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Table 1 Upregulated and downregulated node genes in normal mammary glands of F1 and F3 generation mouse offspring of dams fed a high-fat diet and their unique signaling connections identified via knowledge-fused differential dependency network analysisa

From: Maternal intake of high n-6 polyunsaturated fatty acid diet during pregnancy causes transgenerational increase in mammary cancer risk in mice

Upregulated gene (function) Connections in HF offspring Consequence Connections in control offspring Consequence
Alg6 Encodes glucosyltransferase, critical role in N-glycosylation [1] Sema5b↑ O-glycosylation of thrombospondin type 1 repeat domain-containing proteins; implicated in clear cell renal cell carcinoma [17] as well as other age-related diseases, including cancer [18] Akr1c14↑ 3α-Hydroxysteroid dehydrogenase enzyme; catalyzes conversion of potent testosterones into less potent forms [8]
Dpf3 Chromatin remodeling; associated with increased breast cancer risk, tumor size, earlier onset of disease, and lymph node metastases [2]; also implicated in chronic lymphocytic leukemia through STAT5 regulation [3] Ankef1↓ Calcium ion binding; found as significant predictor of prostate cancer in GWAS SNPs study [19] Parp8↓ Upregulated in acute leukemia [20]; catalyzes posttranslational modification of protein by addition of ADP-ribose moieties; contributes to survival of injured proliferating cells [21]
   Mt-Ts2↑ RNA gene affiliated with noncoding RNA class; possible association with mitochondrial disorders [9]
Grhl3 Regulator of developmental processes; overexpression increases cell migration and invasion by downregulating E-cadherin [4]; strongly implicated in breast cancer [5] Id4↑ A lineage-dependent proto-oncogene that is overexpressed and amplified in a subset of basal-like breast cancers and confers a poor prognosis [22]; suppresses BRCA1 [23, 24] Gpcpd1↓ Downregulation reduces migration capacity of tumor cells and is a prognostic indicator of good outcome in endometrial and ovarian cancers [25]
Igfbp6↓ IGF-1-binding protein; lower expression in malignant breast cancer than in benign tumors [26]; also overexpressed in lung cancer and rhabdomyosarcomas [27] Snora41↓ Long noncoding RNA linked to embryonic stem cell differentiation [28]; upregulated in lung cancer [29]
Magix Function not known Slc26a3↑ Glycoprotein, a marker of chemoresistance in ER+ breast cancer [30] Egr3↓ Mediates E2-induced breast cancer metastasis [31]; upregulated in endocrine-resistant breast cancers [32]; increases aromatase in breast tissue [33]; maintains tumor immunosuppression [34]
Optc Extracellular matrix glycoprotein [6], found translocated to nucleus in chronic lymphocytic leukemia cells [7] Tbx2↑ Regulator of developmental processes; increased expression predicts poor prognosis for many cancer types, including head and neck cancers [35], gastric cancer [36], and breast cancer [37]; contributes to drug resistance in breast cancer [38] Slc6a2↑ Induces norepinephrine uptake [11]; upregulation lowers risk of pancreatic ductal adenocarcinoma [12] and non-small-cell lung cancer [13]
Zbp1↓ Activator of innate immune response [14, 15] with potential to promote effective antitumor CD8+ T-cell immunity [16] Zfp683↑ Essential for formation of mature thymic natural killer cells [39]
Downregulated gene (function) Connections in HF Consequence Connections in CON Consequence
Akr1c14 3α-hydroxysteroid dehydrogenase enzyme; catalyzes conversion of potent testosterones into less potent forms [8] Cdh24↑ Induces cell adhesion; mutation target in cancers with microsatellite instability, particularly gastric and colorectal cancers [40] Alg6↓ Encodes glucosyltransferase, critical role in N-glycosylation [1]
    Snora41↓ Long noncoding RNA linked to embryonic stem cell differentiation [28]; upregulated in lung cancer [29]
Mt-Ts2 RNA gene affiliated with noncoding RNA class; possible association with mitochondrial disorders [9] Egr3↑ Mediates E2-induced breast cancer metastasis [31]; upregulated in endocrine-resistant breast cancers [32]; increases aromatase in breast tissue [33]; maintains tumor immunosuppression [34] Dpf3↓ Polymorphisms in 5′ region associated with increased breast cancer development
Parp8↑ Upregulated in acute leukemia [20]; catalyzes posttranslational modification of protein by addition of ADP-ribose moieties, contributes to survival of injured proliferating cells [21] Zbp1↑ Activator of innate immune response [14, 15] with potential to promote effective antitumor CD8+ T-lymphocyte immunity [16]
Pcdhga8↑ Establishes cell-cell connections [41]   
Slc5a3 Transporter; downregulation impairs cellular functions by causing accumulation of myoinositol, downregulated in type 2 diabetes [10] Gpcpd1↑ Decreased expression increases the migration capacity of tumor cells and worsens prognosis of endometrial and ovarian cancers [25] Ier5l↓ Immediate early response gene; may mediate actions on PUFAs [45]
Zfp467↑ Promotes adipocyte differentiation and inhibits osteoblast differentiation [43] Faap100↓ Required for E3 ligase function [44]
   Lppr2↓ Peptide-ligand binding, GPCR signaling [42]
Slc6a2 Norepinephrine uptake regulator [11]; downregulation increases risk of pancreatic ductal adenocarcinoma [12] and non-small-cell lung cancer [13] Jam3↑ Cell-cell adhesion; upregulation associated with poor prognosis for non-small-cell lung cancer [46] and gastric cancer [47]; promotes ovarian tumors in mice [48] Optc↓ Extracellular matrix glycoprotein [6], found translocated to nucleus in chronic lymphocytic leukemia cells [7]
Slc6a9↑ Transporter that inhibits glycine signaling [49]; solute carrier 6 family is implicated in many cancers [50] Zbp1↑ Activator of innate immune response [14, 15] with potential to promote effective antitumor CD8+ T-cell immunity [16]
   Zfp683↑ Essential for formation of mature thymic natural killer cells [39]
Zbp1 Activator of innate immune response [14, 15] with potential to promote effective antitumor CD8+ T-cell immunity [16] Pcdhga8↑ Establishes cell-cell connections [41] Slc6a2↑ Induces norepinephrine uptake [11]; upregulation lowers risk of pancreatic ductal adenocarcinoma [12] and non-small-cell lung cancer [13]
Optc↑ Extracellular matrix glycoprotein [6] found translocated to nucleus in chronic lymphocytic leukemia cells [7] Jam3↓ Cell-cell adhesion; downregulation linked to better prognosis for non-small-cell lung cancer [46] and gastric cancer [47]; upregulation promotes ovarian tumor in murine model [48]
   Mt-Ts2↑ RNA gene, affiliated with noncoding RNA class, possible association with mitochondrial disorders [9]
   Slc6a9↓ Transporter that inhibits glycine signaling [49]; solute carrier 6 family is implicated in many cancers [50]
  1. Abbreviations: Akr1c14 Aldo-keto reductase family 1, member C14, Alg6 α-1,3-Glucosyltransferase, Ankef1 Ankyrin repeat and EF-hand domain containing 1, Dpf3 Double PHD fingers 3, E2 17-β-Estradiol, Egr3 Early growth response 3, ER Estrogen receptor, Gpcpd1 Glycerophosphocholine phosphodiesterase 1, GPCR G protein-coupled receptor, Grhl3 Grainyhead like transcription factor 3, GWAS Genome-wide association study, HF High fat, Id4 DNA-binding protein inhibitor ID-4, IGF-1 Insulin-like growth factor 1, Igfbp6 Insulin-like growth factor binding protein 6, Jam3 Junctional adhesion molecule 3, Magix MAGI family member, X-linked, Mt-Ts2 Mitochondrially encoded transfer RNA serine 2 (AGU/C), Optc Opticin, Pcdhga8 Protocadherin gamma subfamily A, 8, PUFA Polyunsaturated fatty acid, Sema5b Semaphorin 5B, Slc26a3 Solute carrier family 26 member 3, Slc5a3 Solute carrier family 5 member 3, Slc6a2 Solute carrier family 6 member 2, Snora41 Small nucleolar RNA, H/ACA box 41, SNP Single-nucleotide polymorphism, STAT5 Signal transducer and activator of transcription 5, Tbx2 T-box 2, Zbp1 Z-DNA binding protein 1, Zfp683 Zinc finger protein 683
  2. a Connection of the node genes in control offspring are also shown