A network-based method for predicting disease-associated enhancers

Background Enhancers regulate transcription of target genes, causing a change in expression level. Thus, the aberrant activity of enhancers can lead to diseases. To date, a large number of enhancers have been identified, yet a small portion of them have been found to be associated with diseases. This raises a pressing need to develop computational methods to predict associations between diseases and enhancers. Results In this study, we assumed that enhancers sharing target genes could be associated with similar diseases to predict the association. Thus, we built an enhancer functional interaction network by connecting enhancers significantly sharing target genes, then developed a network diffusion method RWDisEnh, based on a random walk with restart algorithm, on networks of diseases and enhancers to globally measure the degree of the association between diseases and enhancers. RWDisEnh performed best when the disease similarities are integrated with the enhancer functional interaction network by known disease-enhancer associations in the form of a heterogeneous network of diseases and enhancers. It was also superior to another network diffusion method, i.e., PageRank with Priors, and a neighborhood-based one, i.e., MaxLink, which simply chooses the closest neighbors of known disease-associated enhancers. Finally, we showed that RWDisEnh could predict novel enhancers, which are either directly or indirectly associated with diseases. Conclusions Taken together, RWDisEnh could be a potential method for predicting disease-enhancer associations.

Data suggest that the HTR2A functional rs6311 polymorphism, which other studies have associated with differential HTR2A mRNA expression, may modulate the severity of depression symptoms in children with autism spectrum disorder. 2 chr3:119814602-119822600 GSK3B (2932) 25041379 GSK3B protein and mRNA expression were decreased in the dorsolateral prefrontal cortex and temporal lobe of bipolar disorder patients compared to schizophrenia patients and controls. 3 chr9:89720602-89726000 DAPK1 (1612) 21965790 DAPK1 expression did not show any meaningful value in predicting outcome for patients with breast cancer. 26075823 high DAPK1 expression causes increased cancer cell growth and enhanced signaling via the mTOR/S6K pathway; evaluation of breast cancer patient data sets revealed that high DAPK1 expression associates with worse outcomes in women with p53-mutant cancers 28231808 Results show that DNA demethylation of distinct promoter regions is associated with re-expression of the tumor suppressor gene DAPK1. Its knockdown promotes tumor cell migration in breast cancer cell line.

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A significant correlation between changes in the levels of expression and methylation was detected for the three apoptosis-regulatory genes (APAF1, DAPK1, and BCL2). The results suggest that methylation play an important role in the regulation of the apoptosis system genes in breast cancer. chr2:8440002-8455200 ID2 (3398) 23645773 Higher ID2 expression was associated with advanced breast cancer. chr2:60719002-60776000 BCL11A (53335) 27774950 The BCL11A protein is highly expressed in breast cancer and knock-down of BCL11A promotes the apoptosis of MDA-MB-231 cells.
chr17:32559802-32586800 CCL2 (6347)  18790652 observations support a major tumor-promoting role for co-expression of the chemokines in breast malignancy, and agree with the significant association of joint RANTES and MCP-1 expression with advanced stages of breast cancer. 25744294 CCL2 expression is overexpressed in luminal B breast cancer cells and is important for regulating cell growth and survival by inhibiting necrosis and autophagy.

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Constitutive expression of CCL2 by the mouse mammary epithelium induces a state of low level chronic inflammation that increases stromal density and elevates cancer risk. We propose that CCL2-driven inflammation contributes to the increased risk of breast cancer observed in women with high mammographic density. 29107385 these findings collectively indicate that TGF-beta regulates CCL2 expression in a stage-dependent manner during breast cancer progression 4 chr5:110175802-110176800 TSLP (85480) 18684970 There is distinct airways expression of TSLP and chemokines which preferentially attract T helper (Th) type 1-and Th2-type T cells, and influx of T cells bearing their receptors in asthma and chronic obstructive pulmonary disease.

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In Ishikawa H cells that model type I endometrial cancer in the loss of PTEN and RB1, re-expressing PTEN and RB1 increased the apoptotic and G1 phases and decreased the S and G2-M phases, which further sensitize the cells to gefitinib. 17924977 High levels of p-AKT expression occurred independently of the presence of PTEN or PIK3CA mutations in endometrial cancer. 24929707 The study demonstrates that the expression of PTEN is directly regulated by miR-205 in endometrial cancer cells and leads to the inhibition of cellular apoptosis. 26511107 GAS5 acts as an tumor suppressor lncRNA in endometrial cancer. Through inhibiting the expression of miR-103, GAS5 significantly enhanced the expression of PTEN to promote cancer cell apoptosis.

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Study shows that women with polycystic ovarian syndrome and endometrial cancer have an increased endometrial expression of genes (IGF1, IGFBP1 and PTEN) involved in the insulin signaling pathway compared with control women. 26894937 High expression of PTEN was positively correlated with myometrial invasion in endometrial cancer. chr15:54202002-54203000 chr15:54203002-54203600 BCL2 (596) 22252757 BCL-2 expression was significantly more frequent in early clinical stages in both types of endometrial cancer chr17:68734530-68736530 chr17:68746322-68748322 SOX9 (6662)  27262401 These findings indicate that chronic overexpression of Sox9 in the uterine epithelium can induce the development of endometrial hyperplastic lesions. Thus, SOX9 expression may be a factor in the formation of endometrial cancer. Results find that TNF mRNA expression is higher in leprosy patients compared to endemic controls, but does not differ significantly between clinical subgroups. Across leprosy patients, carriage of the minor A allele is associated with low TNF mRNA. Nevertheless, no evidence was found for either allele at this SNP as a risk factor for leprosy per se, or for any subgroups. 11 chr1:59249452-59251452 chr1:59250097-59252097 JUN (3725)  27341307 The positive feedback regulation of OCT4 and c-JUN, resulting in the continuous expression of oncogenes such as c-JUN, seems to play a critical role in the determination of the cell fate decision from induced pluripotent stem cells to cancer stem cells in liver cancer. 12 chr2:60719002-60776000 BCL11A (53335) 23758992 BCL11A overexpression predicts survival and relapse in non-small cell lung cancer and is modulated by microRNA-30a and gene amplification. 13 chr9:21974127-21976127 CDKN2A (1029) 11705866 Up-regulated p16 expression may represent a unique feature of aggressive neuroblastoma. chr11:2190002-2193400 TH (7054) 12358785 Gene expression found upregulated by Glial cell line-derived neurotrophic factor in human neuroblastoma cell lines 12576454 Gene expression is a sensitive and semiquantitative marker for minimal residual disease detection of neuroblastoma 18814238 High expression of TH both in peripheral blood and bone marrow corresponds to metastatic neuroblastoma at diagnosis, residual disease, and poor outcome. 19125082 High tyrosine hydroxylase expression is associated with Minimal residual disease in peripheral blood stem cell harvests from high-risk neuroblastoma. 19285077 SIRT1 regulates tyrosine hydroxylase expression and differentiation of neuroblastoma cells via FOXO3a.

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The purpose of this study is to investigate the clinical significance of tyrosine hydroxylase (TH) expression in peripheral blood (PB) at diagnosis in patients with neuroblastoma.. The treatment intensity should be tailored according to TH expression in PB at diagnosis. 14 chr3:123036602-123074000 ADCY5 (111) 25793868 changes in adipose tissue ADCY5 expression are related to obesity and fat distribution. 15 chr14:105232802-105261000 AKT1 (207) 18231751 PTEN restores drug sensitivity to cisplatin in human ovarian cancer cell line C13K with multidrug-resistance by decreasing the expression of p-Akt.
19067848 Overexpression of P-AKT and NF-kappaB p65 were involved in the carcinogenesis and metastasis of ovarian cancer. 22394200 JNK-potentiated Akt/FoxO3a and JNK-mediated c-Jun pathways co-operatively trigger Puma expression, which determines the threshold for overcoming chemoresistance in ovarian cancer cells.
25815442 the results of the present study demonstrated that the acquired taxol resistance of ovarian cancer cells was associated with ROS-dependent upregulation in the expression of Tyro3 RTK and the subsequent activation of Akt. 26364616 gankyrin regulates HIF-1alpha protein stability and cyclin D1 expression, ultimately mediating FSH-driven ovarian cancer cell proliferation 26713367 Taken together, in current study, we found a novel tumor suppressor, DDX10, is epigenetic silenced by miR-155-5p in ovarian cancer, and the down-regulated expression pattern of DDX10 promotes ovarian cancer proliferation through Akt/NF-kappaB pathway. 28423620 High AKT1 expression is associated with ovarian cancer.

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Data suggest that CAMKK2 is highly expressed in high-grade ovarian cancer and ovarian cancer cell lines; CAMKK2 directly activates Akt1 by phosphorylation at Thr-308 in a Ca2+/calmodulin-dependent manner; CAMKK2 knockdown or inhibition decreases Akt1 phosphorylation at Thr-308 and Ser-473. (CAMKK2 = calcium/calmodulin dependent protein kinase kinase 2; AKT1 = AKT serine/threonine kinase 1) chr17:68697977-68699977 chr17:68734530-68736530 SOX9 (6662) 24661907 Sox9 allows the survival of ovarian cells upon hypoxic condition, through the activation of betaIII-tubulin expression and its aberrant activation is prominent in patients with aggressive ovarian cancer. The CCR5-HHD haplotype, a known genetic determinant of increased susceptibility to HIV-AIDS, and a high copy number of CCL3L1, a known genetic determinant of enhanced CCL3/CCL3L1 chemokine expression, each associated with presence of tuberculosis. chr6:31534802-31548600 TNF (7124) 16133992 During tuberculosis, predisposition of CD4 T-cell subsets to apoptosis may involve both low expression of Bcl-2 and excessive expression of tumor necrosis factor(TNF)-alpha. 19091593 Results reveal the suppressive effect of 1,25(OH)(2)D(3) on single cell expression of IFN-gamma and TNF-alpha by CD3+CD4+ and CD3+CD8+ T cells in pulmonary tuberculosis.

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Gene expression of several TNF-alpha dependent apoptotic genes (TNFR1, TNFR2, FLICE, FLIPs) of peripheral blood cells from cohorts of individuals with active tuberculosis or potential exposure to tuberculosis, was investigated. 25528189 The expression of TNF-alpha and CXCL9 in blood samples stimulated with a bacterial antigen distinguishes active tuberculosis patients from latent disease carriers and healthy controls. Only one gene, pleckstrin , was significantly overexpressed in periodontitis,cardiovascular disease, rheumatoid arthritis and ulcerative colitis , implicating this gene as an important networking link between these chronic inflammatory diseases