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PMID: 29069589 Published · ppublish English Journal Article

Understanding Tissue-Specific Gene Regulation.

Cell reports ·Vol. 21 ·No. 4 ·2017-10-24 ·Pages 1077-1088

Sonawane AR, Platig J, Fagny M, Chen CY, Paulson JN, Lopes-Ramos CM, DeMeo DL, Quackenbush J, Glass K, Kuijjer ML

Abstract

Although all human tissues carry out common processes, tissues are distinguished by gene expression patterns, implying that distinct regulatory programs control tissue specificity. In this study, we investigate gene expression and regulation across 38 tissues profiled in the Genotype-Tissue Expression project. We find that network edges (transcription factor to target gene connections) have higher tissue specificity than network nodes (genes) and that regulating nodes (transcription factors) are less likely to be expressed in a tissue-specific manner as compared to their targets (genes). Gene set enrichment analysis of network targeting also indicates that the regulation of tissue-specific function is largely independent of transcription factor expression. In addition, tissue-specific genes are not highly targeted in their corresponding tissue network. However, they do assume bottleneck positions due to variability in transcription factor targeting and the influence of non-canonical regulatory interactions. These results suggest that tissue specificity is driven by context-dependent regulatory paths, providing transcriptional control of tissue-specific processes.

Keywords
GTEx gene expression gene regulation network biology network medicine regulatory networks tissue specificity transcription factors transcriptional regulation transcriptome
MeSH Terms
Gene Regulatory Networks Genome, Human Humans Organ Specificity Protein Interaction Maps Transcription Factors/genetics,metabolism Transcriptional Activation Transcriptome
Chemicals
Transcription Factors
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Sonawane Abhijeet Rajendra
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Platig John
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Fagny Maud
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Chen Cho-Yi
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Paulson Joseph Nathaniel
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Lopes-Ramos Camila Miranda
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
DeMeo Dawn Lisa
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Quackenbush John
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Glass Kimberly
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
Kuijjer Marieke Lydia
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: [email protected].
References (41)
41 references, click to expand
  1. Architecture of the human regulatory network derived from ENCODE data.
    Nature. 2012 Sep 6;489(7414):91-100 PMID: 22955619
  2. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  3. Passing messages between biological networks to refine predicted interactions.
    PLoS One. 2013 May 31;8(5):e64832 PMID: 23741402
  4. Smooth quantile normalization.
    Biostatistics. 2017 Jul 10;:null PMID: 29036413
  5. The importance of bottlenecks in protein networks: correlation with gene essentiality and expression dynamics.
    PLoS Comput Biol. 2007 Apr 20;3(4):e59 PMID: 17447836
  6. Network biology: understanding the cell's functional organization.
    Nat Rev Genet. 2004 Feb;5(2):101-13 PMID: 14735121
  7. Understanding multicellular function and disease with human tissue-specific networks.
    Nat Genet. 2015 Jun;47(6):569-76 PMID: 25915600
  8. Gene expression profiling of neural stem cells and identification of regulators of neural differentiation during cortical development.
    Stem Cells. 2011 Nov;29(11):1817-28 PMID: 21898698
  9. Gene co-expression network analysis reveals common system-level properties of prognostic genes across cancer types.
    Nat Commun. 2014;5:3231 PMID: 24488081
  10. Human genomics. The human transcriptome across tissues and individuals.
    Science. 2015 May 8;348(6235):660-5 PMID: 25954002
  11. STRING v10: protein-protein interaction networks, integrated over the tree of life.
    Nucleic Acids Res. 2015 Jan;43(Database issue):D447-52 PMID: 25352553
  12. NeuroD2 is necessary for development and survival of central nervous system neurons.
    Dev Biol. 2001 Jun 1;234(1):174-87 PMID: 11356028
  13. Sexually-dimorphic targeting of functionally-related genes in COPD.
    BMC Syst Biol. 2014 Nov 28;8:118 PMID: 25431000
  14. Exploring regulation in tissues with eQTL networks.
    Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):E7841-E7850 PMID: 28851834
  15. GRHL1 acts as tumor suppressor in neuroblastoma and is negatively regulated by MYCN and HDAC3.
    Cancer Res. 2014 May 1;74(9):2604-16 PMID: 24419085
  16. Tissue-aware RNA-Seq processing and normalization for heterogeneous and sparse data.
    BMC Bioinformatics. 2017 Oct 3;18(1):437 PMID: 28974199
  17. Weighted frequent gene co-expression network mining to identify genes involved in genome stability.
    PLoS Comput Biol. 2012;8(8):e1002656 PMID: 22956898
  18. Sharing and Specificity of Co-expression Networks across 35 Human Tissues.
    PLoS Comput Biol. 2015 May 13;11(5):e1004220 PMID: 25970446
  19. A census of human transcription factors: function, expression and evolution.
    Nat Rev Genet. 2009 Apr;10 (4):252-63 PMID: 19274049
  20. Tet1 regulates adult hippocampal neurogenesis and cognition.
    Cell Stem Cell. 2013 Aug 1;13(2):237-45 PMID: 23770080
  21. Community structure in social and biological networks.
    Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):7821-6 PMID: 12060727
  22. Diet-induced weight loss leads to a switch in gene regulatory network control in the rectal mucosa.
    Genomics. 2016 Oct;108(3-4):126-133 PMID: 27524493
  23. A multitude of genes expressed solely in meiotic or postmeiotic spermatogenic cells offers a myriad of contraceptive targets.
    Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12201-6 PMID: 14526100
  24. An Expanded View of Complex Traits: From Polygenic to Omnigenic.
    Cell. 2017 Jun 15;169(7):1177-1186 PMID: 28622505
  25. Nuclear architecture and gene regulation.
    Biochim Biophys Acta. 2008 Nov;1783(11):2174-84 PMID: 18718493
  26. A general framework for weighted gene co-expression network analysis.
    Stat Appl Genet Mol Biol. 2005;4:Article17 PMID: 16646834
  27. Finding community structure in very large networks.
    Phys Rev E Stat Nonlin Soft Matter Phys. 2004 Dec;70(6 Pt 2):066111 PMID: 15697438
  28. Determination and inference of eukaryotic transcription factor sequence specificity.
    Cell. 2014 Sep 11;158(6):1431-1443 PMID: 25215497
  29. Pax3 acts cell autonomously in the neural tube and somites by controlling cell surface properties.
    Development. 2001 Jun;128(11):1995-2005 PMID: 11493522
  30. Subcortical origins of human and monkey neocortical interneurons.
    Nat Neurosci. 2013 Nov;16(11):1588-97 PMID: 24097041
  31. Molecular analysis of an MHC class II deficiency patient reveals a novel mutation in the RFX5 gene.
    Immunogenetics. 1999 Apr;49(4):338-45 PMID: 10079298
  32. A network model for angiogenesis in ovarian cancer.
    BMC Bioinformatics. 2015 Apr 11;16:115 PMID: 25888305
  33. Tbx20 functions as an important regulator of estrogen-mediated cardiomyocyte protection during oxidative stress.
    Int J Cardiol. 2013 Oct 9;168(4):3704-14 PMID: 23871353
  34. RNA-seq analysis of hippocampal tissues reveals novel candidate genes for drug refractory epilepsy in patients with MTLE-HS.
    Genomics. 2016 May;107(5):178-88 PMID: 27094248
  35. The human testis-specific proteome defined by transcriptomics and antibody-based profiling.
    Mol Hum Reprod. 2014 Jun;20(6):476-88 PMID: 24598113
  36. Matrix eQTL: ultra fast eQTL analysis via large matrix operations.
    Bioinformatics. 2012 May 15;28(10):1353-8 PMID: 22492648
  37. FIMO: scanning for occurrences of a given motif.
    Bioinformatics. 2011 Apr 1;27(7):1017-8 PMID: 21330290
  38. YY1 inhibits differentiation and function of regulatory T cells by blocking Foxp3 expression and activity.
    Nat Commun. 2016 Feb 19;7:10789 PMID: 26892542
  39. Circuitry and dynamics of human transcription factor regulatory networks.
    Cell. 2012 Sep 14;150(6):1274-86 PMID: 22959076
  40. Characterization of TBX20 in human hearts and its regulation by TFAP2.
    J Cell Biochem. 2008 Jun 1;104(3):1022-33 PMID: 18275040
  41. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans.
    Science. 2015 May 8;348(6235):648-60 PMID: 25954001
Article Info
Journal
Cell reports
Abbr.
Cell Rep
ISSN
2211-1247
DOI
10.1016/j.celrep.2017.10.001
Email
[email protected]
[email protected]
Published
2017-10-24
Pages
1077-1088
Language
English
Region
United States
NLM ID
101573691
PMCID
PMC5828531
Subset
IM
Grants
NCI NIH HHS · R35 CA197449 · United States
NHLBI NIH HHS · K25 HL133599 · United States
NHLBI NIH HHS · P01 HL105339 · United States
NCI NIH HHS · U01 CA190234 · United States
NIAID NIH HHS · R01 AI099204 · United States
NCI NIH HHS · P50 CA127003 · United States
NCI NIH HHS · P30 CA006516 · United States
NCI NIH HHS · P50 CA165962 · United States
NHLBI NIH HHS · P01 HL114501 · United States
NHLBI NIH HHS · R01 HL111759 · United States
External Links
PubMed source DOI: 10.1016/j.celrep.2017.10.001 PMC Full Text View journal details
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