A Comprehensive Resource of Interacting Protein Regions for Refining Human Transcription Factor Networks

Miyamoto‐Sato, Etsuko; Fujimori, Shigeo; Ishizaka, Masamichi; Hirai, Naoya; Masuoka, Kazuyo; Saito, Rintaro; Ozawa, Yosuke; Hino, Katsuya; Washio, Takumi; Tomita, Masaru; Yamashita, Tatsuhiro; Oshikubo, Tomohiro; Akasaka, Hidetoshi; Sugiyama, Jun; Matsumoto, Yasuo; Yanagawa, Hiroshi

doi:10.1371/journal.pone.0009289

Cited by 58 publications

(60 citation statements)

References 57 publications

(121 reference statements)

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“…This analysis revealed that ETS1 could bind to the histone de-acetylation-related molecule HDAC1 and that ELK1 could bind to the DNA methylation-related molecule ARID4B 28,29 (Supplementary Fig. 9a).…”

Section: Resultsmentioning

confidence: 97%

Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression

et al. 2014

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Cancer-related deregulation of miRNA biogenesis has been suggested, but the underlying mechanisms remain elusive. Here, we report a previously unrecognized effect of hypoxia in the downregulation of Drosha and Dicer in cancer cells that leads to dysregulation of miRNA biogenesis and increased tumor progression. We show that hypoxia mediated downregulation of Drosha is dependent on ETS1/ELK1 transcription factors. Moreover, mature miRNA array and deep sequencing studies reveal altered miRNA maturation in cells under hypoxic conditions. At a functional level, this phenomenon results in increased cancer progression in vitro and in vivo, and data from patient samples are suggestive of miRNA biogenesis downregulation in hypoxic tumors. Rescue of Drosha by siRNAs targeting ETS1/ELK1 in vivo results in significant tumor regression. These findings provide a new link in the mechanistic understanding of global miRNA downregulation in the tumor microenvironment.

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Section: Resultsmentioning

confidence: 97%

Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression

et al. 2014

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“…The identification of one network, including NKX2.5/GATA4, provided a robust positive control as protein-protein interactions and substantial contributions by these molecules to CHD are previously described. Direct protein-protein interactions between ETS1/JUN/TOP2A have also been reported, 54-56 but this network has not been previously implicated in CHD. In an expanded network analysis of these molecules that included rare LOF mutations identified from exome sequencing, JUN was linked to SMAD2 and SMAD4, molecules that participate in cardiac development through the TGF-β signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Increased Frequency of De Novo Copy Number Variants in Congenital Heart Disease by Integrative Analysis of Single Nucleotide Polymorphism Array and Exome Sequence Data

Glessner

Bick

Ito

et al. 2014

Circulation Research

239

208

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Rationale Congenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown etiology. Objective To determine the contribution of de novo copy number variants (CNVs) in the etiology of sporadic CHD. Methods and Results We studied 538 CHD trios using genome-wide dense single nucleotide polymorphism (SNP) arrays and/or whole exome sequencing (WES). Results were experimentally validated using digital droplet PCR. We compared validated CNVs in CHD cases to CNVs in 1,301 healthy control trios. The two complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either SNP array (p=7x10−5, Odds Ratio (OR)=4.6) or WES data (p=6x10−4, OR=3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic (p=0.02, OR=2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in WES and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q sub-telomeric deletions. Conclusions We demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.

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“…p53 by interfering with its murine double minute 2 (MDM2)-dependent proteasomal degradation (13), and there is evidence for an interaction between PRRC2C and MDM2 (48). The role of the PRRC2C splice variants in the regulation of p53 by MDM2 merits further investigation.…”

Section: Discussionmentioning

confidence: 99%

Identification of Alternative Splicing Events Regulated by the Oncogenic Factor SRSF1 in Lung Cancer

et al. 2014

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Abnormal alternative splicing has been associated with cancer. Genome-wide microarrays can be used to detect differential splicing events. In this study, we have developed ExonPointer, an algorithm that uses data from exon and junction probes to identify annotated cassette exons. We used the algorithm to profile differential splicing events in lung adenocarcinoma A549 cells after downregulation of the oncogenic serine/arginine-rich splicing factor 1 (SRSF1). Data were generated using two different microarray platforms. The PCR-based validation rate of the top 20 ranked genes was 60% and 100%. Functional enrichment analyses found a substantial number of splicing events in genes related to RNA metabolism. These analyses also identified genes associated with cancer and developmental and hereditary disorders, as well as biologic processes such as cell division, apoptosis, and proliferation. Most of the top 20 ranked genes were validated in other adenocarcinoma and squamous cell lung cancer cells, with validation rates of 80% to 95% and 70% to 75%, respectively. Moreover, the analysis allowed us to identify four genes, ATP11C, IQCB1, TUBD1, and proline-rich coiled-coil 2C (PRRC2C), with a significantly different pattern of alternative splicing in primary non-small cell lung tumors compared with normal lung tissue. In the case of PRRC2C, SRSF1 downregulation led to the skipping of an exon overexpressed in primary lung tumors. Specific siRNA downregulation of the exon-containing variant significantly reduced cell growth. In conclusion, using a novel analytical tool, we have identified new splicing events regulated by the oncogenic splicing factor SRSF1 in lung cancer. Cancer Res; 74(4); 1105-15. Ó2013 AACR.

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A Comprehensive Resource of Interacting Protein Regions for Refining Human Transcription Factor Networks

Cited by 58 publications

References 57 publications

Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression

Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression

Increased Frequency of De Novo Copy Number Variants in Congenital Heart Disease by Integrative Analysis of Single Nucleotide Polymorphism Array and Exome Sequence Data

Identification of Alternative Splicing Events Regulated by the Oncogenic Factor SRSF1 in Lung Cancer

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