Abstract
We have developed a method for reconstructing gene association networks and have applied this method to gene profiles from 3T3-L1 cells. Priorization of the candidate genes pinpointed a transcript annotated as APMAP (adipocyte plasma membrane-associated protein). Functional studies showed that APMAP is upregulated in murine and human adipogenic cell models as well as in a genetic mouse model of obesity. Silencing APMAP in 3T3-L1 cells strongly impaired the differentiation into adipocytes. Moreover, APMAP expression was strongly induced by the PPARγ ligand rosiglitazone in adipocytes in vitro and in vivo in adipose tissue. Using ChIP-qPCR and luciferase reporter assays, we show a functional PPARγ binding site. In addition, we provide evidence that the extracellular C-terminal domain of APMAP is required for the function of APMAP in adipocyte differentiation. Finally, we demonstrate that APMAP translocates from the endoplasmatic reticulum to the plasma membrane during adipocyte differentiation.
Similar content being viewed by others
References
Green H, Kehinde O (1975) An established preadipose cell line and its differentiation in culture II. Factors affecting the adipose conversion. Cell 5:19–27
Farmer SR (2006) Transcriptional control of adipocyte formation. Cell Metab 4:263–273
Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79:1147–1156
Lefterova MI, Lazar MA (2009) New developments in adipogenesis. Trends Endocrinol Metab 20:107–114
Birsoy K, Chen Z, Friedman J (2008) Transcriptional regulation of adipogenesis by KLF4. Cell Metab 7:339–347
Chen Z, Torrens JI, Anand A, Spiegelman BM, Friedman JM (2005) Krox20 stimulates adipogenesis via C/EBPbeta-dependent and -independent mechanisms. Cell Metab 1:93–106
Tong Q, Dalgin G, Xu H, Ting CN, Leiden JM, Hotamisligil GS (2000) Function of GATA transcription factors in preadipocyte–adipocyte transition. Science 290:134–138
Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA (2000) Inhibition of adipogenesis by Wnt signaling. Science 289:950–953
Lefterova MI, Zhang Y, Steger DJ, Schupp M, Schug J, Cristancho A, Feng D, Zhuo D, Stoeckert CJ Jr, Liu XS, Lazar MA (2008) PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev 22:2941–2952
Nielsen R, Pedersen TA, Hagenbeek D, Moulos P, Siersbaek R, Megens E, Denissov S, Borgesen M, Francoijs KJ, Mandrup S, Stunnenberg HG (2008) Genome-wide profiling of PPARgamma:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis. Genes Dev 22:2953–2967
Hackl H, Burkard TR, Sturn A, Rubio R, Schleiffer A, Tian S, Quackenbush J, Eisenhaber F, Trajanoski Z (2005) Molecular processes during fat cell development revealed by gene expression profiling and functional annotation. Genome Biol 6:R108
Di Camillo B, Sanchez-Cabo F, Toffolo G, Nair SK, Trajanoski Z, Cobelli C (2005) A quantization method based on threshold optimization for microarray short time series. BMC Bioinformatics 6(Suppl 4):S11
Liang S, Fuhrman S, Somogyi R (1998) Reveal, a general reverse engineering algorithm for inference of genetic network architectures. Pac Symp Biocomput 18–29
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504
Matys V, Kel-Margoulis OV, Fricke E, Liebich I, Land S, Barre-Dirrie A, Reuter I, Chekmenev D, Krull M, Hornischer K, Voss N, Stegmaier P, Lewicki-Potapov B, Saxel H, Kel AE, Wingender E (2006) TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucleic Acids Res 34:D108–D110
Bryne JC, Valen E, Tang MH, Marstrand T, Winther O, da Piedade I, Krogh A, Lenhard B, Sandelin A (2008) JASPAR, the open access database of transcription factor-binding profiles: new content and tools in the 2008 update. Nucleic Acids Res 36:D102–D106
Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D (2002) The human genome browser at UCSC. Genome Res 12:996–1006
Pruitt KD, Tatusova T, Maglott DR (2005) NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res 33:D501–D504
Quandt K, Frech K, Karas H, Wingender E, Werner T (1995) MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. Nucleic Acids Res 23:4878–4884
Soukas A, Socci ND, Saatkamp BD, Novelli S, Friedman JM (2001) Distinct transcriptional profiles of adipogenesis in vivo and in vitro. J Biol Chem 276:34167–34174
Pabinger S, Thallinger GG, Snajder R, Eichhorn H, Rader R, Trajanoski Z (2009) QPCR: application for real-time PCR data management and analysis. BMC Bioinformatics 10:268
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25:25–29
Kershaw EE, Schupp M, Guan HP, Gardner NP, Lazar MA, Flier JS (2007) PPARgamma regulates adipose triglyceride lipase in adipocytes in vitro and in vivo. Am J Physiol Endocrinol Metab 293:E1736–E1745
Albrektsen T, Richter HE, Clausen JT, Fleckner J (2001) Identification of a novel integral plasma membrane protein induced during adipocyte differentiation. Biochem J 359:393–402
Schneider G, Neuberger G, Wildpaner M, Tian S, Berezovsky I, Eisenhaber F (2006) Application of a sensitive collection heuristic for very large protein families: evolutionary relationship between adipose triglyceride lipase (ATGL) and classic mammalian lipases. BMC Bioinformatics 7:164
Ooi HS, Kwo CY, Wildpaner M, Sirota FL, Eisenhaber B, Maurer-Stroh S, Wong WC, Schleiffer A, Eisenhaber F, Schneider G (2009) ANNIE: integrated de novo protein sequence annotation. Nucleic Acids Res 37:W435–W440
Schaffer AA, Aravind L, Madden TL, Shavirin S, Spouge JL, Wolf YI, Koonin EV, Altschul SF (2001) Improving the accuracy of PSI-BLAST protein database searches with composition-based statistics and other refinements. Nucleic Acids Res 29:2994–3005
Stockigt J, Barleben L, Panjikar S, Loris EA (2008) 3D-Structure and function of strictosidine synthase–the key enzyme of monoterpenoid indole alkaloid biosynthesis. Plant Physiol Biochem 46:340–355
Harel M, Aharoni A, Gaidukov L, Brumshtein B, Khersonsky O, Meged R, Dvir H, Ravelli RB, McCarthy A, Toker L, Silman I, Sussman JL, Tawfik DS (2004) Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes. Nat Struct Mol Biol 11:412–419
Scharff EI, Koepke J, Fritzsch G, Lucke C, Ruterjans H (2001) Crystal structure of diisopropylfluorophosphatase from Loligo vulgaris. Structure 9:493–502
Tanaka Y, Morikawa K, Ohki Y, Yao M, Tsumoto K, Watanabe N, Ohta T, Tanaka I (2007) Structural and mutational analyses of Drp35 from Staphylococcus aureus: a possible mechanism for its lactonase activity. J Biol Chem 282:5770–5780
Andreeva A, Howorth D, Chandonia JM, Brenner SE, Hubbard TJ, Chothia C, Murzin AG (2008) Data growth and its impact on the SCOP database: new developments. Nucleic Acids Res 36:D419–D425
Cole C, Barber JD, Barton GJ (2008) The Jpred 3 secondary structure prediction server. Nucleic Acids Res 36:W197–W201
Ilhan A, Gartner W, Nabokikh A, Daneva T, Majdic O, Cohen G, Bohmig GA, Base W, Horl WH, Wagner L (2008) Localization and characterization of the novel protein encoded by C20orf3. Biochem J 414:485–495
Scheideler M, Elabd C, Zaragosi LE, Chiellini C, Hackl H, Sanchez-Cabo F, Yadav S, Duszka K, Friedl G, Papak C, Prokesch A, Windhager R, Ailhaud G, Dani C, Amri EZ, Trajanoski Z (2008) Comparative transcriptomics of human multipotent stem cells during adipogenesis and osteoblastogenesis. BMC Genomics 9:340
Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP, Walker JR, Hogenesch JB (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 101:6062–6067
Tomaru T, Steger DJ, Lefterova MI, Schupp M, Lazar MA (2009) Adipocyte-specific expression of murine resistin is mediated by synergism between peroxisome proliferator-activated receptor gamma and CCAAT/enhancer-binding proteins. J Biol Chem 284:6116–6125
Basso K, Margolin AA, Stolovitzky G, Klein U, Dalla-Favera R, Califano A (2005) Reverse engineering of regulatory networks in human B cells. Nat Genet 37:382–390
Schafer J, Strimmer K (2005) An empirical Bayes approach to inferring large-scale gene association networks. Bioinformatics 21:754–764
Castelo R, Roverato A (2009) Reverse engineering molecular regulatory networks from microarray data with qp-graphs. J Comput Biol 16:213–227
Katoh K, Toh H (2008) Recent developments in the MAFFT multiple sequence alignment program. Brief Bioinform 9:286–298
Acknowledgments
This work was supported by the Austrian Ministry for Science and Research (GEN-AU projects GOLD and BIN) and the Austrian Science Fund SFB (Project Lipotoxicity). PPARγ-MEFs were a gift from Dr. E. Rosen. OP9 cells were kindly provided by B. Pickel and SGBS cells by Novo Department of Pediatrics and Adolescent Medicine, University of Ulm. We thank David J. Steger and Mitch A. Lazar for providing ChIP material. The authors acknowledge the technical assistance provided by Stephan Seifriedsberger, Florian Stoeger, Martina Schweiger and Marie Loh.
Author information
Authors and Affiliations
Corresponding authors
Additional information
J. G. Bogner-Strauss and A. Prokesch contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Bogner-Strauss, J.G., Prokesch, A., Sanchez-Cabo, F. et al. Reconstruction of gene association network reveals a transmembrane protein required for adipogenesis and targeted by PPARγ. Cell. Mol. Life Sci. 67, 4049–4064 (2010). https://doi.org/10.1007/s00018-010-0424-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00018-010-0424-5