, Volume 73, Issue 4, pp 415–423 | Cite as

A network-based analysis of the human TET Gene Family

  • Shinji Ohsawa
  • Toshiaki Umemura
  • Hiromichi Akahori
  • Tomoyoshi Terada
  • Yoshinori MutoEmail author
Original Article


Ten-eleven translocation (TET) proteins, a family of Fe2+- and 2-oxoglutarate-dependent dioxygenases, are involved in DNA demethylation. Three TET paralogs have been identified (TET1, TET2, and TET3) and they show different patterns of tissue-specific expression. In our previous evolutionary studies, we found that the TET1 and TET2 genes underwent positive selection more frequently than the TET3 gene, possibly due to changes in the selective constraints during their evolutionary process. In this study, we performed a network-based analysis of the mRNA expression profiles of TET knockdown and the TET-containing co-expression modules identified in early human developmental stages. Analyses based on the PPI subnetwork demonstrated that TET DEGs PPI subnetwork genes were more evolutionarily conserved than all the human-chimpanzee orthologs during evolutionary history. GO annotation of gene co-expression modules containing a TET gene ortholog revealed particular features of the potential role of TET gene family members. Our study implicated the TET1 module in fundamental aspects of cellular physiology, such as the regulation of glucose metabolism, and the TET2 module in GPCR signal transduction. The TET3 module was related to signaling pathways involved in developmental regulation. The evolutionary rate and phylogenetic age distribution analysis of network member genes also support these network-based analyses. The present study provides an integrated view of TET gene family properties and might be informative for elucidating the molecular mechanisms of their biological functions.


Ten-eleven translocation (TET) proteins Protein-protein interaction network Molecular evolution Co-expression modules Signaling pathway 

Supplementary material

11756_2018_41_Fig5_ESM.jpg (241 kb)
Fig. S1

Phylogenetic age distribution of the TET knockdown PPI subnetworks genes. This Fig. compares the age distribution of TET knockdown PPI subnetworks genes (black) and all the human background genes (brown; N=19911). (JPG 241 kb)

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High resolution image (EPS 2156 kb)
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Fig. S2

Weighted gene co-expression network analysis (WGCNA) of the transcriptome in early human embryonic development. (A) Clustering dendrogram with genes showing module membership by color. (B) The number of genes in each module is represented by color. (JPG 698 kb)

11756_2018_41_MOESM2_ESM.eps (7.7 mb)
High resolution image (EPS 7878 kb)
11756_2018_41_MOESM3_ESM.xls (62 kb)
Table S1 GO terms of the DEGs for TET1 (red), TET2 (green), and TET3 (blue) depletion. Gray-shaded terms represent common biological phenomena in the DEGs for TET1, TET2, and TET3 depletion. (XLS 61 kb)
11756_2018_41_MOESM4_ESM.docx (15 kb)
Table S2 Topological parameters of the downregulated and upregulated DEGs PPI subnetworks constructed by using PPI database, mentha. (DOCX 14 kb)
11756_2018_41_MOESM5_ESM.xlsx (12 kb)
Table S3 The top 10 enriched MSigDB pathways for TET knockdown PPI subnetworks genes. (XLSX 12 kb)
11756_2018_41_MOESM6_ESM.xlsx (12 kb)
Table S4 The top 10 enriched MSigDB pathways for TET-containing module member genes. (XLSX 12 kb)


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Copyright information

© Institure of Molecular Biology, Slovak Academy of Sciences 2018

Authors and Affiliations

  1. 1.United Graduate School of Drug Discovery and Medical Information SciencesGifu UniversityGifuJapan
  2. 2.Department of Functional BioscienceGifu University School of MedicineGifuJapan
  3. 3.Department of Nursing, Ogaki Women’s CollegeOgakiJapan
  4. 4.Graduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan

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