Insights from Systems Biology in Physiological Studies: Learning from Context

Systems biology presents an integrated view of biological systems, focusing on the relations between elements, whether functional or evolutionary, and providing a rich framework for the comprehension of life. At the same time, many low-throughput experimental studies are performed without influence from this integrated view, whilst high-throughput experiments use low-throughput results in their validation and interpretation. We propose an inversion in this logic, and ask which benefits could be obtained from a holistic view coming from high-throughput studies―and systems biology in particular―in interpreting and designing low-throughput experiments. By exploring some key examples from the renal and adrenal physiology, we try to show that network and modularity theory, along with observed patterns of association between elements in a biological system, can have profound effects on our ability to draw meaningful conclusions from experiments.

[1]  Uri Alon,et al.  Dynamic proteomics reveals bimodal protein dynamics of cancer cells in response to HSP90 inhibitor , 2017, BMC Systems Biology.

[2]  T. Santa-Coloma,et al.  The Chloride Anion Acts as a Second Messenger in Mammalian Cells - Modifying the Expression of Specific Genes , 2016, Cellular Physiology and Biochemistry.

[3]  Davide Heller,et al.  eggNOG 4.5: a hierarchical orthology framework with improved functional annotations for eukaryotic, prokaryotic and viral sequences , 2015, Nucleic Acids Res..

[4]  A. Barabasi,et al.  Uncovering disease-disease relationships through the incomplete interactome , 2015, Science.

[5]  R. Kolodner,et al.  S-Score: A Scoring System for the Identification and Prioritization of Predicted Cancer Genes , 2014, PloS one.

[6]  R. Milo,et al.  Noise Genetics: Inferring Protein Function by Correlating Phenotype with Protein Levels and Localization in Individual Human Cells , 2014, PLoS genetics.

[7]  V. Babich,et al.  The biophysical and molecular basis of intracellular pH sensing by Na+/H+ exchanger‐3 , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  Jason A. Corwin,et al.  Cytoplasmic genetic variation and extensive cytonuclear interactions influence natural variation in the metabolome , 2013, eLife.

[9]  Chris Sander,et al.  Drug Synergy Screen and Network Modeling in Dedifferentiated Liposarcoma Identifies CDK4 and IGF1R as Synergistic Drug Targets , 2013, Science Signaling.

[10]  Tong Wang,et al.  Proximal tubule specific knockout of the Na+/H+ exchanger NHE3: effects on bicarbonate absorption and ammonium excretion , 2013, Journal of Molecular Medicine.

[11]  A. Girardi,et al.  Fructose Acutely Stimulates NHE3 Activity in Kidney Proximal Tubule , 2012, Kidney and Blood Pressure Research.

[12]  Edson L. Folador,et al.  Computational Prediction of Protein-Protein Interactions in Leishmania Predicted Proteomes , 2012, PloS one.

[13]  O. Moe,et al.  Proximal tubule Na+/H+ exchanger activity in adult NHE8-/-, NHE3-/-, and NHE3-/-/NHE8-/- mice. , 2012, American journal of physiology. Renal physiology.

[14]  M. Jarvelin,et al.  Identification of IL6R and chromosome 11q13.5 as risk loci for asthma , 2011, The Lancet.

[15]  G. Fuellen,et al.  Derivation of an Interaction/regulation Network Describing Pluripotency in Human , 2022 .

[16]  Baldomero Oliva,et al.  BIPS: BIANA Interolog Prediction Server. A tool for protein–protein interaction inference , 2012, Nucleic Acids Res..

[17]  P. Braun Interactome mapping for analysis of complex phenotypes: Insights from benchmarking binary interaction assays , 2012, Proteomics.

[18]  A. Girardi,et al.  Distinct mechanisms underlie adaptation of proximal tubule Na+/H+ exchanger isoform 3 in response to chronic metabolic and respiratory acidosis , 2012, Pflügers Archiv - European Journal of Physiology.

[19]  R. Cole,et al.  Calmodulin Kinase II Constitutively Binds, Phosphorylates, and Inhibits Brush Border Na+/H+ Exchanger 3 (NHE3) by a NHERF2 Protein-dependent Process* , 2012, The Journal of Biological Chemistry.

[20]  George F R Ellis,et al.  Top-down causation and emergence: some comments on mechanisms , 2012, Interface Focus.

[21]  P. Visscher,et al.  Five years of GWAS discovery. , 2012, American journal of human genetics.

[22]  H. Kitano,et al.  Software for systems biology: from tools to integrated platforms , 2011, Nature Reviews Genetics.

[23]  Avi Ma’ayan Introduction to Network Analysis in Systems Biology , 2011, Science Signaling.

[24]  Manuel A. R. Ferreira,et al.  Identification of IL6R and chromosome 11q13.5 as risk loci for asthma , 2011, The Lancet.

[25]  Jonathan D. G. Jones,et al.  Evidence for Network Evolution in an Arabidopsis Interactome Map , 2011, Science.

[26]  E. Marcotte,et al.  Prioritizing candidate disease genes by network-based boosting of genome-wide association data. , 2011, Genome research.

[27]  N. Rebouças,et al.  Essential regulatory elements for NHE3 gene transcription in renal proximal tubule cells. , 2011, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[28]  Leszek P. Pryszcz,et al.  MetaPhOrs: orthology and paralogy predictions from multiple phylogenetic evidence using a consistency-based confidence score , 2010, Nucleic acids research.

[29]  Erika Check Hayden,et al.  Human genome at ten: Life is complicated , 2010, Nature.

[30]  Gary D Bader,et al.  The Genetic Landscape of a Cell , 2010, Science.

[31]  Kwang-Hyun Cho,et al.  Hub genes with positive feedbacks function as master switches in developmental gene regulatory networks , 2009, Bioinform..

[32]  E. Stone,et al.  Systems Genetics of Complex Traits in Drosophila melanogaster , 2009, Nature Genetics.

[33]  C. Yun,et al.  IRBIT, Inositol 1,4,5-Triphosphate (IP3) Receptor-binding Protein Released with IP3, Binds Na+/H+ Exchanger NHE3 and Activates NHE3 Activity in Response to Calcium* , 2008, Journal of Biological Chemistry.

[34]  A. Barabasi,et al.  High-Quality Binary Protein Interaction Map of the Yeast Interactome Network , 2008, Science.

[35]  A. Pandey,et al.  Casein kinase 2 binds to the C terminus of Na+/H+ exchanger 3 (NHE3) and stimulates NHE3 basal activity by phosphorylating a separate site in NHE3. , 2008, Molecular biology of the cell.

[36]  Dragomir R. Radev,et al.  Identifying gene-disease associations using centrality on a literature mined gene-interaction network , 2008, ISMB.

[37]  David Warde-Farley,et al.  GeneMANIA: a real-time multiple association network integration algorithm for predicting gene function , 2008, Genome Biology.

[38]  A. Bicknell The Tissue‐Specific Processing of Pro‐Opiomelanocortin , 2008, Journal of neuroendocrinology.

[39]  David S Sanders,et al.  Newly identified genetic risk variants for celiac disease related to the immune response , 2008, Nature Genetics.

[40]  Fidel Ramírez,et al.  Computing topological parameters of biological networks , 2008, Bioinform..

[41]  G. Wagner,et al.  The road to modularity , 2007, Nature Reviews Genetics.

[42]  U. Alon Network motifs: theory and experimental approaches , 2007, Nature Reviews Genetics.

[43]  A. Barabasi,et al.  The human disease network , 2007, Proceedings of the National Academy of Sciences.

[44]  Jinn-Moon Yang,et al.  3D-partner: a web server to infer interacting partners and binding models , 2007, Nucleic Acids Res..

[45]  Qiong Gao,et al.  Resources for integrative systems biology: from data through databases to networks and dynamic system models , 2006, Briefings Bioinform..

[46]  Hunter B. Fraser,et al.  Coevolution, modularity and human disease. , 2006, Current opinion in genetics & development.

[47]  Martin G. Everett,et al.  A Graph-theoretic perspective on centrality , 2006, Soc. Networks.

[48]  M. Radrizzani,et al.  Relative contribution of V‐H+ATPase and NA+/H+ exchanger to bicarbonate reabsorption in proximal convoluted tubules of old rats , 2006, Aging cell.

[49]  P. Dudeja,et al.  Transcriptional stimulation of the human NHE3 promoter activity by PMA: PKC independence and involvement of the transcription factor EGR-1. , 2006, The Biochemical journal.

[50]  Mike Tyers,et al.  BioGRID: a general repository for interaction datasets , 2005, Nucleic Acids Res..

[51]  K. Strange The end of "naive reductionism": rise of systems biology or renaissance of physiology? , 2005, American journal of physiology. Cell physiology.

[52]  W. Bains Paradoxes of non-trivial gene networks: how cancer-causing mutations can appear to be cancer-protective. , 2004, Rejuvenation research.

[53]  J. Stelling,et al.  Robustness of Cellular Functions , 2004, Cell.

[54]  Lan V. Zhang,et al.  Evidence for dynamically organized modularity in the yeast protein–protein interaction network , 2004, Nature.

[55]  M. Gerstein,et al.  Annotation transfer between genomes: protein-protein interologs and protein-DNA regulogs. , 2004, Genome research.

[56]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[57]  Hanno Steen,et al.  Development of human protein reference database as an initial platform for approaching systems biology in humans. , 2003, Genome research.

[58]  M. Low,et al.  Lack of Proopiomelanocortin Peptides Results in Obesity and Defective Adrenal Function but Normal Melanocyte Pigmentation in the Murine C57BL/6 Genetic Background , 2003, Annals of the New York Academy of Sciences.

[59]  J. Cassiman,et al.  The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions. , 2002, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[60]  G. Giebisch,et al.  Role of NHE isoforms in mediating bicarbonate reabsorption along the nephron. , 2001, American journal of physiology. Renal physiology.

[61]  M. G. Lee,et al.  Novel amiloride-sensitive sodium-dependent proton secretion in the mouse proximal convoluted tubule. , 2000, The Journal of clinical investigation.

[62]  M. Vidal,et al.  Protein interaction mapping in C. elegans using proteins involved in vulval development. , 2000, Science.

[63]  L. Yaswen,et al.  Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin , 1999, Nature Medicine.

[64]  P. Aronson,et al.  Specific Association of Megalin and the Na+/H+ Exchanger Isoform NHE3 in the Proximal Tubule* , 1999, The Journal of Biological Chemistry.

[65]  Agnieszka Sidor,et al.  NHE3 Kinase A Regulatory Protein E3KARP Binds the Epithelial Brush Border Na+/H+ Exchanger NHE3 and the Cytoskeletal Protein Ezrin* , 1998, The Journal of Biological Chemistry.

[66]  D. Goltzman,et al.  Structurally Diverse N-terminal Peptides of Parathyroid Hormone (PTH) and PTH-related Peptide (PTHRP) Inhibit the Na+/H+ Exchanger NHE3 Isoform by Binding to the PTH/PTHRP Receptor Type I and Activating Distinct Signaling Pathways* , 1996, The Journal of Biological Chemistry.

[67]  M. Baum Developmental Changes in Rabbit Juxtamedullary Proximal Convoluted Tubule Acidification , 1992, Pediatric Research.

[68]  M. DePamphilis,et al.  HUMAN DISEASE , 1957, The Ulster Medical Journal.

[69]  Harald Mischak,et al.  Integrating proteomics profiling data sets: a network perspective. , 2015, Methods in molecular biology.

[70]  O. Moe,et al.  Renal Acid-Base Physiology Proximal tubule Na / H exchanger activity in adult NHE 8 / , NHE 3 / , and NHE 3 / / NHE 8 / mice , 2012 .

[71]  C. J. Lote,et al.  The Proximal Tubule , 2012 .

[72]  J. Verlander,et al.  Role of NH3 and NH4+ transporters in renal acid-base transport. , 2011, American journal of physiology. Renal physiology.

[73]  Erika Check Hayden Human genome at ten: Life is complicated. , 2010, Nature.

[74]  A. Yoshiki,et al.  Mouse phenome research: implications of genetic background. , 2006, ILAR journal.

[75]  O. Loewi,et al.  Über humorale übertragbarkeit der Herznervenwirkung , 2005, Pflüger's Archiv für die gesamte Physiologie des Menschen und der Tiere.

[76]  Martin Vingron,et al.  IntAct: an open source molecular interaction database , 2004, Nucleic Acids Res..

[77]  Christian von Mering,et al.  STRING: a database of predicted functional associations between proteins , 2003, Nucleic Acids Res..

[78]  Judith A. Blake,et al.  The Mouse Genome Database (MGD). A comprehensive public resource of genetic, phenotypic and genomic data. The Mouse Genome Informatics Group , 1997, Nucleic Acids Res..

[79]  L. Hamm,et al.  Effects of barium and 5-(N-ethyl-N-isopropyl)-amiloride on proximal tubule ammonia transport. , 1992, The American journal of physiology.