in human cells using a combined computational-experimental framework for large-scale metabolic profiling of adherent cell lines. By integrating intracellular metabolic profiles of 54 cancer cell lines with transcriptomic and proteomic data, we unraveled a large space of associations between TRs and metabolic pathways. We found a global regulatory signature coordinating glucose- and one-carbon metabolism, suggesting that regulation of carbon metabolism in cancer may be more diverse and flexible than previously appreciated. Here, we demonstrate how this TR-metabolite map can serve as a resource to predict TRs potentially responsible for metabolic transformation in patient-derived tumor samples, opening new opportunities in understanding disease etiology, selecting therapeutic treat- ments and in designing modulators of cancer-related TRs. 1 Institute of Molecular Systems Biology, ETH Zurich, Otto-Stern-Weg 3, CH-8093 Zurich, Switzerland. Correspondence and requests for materials should be addressed to M.Z. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:1841 | https://doi.org/10.1038/s41467-019-09695-9 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-09695-9 ranscriptional regulators (TRs) are at the interface between implemented by the additional quantification of total protein the cell’s ability to sense and respond to external stimuli or abundance and is based on the assumption that protein content T 1 changes in internal cell-state .
    [Show full text]
  • Micro-Rnas Dependent Regulation of DNMT and Hif1α Gene Expression
    www.nature.com/scientificreports OPEN micro-RNAs dependent regulation of DNMT and HIF1α gene expression in thrombotic disorders Received: 3 August 2018 Aatira Vijay1, Prabhash Kumar Jha1, Iti Garg1, Manish Sharma1, Mohammad Zahid Ashraf1,2 & Accepted: 21 November 2018 Bhuvnesh Kumar1 Published: xx xx xxxx MicroRNAs (miRNAs) are involved in a wide variety of cellular processes and post-transcriptionally regulate several mechanism and diseases. However, contribution of miRNAs functioning during hypoxia and DNA methylation together is less understood. The current study was aimed to fnd a shared miRNAs signature upstream to hypoxia (via HIF gene family members) and methylation (via DNMT gene family members). This was followed by the global validation of the hypoxia related miRNA signature using miRNA microarray meta-analysis of the hypoxia induced human samples. We further concluded the study by looking into thrombosis related terms and pathways enriched during protein-protein interaction (PPI) network analysis of these two sets of gene family. Network prioritization of these shared miRNAs reveals miR-129, miR-19band miR-23b as top regulatory miRNAs. A comprehensive meta-analysis of microarray datasets of hypoxia samples revealed 29 diferentially expressed miRNAs. GSEA of the interacting genes in the DNMT-HIF PPI network indicated thrombosis associated pathways including “Hemostasis”, “TPO signaling pathway” and “angiogenesis”. Interestingly, the study has generated a novel database of candidate miRNA signatures shared between hypoxia and methylation, and their relation to thrombotic pathways, which might aid in the development of potential therapeutic biomarkers. Venous thromboembolism (VTE) is the third most fatal cardiovascular complication. Around one in every three patients with VTE, develops pulmonary embolism (PE)-a condition in which thrombus drifs through the blood fow and gets lodged into the lungs; two in every three patients manifest deep vein thrombosis (DVT)1.
    [Show full text]
  • Induction of Therapeutic Tissue Tolerance Foxp3 Expression Is
    Downloaded from http://www.jimmunol.org/ by guest on October 2, 2021 is online at: average * The Journal of Immunology , 13 of which you can access for free at: 2012; 189:3947-3956; Prepublished online 17 from submission to initial decision 4 weeks from acceptance to publication September 2012; doi: 10.4049/jimmunol.1200449 http://www.jimmunol.org/content/189/8/3947 Foxp3 Expression Is Required for the Induction of Therapeutic Tissue Tolerance Frederico S. Regateiro, Ye Chen, Adrian R. Kendal, Robert Hilbrands, Elizabeth Adams, Stephen P. Cobbold, Jianbo Ma, Kristian G. Andersen, Alexander G. Betz, Mindy Zhang, Shruti Madhiwalla, Bruce Roberts, Herman Waldmann, Kathleen F. Nolan and Duncan Howie J Immunol cites 35 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription http://www.jimmunol.org/content/suppl/2012/09/17/jimmunol.120044 9.DC1 This article http://www.jimmunol.org/content/189/8/3947.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of October 2, 2021.
    [Show full text]
  • Content Based Search in Gene Expression Databases and a Meta-Analysis of Host Responses to Infection
    Content Based Search in Gene Expression Databases and a Meta-analysis of Host Responses to Infection A Thesis Submitted to the Faculty of Drexel University by Francis X. Bell in partial fulfillment of the requirements for the degree of Doctor of Philosophy November 2015 c Copyright 2015 Francis X. Bell. All Rights Reserved. ii Acknowledgments I would like to acknowledge and thank my advisor, Dr. Ahmet Sacan. Without his advice, support, and patience I would not have been able to accomplish all that I have. I would also like to thank my committee members and the Biomed Faculty that have guided me. I would like to give a special thanks for the members of the bioinformatics lab, in particular the members of the Sacan lab: Rehman Qureshi, Daisy Heng Yang, April Chunyu Zhao, and Yiqian Zhou. Thank you for creating a pleasant and friendly environment in the lab. I give the members of my family my sincerest gratitude for all that they have done for me. I cannot begin to repay my parents for their sacrifices. I am eternally grateful for everything they have done. The support of my sisters and their encouragement gave me the strength to persevere to the end. iii Table of Contents LIST OF TABLES.......................................................................... vii LIST OF FIGURES ........................................................................ xiv ABSTRACT ................................................................................ xvii 1. A BRIEF INTRODUCTION TO GENE EXPRESSION............................. 1 1.1 Central Dogma of Molecular Biology........................................... 1 1.1.1 Basic Transfers .......................................................... 1 1.1.2 Uncommon Transfers ................................................... 3 1.2 Gene Expression ................................................................. 4 1.2.1 Estimating Gene Expression ............................................ 4 1.2.2 DNA Microarrays ......................................................
    [Show full text]
  • DDIT4/REDD1/RTP801 Is a Novel Negative Regulator of Schwann Cell Myelination
    The Journal of Neuroscience, September 18, 2013 • 33(38):15295–15305 • 15295 Cellular/Molecular DDIT4/REDD1/RTP801 Is a Novel Negative Regulator of Schwann Cell Myelination Roberta Noseda,1,2 Sophie Belin,1 Franc¸oise Piguet,1 Ilaria Vaccari,1 Stefania Scarlino,1 Paola Brambilla,3 Filippo Martinelli Boneschi,3 Maria Laura Feltri,4 Lawrence Wrabetz,4 Angelo Quattrini,3 Elena Feinstein,5 Richard L. Huganir,6 and Alessandra Bolino1 1Dulbecco Telethon Institute at Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, 20132 Milan, Italy, 2UniSR, Vita Salute San Raffaele University, 20132 Milan, Italy, 3Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, 20132 Milan, Italy, 4Hunter James Kelly Research Institute, University at Buffalo, State University of New York, Buffalo, New York 14203, 5Quark Pharmaceuticals, 70400 Ness Ziona, Israel, and 6The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 Signals that promote myelination must be tightly modulated to adjust myelin thickness to the axonal diameter. In the peripheral nervous system, axonal neuregulin 1 type III promotes myelination by activating erbB2/B3 receptors and the PI3K/AKT/mTOR pathway in Schwann cells. Conversely, PTEN (phosphatase and tensin homolog on chromosome 10) dephosphorylates PtdIns(3,4,5)P3 and nega- tively regulates the AKT pathway and myelination. Recently, the DLG1/SAP97 scaffolding protein was described to interact with PTEN to enhance PIP3 dephosphorylation. Here we now report that nerves from mice with conditional inactivation of Dlg1 in Schwann cells display only a transient increase in myelin thickness during development, suggesting that DLG1 is a transient negative regulator of myelination. Instead, we identified DDIT4/RTP801/REDD1 as a sustained negative modulator of myelination.
    [Show full text]