Network perturbation by recurrent regulatory variants in cancer

<div><p>Cancer driving genes have been identified as recurrently affected by variants that alter protein-coding sequences. However, a majority of cancer variants arise in noncoding regions, and some of them are thought to play a critical role through transcriptional perturbation. Here we identified putative transcriptional driver genes based on combinatorial variant recurrence in <i>cis</i>-regulatory regions. The identified genes showed high connectivity in the cancer type-specific transcription regulatory network, with high outdegree and many downstream genes, highlighting their causative role during tumorigenesis. In the protein interactome, the identified transcriptional drivers were not as highly connected as coding driver genes but appeared to form a network module centered on the coding drivers. The coding and regulatory variants associated via these interactions between the coding and transcriptional drivers showed exclusive and complementary occurrence patterns across tumor samples. Transcriptional cancer drivers may act through an extensive perturbation of the regulatory network and by altering protein network modules through interactions with coding driver genes.</p></div

Network module of coding drivers and transcriptional drivers.

<p>(A) Schematic view of a network module consisting of the central CD and its partner TDs. (B) ROC graphs for the prediction of the 20/20 CD (left) and CGC CD (right) based on the modular recurrence level. The gray curves are results when the <i>cis</i>-regulatory recurrence level of the CD alone was used. The colored curves are resulted from a modular extension of recurrence based on the average, sum, or maximum of the neighbor TDs (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005449#sec003" target="_blank">Methods</a> for detail). (C) Network-level recurrence patterns of the TP53 module. The yellow and blue bars at the center indicate the coding recurrence levels of TP53 in breast cancer and liver cancer, respectively. The violet and green bars at the circumferences represent the regulatory recurrence levels of TP53-interacting genes in the functional network in breast cancer and liver cancer, respectively.</p

Combinatorial <i>cis</i>-regulatory recurrence.

<p>(A) Illustration of our recurrence model. Four variants from different samples are scattered in <i>cis</i>-regulatory regions but converge on the same gene via chromatin interactions. (B) A radar plot showing the significance of enrichment for eight cancer-related Gene Ontology terms. The length of the plot scales with log₁₀ (P value). The P values were derived from the hypergeometric distribution and adjusted for multiple testing by the Bonferroni correction. (C) Relative causal score of the TDs grouped by the recurrence level and the CDs (CGC and 20/20) in the Bayesian network of breast cancer. Causal scores were calculated as described in the Methods and normalized by dividing by the average causal score of all genes in the network. (D) The relative degree of the TDs and CDs in the coexpression network in breast cancer. The degree was divided by the network average. (E) Schematic illustration of genomic simulation (<i>in silico</i> or clinical) in which variants are randomized, and epigenomic simulation in which K562 chromatin interactome is used in place of MCF-7 and HepG2.</p

Overrepresentation of interactions between coding drivers and transcriptional drivers in the protein interactome.

<p>The significance of enrichment was estimated as the observed-to-expected ratio of the number of interactions for each TD category grouped by the recurrence level as combined for breast and liver cancer. The expected number was obtained by permuting the links or nodes of the network. The permutation was repeated 1,000 times. (A) Enrichment of interactions between the TDs and CGC CDs. (B) Enrichment of interactions between the TDs and 20/20 CDs.</p

Complementary recurrence of variants of coding drivers and interacting transcriptional drivers.

<p>(A) Schematic illustration and description of the variant complementarity measure between the interacting CD and TD. (B) Variant complementarity of interacting CD-TD pairs (red boxplots), all CD-TD pairs (blue boxplots), and all pairs (inclusive of non-recurrent genes) with background coding-regulatory variants (gray boxplots). (C) Complementary recurrence patterns between coding variants of TP53 and regulatory variants of top 5 genes with highest complementarity in breast cancer and top 5 genes with highest complementarity in liver cancer. Each column indicates each breast or liver cancer sample. Regarding variant types, the same color-coding as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005449#pcbi.1005449.g003" target="_blank">Fig 3C</a> was used.</p

Additional file 1: of MUFFINN: cancer gene discovery via network analysis of somatic mutation data

Supplementary online information including supplementary Figures S1–S9 and supplementary Table S1. (PDF 4546 kb

Regulating Charge Injection in Ambipolar Organic Field-Effect Transistors by Mixed Self-Assembled Monolayers

We report on a technique using mixed self-assembled monolayers (SAMs) to finely regulate ambipolar charge injection in polymer organic field-effect transistors. Differing from the other works that employ single SAM specifically for efficient charge injection in <i>p</i>-type and <i>n</i>-type transistors, we blend two different SAMs of alkyl- and perfluoroalkyl thiols at different ratios and apply them to ambipolar OFETs and inverter. Thanks to the utilization of ambipolar semiconductor and one SAM mixture, the device and circuit fabrications are facile with only one step for semiconductor deposition and another for SAM treatment. This is much simpler with respect to the conventional scheme for the unipolar-device-based complementary circuitry that demands separate deposition and processing for individual <i>p</i>-channel and <i>n</i>-channel transistors. Our results show that the mixed-SAM treatments not only improve ambipolar charge injection manifesting as higher hole- and electron-mobility and smaller threshold voltage but also gradually tune the device characteristics to reach a desired condition for circuit application. Therefore, this simple but useful approach is promising for ambipolar electronics

Table_1_Effect of structural variation in the promoter region of RsMYB1.1 on the skin color of radish taproot.docx

Accumulation of anthocyanins in the taproot of radish is an agronomic trait beneficial for human health. Several genetic loci are related to a red skin or flesh color of radish, however, the functional divergence of candidate genes between non-red and red radishes has not been investigated. Here, we report that a novel genetic locus on the R2 chromosome, where RsMYB1.1 is located, is associated with the red color of the skin of radish taproot. A genome-wide association study (GWAS) of 66 non-red-skinned (nR) and 34 red-skinned (R) radish accessions identified three nonsynonymous single nucleotide polymorphisms (SNPs) in the third exon of RsMYB1.1. Although the genotypes of SNP loci differed between the nR and R radishes, no functional difference in the RsMYB1.1 proteins of nR and R radishes in their physical interaction with RsTT8 was detected by yeast-two hybrid assay or in anthocyanin accumulation in tobacco and radish leaves coexpressing RsMYB1.1 and RsTT8. By contrast, insertion- or deletion-based GWAS revealed that one large AT-rich low-complexity sequence of 1.3–2 kb was inserted in the promoter region of RsMYB1.1 in the nR radishes (RsMYB1.1nR), whereas the R radishes had no such insertion; this represents a presence/absence variation (PAV). This insertion sequence (RsIS) was radish specific and distributed among the nine chromosomes of Raphanus genomes. Despite the extremely low transcription level of RsMYB1.1nR in the nR radishes, the inactive RsMYB1.1nR promoter could be functionally restored by deletion of the RsIS. The results of a transient expression assay using radish root sections suggested that the RsIS negatively regulates the expression of RsMYB1.1nR, resulting in the downregulation of anthocyanin biosynthesis genes, including RsCHS, RsDFR, and RsANS, in the nR radishes. This work provides the first evidence of the involvement of PAV in an agronomic trait of radish.</p

Presentation_1_Effect of structural variation in the promoter region of RsMYB1.1 on the skin color of radish taproot.pptx

Accumulation of anthocyanins in the taproot of radish is an agronomic trait beneficial for human health. Several genetic loci are related to a red skin or flesh color of radish, however, the functional divergence of candidate genes between non-red and red radishes has not been investigated. Here, we report that a novel genetic locus on the R2 chromosome, where RsMYB1.1 is located, is associated with the red color of the skin of radish taproot. A genome-wide association study (GWAS) of 66 non-red-skinned (nR) and 34 red-skinned (R) radish accessions identified three nonsynonymous single nucleotide polymorphisms (SNPs) in the third exon of RsMYB1.1. Although the genotypes of SNP loci differed between the nR and R radishes, no functional difference in the RsMYB1.1 proteins of nR and R radishes in their physical interaction with RsTT8 was detected by yeast-two hybrid assay or in anthocyanin accumulation in tobacco and radish leaves coexpressing RsMYB1.1 and RsTT8. By contrast, insertion- or deletion-based GWAS revealed that one large AT-rich low-complexity sequence of 1.3–2 kb was inserted in the promoter region of RsMYB1.1 in the nR radishes (RsMYB1.1nR), whereas the R radishes had no such insertion; this represents a presence/absence variation (PAV). This insertion sequence (RsIS) was radish specific and distributed among the nine chromosomes of Raphanus genomes. Despite the extremely low transcription level of RsMYB1.1nR in the nR radishes, the inactive RsMYB1.1nR promoter could be functionally restored by deletion of the RsIS. The results of a transient expression assay using radish root sections suggested that the RsIS negatively regulates the expression of RsMYB1.1nR, resulting in the downregulation of anthocyanin biosynthesis genes, including RsCHS, RsDFR, and RsANS, in the nR radishes. This work provides the first evidence of the involvement of PAV in an agronomic trait of radish.</p

Carbon-Impurity Affected Depth Elemental Distribution in Solution-Processed Inorganic Thin Films for Solar Cell Application

A common feature of the inorganic thin films including Cu­(In,Ga)­(S,Se)₂ fabricated by nonvacuum solution-based approaches is the doubled-layered structure, with a top dense inorganic film and a bottom carbon-containing residual layer. Although the latter has been considered to be the main efficiency limiting factor, (as a source of high series resistance), the exact influence of this layer is still not clear, and contradictory views are present. In this study, using a CISe as a model system, we report experimental evidence indicating that the carbon residual layer itself is electrically benign to the device performance. Conversely, carbon was found to play a significant role in determining the depth elemental distribution of final film, in which carbon selectively hinders the diffusion of Cu during selenization, resulting in significantly Cu-deficient top CISe layer while improving the film morphology. This carbon-affected compositional and morphological impact on the top CISe films is a determining factor for the device efficiency, which was supported by the finding that CISe solar cells processed from the precursor film containing intermediate amount of carbon demonstrated high efficiencies of up to 9.15% whereas the performances of the devices prepared from the precursor films with very high and very low carbon were notably poor