TICA: Transcriptional Interaction and Coregulation Analyzer

Transcriptional regulation is critical to cellular processes of all organisms. Regulatory mechanisms often involve more than one transcription factor(TF) from different families, binding together and attaching to the DNA as a single complex. However, only a fraction of the regulatory partners of each TF is currently known. In this paper, we present the Transcriptional Interaction and Coregulation Analyzer(TICA), a novel methodology for predicting heterotypic physical interaction of TFs. TICA employs a data-driven approach to infer interaction phenomena from chromatin immunoprecipitation and sequencing(ChIP-seq) data. Its prediction rules are based on the distribution of minimal distance couples of paired binding sites belonging to different TFs which are located closest to each other in promoter regions. Notably, TICA uses only binding site information from input ChIP-seq experiments, bypassing the need to do motif calling on sequencing data. We present our method and test it on ENCODE ChIP-seq datasets, using three cell lines as reference including HepG2, GM12878, and K562. TICA positive predictions on ENCODE ChIP-seq data are strongly enriched when compared to protein complex(CORUM) and functional interaction(BioGRID) databases. We also compare TICA against both motif/ChIP-seq based methods for physical TF–TF interaction prediction and published literature. Based on our results, TICA offers significant specificity(average 0.902) while maintaining a good recall(average 0.284) with respect to CORUM, providing a novel technique for fast analysis of regulatory effect in cell lines. Furthermore, predictions by TICA are complementary to other methods for TF–TF interaction prediction(in particular, TACO and CENTDIST). Thus, combined application of these prediction tools results in much improved sensitivity in detecting TF–TF interactions compared to TICA alone(sensitivity of 0.526 when combining TICA with TACO and 0.585 when combining with CENTDIST)with little compromise in specificity(specificity 0.760 when combining with TACO and 0.643 with CENTDIST). TICA is publicly available at http://geco.deib.polimi.it/tica/.

Corepressor metastasis-associated protein 3 modulates epithelial-to-mesenchymal transition and metastasis

Worldwide,metastasis is the leading cause of more than 90%of cancer-related deaths.Currently,no specific therapies effectively impede metastasis.Metastatic processes are controlled by complex regulatory networks and transcriptional hierarchy.Corepressor metastasis-associated protein 3(MTA3)has been confirmed as a novel component of nucleosome remodeling and histone deacetylation(NuRD).Increasing evidence supports the theory that,in the recruitment of transcription factors,coregulators function as master regulators rather than passive passengers.As a master regulator,MTA3 governs the target selection for Nu RD and functions as a transcriptional repressor.MTA3dysregulation is associated with tumor progression,invasion,and metastasis in various cancers.MTA3 is also a key regulator of E-cadherin expression and epithelial-to-mesenchymal transition.Elucidating the functions of MTA3 might help to find additional therapeutic approaches for targeting components of NuRD.

Androgen receptor co-regulation in prostate cancer

Prostate cancer(PCa)progression relies on androgen receptor(AR)action.Preventing AR’s ligand-activation is the frontline treatment for metastatic PCa.Androgen deprivation therapy(ADT)that inhibits AR ligand-binding initially induces remission but eventually fails,mainly because of adaptive PCa responses that restore AR action.The vast majority of castration-resistant PCa(CRPC)continues to rely on AR activity.Novel therapeutic strategies are being explored that involve targeting other critical AR domains such as those that mediate its constitutively active transactivation function,its DNA binding ability,or its interaction with co-operating transcriptional regulators.Considerable molecular and clinical variability has been found in AR’s interaction with its ligands,DNA binding motifs,and its associated coregulators and transcription factors.Here,we review evidence that each of these levels of AR regulation can individually and differentially impact transcription by AR.In addition,we examine emerging insights suggesting that each can also impact the other,and that all three may collaborate to induce gene-specific AR target gene expression,likely via AR allosteric effects.For the purpose of this review,we refer to the modulating influence of these differential and/or interdependent contributions of ligands,cognate DNA-binding motifs and critical regulatory protein interactions on AR’s transcriptional output,which may influence the efficiency of the novel PCa therapeutic approaches under consideration,as co-regulation of AR activity.

Expression and role of nuclear receptor coregulators in colorectal cancer

Colorectal cancer(CRC) is one of the most common human cancers and the cause of about 700000 deaths per year worldwide. Deregulation of the WNT/β-catenin pathway is a key event in CRC initiation. This pathway interacts with other nuclear signaling pathways, including members of the nuclear receptor superfamily and their transcription coregulators. In this review, we provide an overview of the literature dealing with the main coactivators(NCo A-1 to 3, NCo A-6, PGC1-α, p300, CREBBP and MED1) and corepressors(N-Co R1 and 2, NRIP1 and MTA1) of nuclear receptors and summarize their links with the WNT/β-catenin signaling cascade, their expression in CRC and their role in intestinal physiopathology.

Role of steroid receptor-associated and regulated protein in tumor progression and progesterone receptor signaling in endometrial cancer

Background:Steroid receptor-associated and regulated protein(SRARP)suppresses tumor progression and modulates steroid receptor signaling by interacting with estrogen receptors and androgen receptors in breast cancer.In endometrial cancer(EC),progesterone receptor(PR)signaling is crucial for responsiveness to progestin therapy.The aim of this study was to investigate the role of SRARP in tumor progression and PR signaling in EC.Methods:Ribonucleic acid sequencing data from the Cancer Genome Atlas,Clinical Proteomic Tumor Analysis Consortium,and Gene Expression Omnibus were used to analyze the clinical significance of SRARP and its correlation with PR expression in EC.The correlation between SRARP and PR expression was validated in EC samples obtained from Peking University People’s Hospital.SRARP function was investigated by lentivirus-mediated overexpression in Ishikawa and HEC-50B cells.Cell Counting Kit-8 assays,cell cycle analyses,wound healing assays,and Transwell assays were used to evaluate cell proliferation,migration,and invasion.Western blotting and quantitative real-time polymerase chain reaction were used to evaluate gene expression.The effects of SRARP on the regulation of PR signaling were determined by co-immunoprecipitation,PR response element(PRE)luciferase reporter assay,and PR downstream gene detection.Results:Higher SRARP expression was significantly associated with better overall survival and disease-free survival and less aggressive EC types.SRARP overexpression suppressed growth,migration,and invasion in EC cells,increased E-cadherin expression,and decreased N-cadherin and Wnt family member 7A(WNT7A)expression.SRARP expression was positively correlated with PR expression in EC tissues.In SRARP-overexpressing cells,PR isoform B(PRB)was upregulated and SRARP bound to PRB.Significant increases in PRE-based luciferase activity and expression levels of PR target genes were observed in response to medroxyprogesterone acetate.Conclusions:This study illustrates that SRARP exerts a tumor-suppressive effect by inhibiting the epithelial-mesenchymal transition via Wnt signaling in EC.In addition,SRARP positively modulates PR expression and interacts with PR to regulate PR downstream target genes.

Androgen receptor coregulator ARA267-α interacts with death receptor-6 revealed by the yeast two-hybrid

ARA267-a is a newly identified androgen receptor coactivator. In order to further elucidate its precise role in cells, using the ARA267- a fragment containing four PHD and one SET conserved domains as bait we revealed an ARA267-a-PHD-SET-interacting protein, death receptor-6 (DR6), in the yeast two-hybrid screening. DR6 is the member of TNF receptor family and has a death domain in its intracellular cytoplasmic portion (DR6cp) to mediate the cell apoptosis. The interaction between ARA267-a-PHD-SET and DR6cp was confirmed in vitro and in vivo. Our finding implied that androgen signaling pathway might cross talk with apoptosis sig-naling pathway through the interaction between ARA267-a and DR6.