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
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] |