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1.
Methods Mol Biol ; 2493: 67-75, 2022.
Article in English | MEDLINE | ID: mdl-35751809

ABSTRACT

Insertions and deletions (indels) are primarily detected from DNA sequencing (DNA-seq) data, but their transcriptional consequences remain unexplored due to challenges in distinguishing medium- and large-sized indels from RNA splicing events in RNA-seq data. We introduce transIndel, a splice-aware algorithm that parses the chimeric alignments predicted by a short read aligner and reconstructs the mid-sized insertions and large deletions based on the linear alignments of split reads from DNA-seq or RNA-seq data. Here, we describe the method and provide a tutorial on the installation and application of transIndel.


Subject(s)
INDEL Mutation , Software , Algorithms , DNA , RNA Splicing
2.
Nat Commun ; 12(1): 6377, 2021 11 04.
Article in English | MEDLINE | ID: mdl-34737261

ABSTRACT

Endocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal. Here, we demonstrate the stem cell transcription factor Krüppel-like factor 5 (KLF5) is low or absent in prostate cancers prior to endocrine therapy, but induced in a subset of CRPC, including CRPC displaying lineage plasticity. KLF5 and AR physically interact on chromatin and drive opposing transcriptional programs, with KLF5 promoting cellular migration, anchorage-independent growth, and basal epithelial cell phenotypes. We identify ERBB2 as a point of transcriptional convergence displaying activation by KLF5 and repression by AR. ERBB2 inhibitors preferentially block KLF5-driven oncogenic phenotypes. These findings implicate KLF5 as an oncogene that can be upregulated in CRPC to oppose AR activities and promote lineage plasticity.


Subject(s)
Kruppel-Like Transcription Factors/metabolism , Neuroendocrine Cells/metabolism , Prostatic Neoplasms, Castration-Resistant/metabolism , Receptor, ErbB-2/metabolism , Receptors, Androgen/metabolism , Cell Line, Tumor , Humans , Male , Neoplasm Staging , Neuroendocrine Cells/pathology , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/pathology , Signal Transduction , Transcriptional Activation
3.
STAR Protoc ; 2(3): 100788, 2021 09 17.
Article in English | MEDLINE | ID: mdl-34522901

ABSTRACT

Exitron splicing (EIS) events in cancers can disrupt functional protein domains to cause cancer driver effects. EIS has been recognized as a new source of tumor neoantigens. Here, we describe an integrated protocol for EIS and EIS-derived neoantigen identification using RNA-seq data. The protocol constitutes a step-by-step guide from data collection to neoantigen prediction. For complete details on the use and execution of this protocol, please refer to Wang et al. (2021).


Subject(s)
Antigens, Neoplasm/genetics , Genomics/methods , RNA Splicing/genetics , RNA-Seq/methods , Databases, Genetic , Humans , Neoplasms/genetics , Software
4.
BMC Genomics ; 22(1): 574, 2021 Jul 27.
Article in English | MEDLINE | ID: mdl-34315441

ABSTRACT

BACKGROUND: Long non-coding RNAs (lncRNAs) are a growing focus in cancer research. Deciphering pathways influenced by lncRNAs is important to understand their role in cancer. Although knock-down or overexpression of lncRNAs followed by gene expression profiling in cancer cell lines are established approaches to address this problem, these experimental data are not available for a majority of the annotated lncRNAs. RESULTS: As a surrogate, we present lncGSEA, a convenient tool to predict the lncRNA associated pathways through Gene Set Enrichment Analysis of gene expression profiles from large-scale cancer patient samples. We demonstrate that lncGSEA is able to recapitulate lncRNA associated pathways supported by literature and experimental validations in multiple cancer types. CONCLUSIONS: LncGSEA allows researchers to infer lncRNA regulatory pathways directly from clinical samples in oncology. LncGSEA is written in R, and is freely accessible at https://github.com/ylab-hi/lncGSEA .


Subject(s)
Neoplasms , RNA, Long Noncoding , Gene Expression Profiling , Humans , Microarray Analysis , Neoplasms/genetics , RNA, Long Noncoding/genetics , Transcriptome
5.
Mol Cell ; 81(10): 2246-2260.e12, 2021 05 20.
Article in English | MEDLINE | ID: mdl-33861991

ABSTRACT

Exitron splicing (EIS) creates a cryptic intron (called an exitron) within a protein-coding exon to increase proteome diversity. EIS is poorly characterized, but emerging evidence suggests a role for EIS in cancer. Through a systematic investigation of EIS across 33 cancers from 9,599 tumor transcriptomes, we discovered that EIS affected 63% of human coding genes and that 95% of those events were tumor specific. Notably, we observed a mutually exclusive pattern between EIS and somatic mutations in their affected genes. Functionally, we discovered that EIS altered known and novel cancer driver genes for causing gain- or loss-of-function, which promotes tumor progression. Importantly, we identified EIS-derived neoepitopes that bind to major histocompatibility complex (MHC) class I or II. Analysis of clinical data from a clear cell renal cell carcinoma cohort revealed an association between EIS-derived neoantigen load and checkpoint inhibitor response. Our findings establish the importance of considering EIS alterations when nominating cancer driver events and neoantigens.


Subject(s)
Epitopes/genetics , Exons/genetics , Gene Expression Profiling , Introns/genetics , Neoplasms/genetics , Oncogenes , RNA Splicing/genetics , Amino Acid Sequence , Cell Line , Cohort Studies , Humans , Mutation/genetics
6.
Nat Commun ; 12(1): 772, 2021 02 03.
Article in English | MEDLINE | ID: mdl-33536424

ABSTRACT

Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.


Subject(s)
Genetic Heterogeneity , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study/methods , Lupus Erythematosus, Systemic/genetics , Polymorphism, Single Nucleotide , Asian People/genetics , Case-Control Studies , Genetic Predisposition to Disease/ethnology , Genotype , Humans , Linkage Disequilibrium , Lupus Erythematosus, Systemic/ethnology , White People/genetics
7.
Gigascience ; 9(8)2020 08 01.
Article in English | MEDLINE | ID: mdl-32852038

ABSTRACT

BACKGROUND: Internal tandem duplications (ITDs) are tandem duplications within coding exons and are important prognostic markers and drug targets for acute myeloid leukemia (AML). Next-generation sequencing has enabled the discovery of ITD at single-nucleotide resolution. ITD allele frequency is used in the risk stratification of patients with AML; higher ITD allele frequency is associated with poorer clinical outcomes. However, the ITD allele frequency data are often unavailable to treating physicians and the detection of ITDs with accurate variant allele frequency (VAF) estimation remains challenging for short-read sequencing. RESULTS: Here we present the ScanITD approach, which performs a stepwise seed-and-realignment procedure for ITD detection with accurate VAF prediction. The evaluations on simulated and real data demonstrate that ScanITD outperforms 3 state-of-the-art ITD detectors, especially for VAF estimation. Importantly, ScanITD yields better accuracy than general-purpose structural variation callers for predicting ITD size range duplications. CONCLUSIONS: ScanITD enables the accurate identification of ITDs with robust VAF estimation. ScanITD is written in Python and is open-source software that is freely accessible at https://github.com/ylab-hi/ScanITD.


Subject(s)
Leukemia, Myeloid, Acute , Tandem Repeat Sequences , Gene Frequency , High-Throughput Nucleotide Sequencing , Humans , Leukemia, Myeloid, Acute/genetics , Mutation , fms-Like Tyrosine Kinase 3
8.
J Biol Chem ; 295(28): 9335-9348, 2020 07 10.
Article in English | MEDLINE | ID: mdl-32393580

ABSTRACT

The oncogene RAS is one of the most widely studied proteins in cancer biology, and mutant active RAS is a driver in many types of solid tumors and hematological malignancies. Yet the biological effects of different RAS mutations and the tissue-specific clinical implications are complex and nuanced. Here, we identified an internal tandem duplication (ITD) in the switch II domain of NRAS from a patient with extremely aggressive colorectal carcinoma. Results of whole-exome DNA sequencing of primary and metastatic tumors indicated that this mutation was present in all analyzed metastases and excluded the presence of any other clear oncogenic driver mutations. Biochemical analysis revealed increased interaction of the RAS ITD with Raf proto-oncogene Ser/Thr kinase (RAF), leading to increased phosphorylation of downstream MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK). The ITD prevented interaction with neurofibromin 1 (NF1)-GTPase-activating protein (GAP), providing a mechanism for sustained activity of the RAS ITD protein. We present the first crystal structures of NRAS and KRAS ITD at 1.65-1.75 Å resolution, respectively, providing insight into the physical interactions of this class of RAS variants with its regulatory and effector proteins. Our in-depth bedside-to-bench analysis uncovers the molecular mechanism underlying a case of highly aggressive colorectal cancer and illustrates the importance of robust biochemical and biophysical approaches in the implementation of individualized medicine.


Subject(s)
Colorectal Neoplasms , GTP Phosphohydrolases , MAP Kinase Signaling System , Membrane Proteins , Mutation , Proto-Oncogene Proteins p21(ras) , Colorectal Neoplasms/enzymology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Crystallography, X-Ray , GTP Phosphohydrolases/chemistry , GTP Phosphohydrolases/genetics , GTP Phosphohydrolases/metabolism , HEK293 Cells , Humans , Membrane Proteins/chemistry , Membrane Proteins/genetics , Membrane Proteins/metabolism , Protein Domains , Proto-Oncogene Mas , Proto-Oncogene Proteins p21(ras)/chemistry , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Exome Sequencing , raf Kinases/genetics , raf Kinases/metabolism
9.
Mol Ther Nucleic Acids ; 19: 318-329, 2020 Mar 06.
Article in English | MEDLINE | ID: mdl-31877408

ABSTRACT

Although recent advances in genetic studies have shed light on systemic lupus erythematosus (SLE), its detailed mechanisms remain elusive. In this study, using datasets on SLE transcriptomic profiles, we identified 750 differentially expressed genes (DEGs) in T and B lymphocytes and peripheral blood cells. Using transcription factor (TF) binding data derived from chromatin immunoprecipitation sequencing (ChIP-seq) experiments from the Encyclopedia of DNA Elements (ENCODE) project, we inferred networks of co-regulated genes (NcRGs) based on binding profiles of the upregulated DEGs by significantly enriched TFs. Modularization analysis of NcRGs identified co-regulatory modules among the DEGs and master TFs vital for each module. Remarkably, the co-regulatory modules stratified the common SLE interferon (IFN) signature and revealed SLE pathogenesis pathways, including the complement cascade, cell cycle regulation, NETosis, and epigenetic regulation. By integrative analyses of disease-associated genes (DAGs), DEGs, and enriched TFs, as well as proteins interacting with them, we identified a hierarchical regulatory cascade with TFs regulated by DAGs, which in turn regulates gene expression. Integrative analysis of multi-omics data provided valuable molecular insights into the molecular mechanisms of SLE.

10.
Bioinformatics ; 35(20): 4159-4161, 2019 10 15.
Article in English | MEDLINE | ID: mdl-30887025

ABSTRACT

SUMMARY: Insertion and deletion (indels) have been recognized as an important source generating tumor-specific mutant peptides (neoantigens). The focus of indel-derived neoantigen identification has been on leveraging DNA sequencing such as whole exome sequencing, with the effort of using RNA-seq less well explored. Here we present ScanNeo, a fast-streamlined computational pipeline for analyzing RNA-seq to predict neoepitopes derived from small to large-sized indels. We applied ScanNeo in a prostate cancer cell line and validated our predictions with matched mass spectrometry data. Finally, we demonstrated that indel neoantigens predicted from RNA-seq were associated with checkpoint inhibitor response in a cohort of melanoma patients. AVAILABILITY AND IMPLEMENTATION: ScanNeo is implemented in Python. It is freely accessible at the GitHub repository (https://github.com/ylab-hi/ScanNeo). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Subject(s)
RNA-Seq , Software , Humans , INDEL Mutation , Male , Sequence Analysis, RNA , Exome Sequencing
11.
Bioinformatics ; 35(7): 1244-1246, 2019 04 01.
Article in English | MEDLINE | ID: mdl-30169743

ABSTRACT

SUMMARY: HLA allele imputation from SNP genotypes has become increasingly useful, but its accuracy is heavily dependent on the reference panels used. HLA-IMPUTER implements HIBAG algorithm for HLA imputation with different population specific reference panels, including a new Han Chinese reference panel derived from 10 689 samples. We provide a convenient platform for researchers to impute HLA alleles and perform association analysis. AVAILABILITY AND IMPLEMENTATION: http://wyanglab.org: 3838/RefPanelWebsite/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Subject(s)
Polymorphism, Single Nucleotide , Software , Alleles , Asian People , Genome-Wide Association Study , Genotype , HLA Antigens , Humans
12.
Ann Rheum Dis ; 77(7): 1078-1084, 2018 07.
Article in English | MEDLINE | ID: mdl-29625966

ABSTRACT

OBJECTIVES: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. Through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. This study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning. METHODS: We conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning. RESULTS: We identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, pmeta=4.40E-08), MFHAS1 (rs2428, pmeta=1.17E-08) and CSNK2A2 (rs2731783, pmeta=1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, pmeta=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 in B-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (OR=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE. CONCLUSION: This study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.


Subject(s)
Antigens, Differentiation, T-Lymphocyte/genetics , Cell Cycle Proteins/genetics , DNA-Binding Proteins/genetics , Genetic Predisposition to Disease/epidemiology , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/genetics , Oncogene Proteins/genetics , Case-Control Studies , Casein Kinase II/genetics , Databases, Factual , Drug Repositioning , Female , Genome-Wide Association Study , Humans , Immunosuppressive Agents/therapeutic use , Lupus Erythematosus, Systemic/diagnosis , Male , Molecular Targeted Therapy/methods , Reproducibility of Results , Treatment Outcome
13.
Biol Sex Differ ; 8(1): 35, 2017 11 02.
Article in English | MEDLINE | ID: mdl-29096703

ABSTRACT

BACKGROUND: Sex is an important but understudied factor in the genetics of human diseases. Analyses using a combination of gene expression data, ENCODE data, and evolutionary data of sex-biased gene expression in human tissues can give insight into the regulatory and evolutionary forces acting on sex-biased genes. METHODS: In this study, we analyzed the differentially expressed genes between males and females. On the X chromosome, we used a novel method and investigated the status of genes that escape X-chromosome inactivation (escape genes), taking into account the clonality of lymphoblastoid cell lines (LCLs). To investigate the regulation of sex-biased differentially expressed genes (sDEG), we conducted pathway and transcription factor enrichment analyses on the sDEGs, as well as analyses on the genomic distribution of sDEGs. Evolutionary analyses were also conducted on both sDEGs and escape genes. RESULTS: Genome-wide, we characterized differential gene expression between sexes in 462 RNA-seq samples and identified 587 sex-biased genes, or 3.2% of the genes surveyed. On the X chromosome, sDEGs were distributed in evolutionary strata in a similar pattern as escape genes. We found a trend of negative correlation between the gene expression breadth and nonsynonymous over synonymous mutation (dN/dS) ratios, showing a possible pleiotropic constraint on evolution of genes. Genome-wide, nine transcription factors were found enriched in binding to the regions surrounding the transcription start sites of female-biased genes. Many pathways and protein domains were enriched in sex-biased genes, some of which hint at sex-biased physiological processes. CONCLUSIONS: These findings lend insight into the regulatory and evolutionary forces shaping sex-biased gene expression and their involvement in the physiological and pathological processes in human health and diseases.


Subject(s)
Evolution, Molecular , Gene Expression Regulation , Gene Expression , Genes, X-Linked , Sex Characteristics , Female , Genome, Human , Humans , Male
14.
Nat Genet ; 48(8): 940-946, 2016 08.
Article in English | MEDLINE | ID: mdl-27399966

ABSTRACT

Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.


Subject(s)
Asian People/genetics , Genetic Loci/genetics , Genome-Wide Association Study , Lupus Erythematosus, Systemic/genetics , Polymorphism, Single Nucleotide/genetics , White People/genetics , Case-Control Studies , Genetic Predisposition to Disease , Humans
15.
Hum Mol Genet ; 24(1): 274-84, 2015 Jan 01.
Article in English | MEDLINE | ID: mdl-25149475

ABSTRACT

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects mainly females. What role the X chromosome plays in the disease has always been an intriguing question. In this study, we examined the genetic variants on the X chromosome through meta-analysis of two genome-wide association studies (GWAS) on SLE on Chinese Han populations. Prominent association signals from the meta-analysis were replicated in 4 additional Asian cohorts, with a total of 5373 cases and 9166 matched controls. We identified a novel variant in PRPS2 on Xp22.3 as associated with SLE with genome-wide significance (rs7062536, OR = 0.84, P = 1.00E-08). Association of the L1CAM-MECP2 region with SLE was reported previously. In this study, we identified independent contributors in this region in NAA10 (rs2071128, OR = 0.81, P = 2.19E-13) and TMEM187 (rs17422, OR = 0.75, P = 1.47E-15), in addition to replicating the association from IRAK1-MECP2 region (rs1059702, OR = 0.71, P = 2.40E-18) in Asian cohorts. The X-linked susceptibility variants showed higher effect size in males than that in females, similar to results from a genome-wide survey of associated SNPs on the autosomes. These results suggest that susceptibility genes identified on the X chromosome, while contributing to disease predisposition, might not contribute significantly to the female predominance of this prototype autoimmune disease.


Subject(s)
Asian People/genetics , Chromosomes, Human, X/genetics , Genes, X-Linked , Lupus Erythematosus, Systemic/genetics , Ribose-Phosphate Pyrophosphokinase/genetics , China , Female , Genome-Wide Association Study , Humans , Male , Polymorphism, Single Nucleotide
16.
J Proteome Res ; 13(1): 126-36, 2014 Jan 03.
Article in English | MEDLINE | ID: mdl-24328083

ABSTRACT

We upgraded the preliminary CCPD 1.0 to CCPD 2.0 using the latest deep-profiling proteome (CCPD 2013) of three hepatocellular carcinoma (HCC) cell lines, namely, Hep3B, MHCC97H, and HCCLM3 (ProteomeXchange identifiers: PXD000529, PXD000533, and PXD000535). CCPD 2.0 totally covered 63.6% (438/689) of Chr. 8-coded proteins and 62.6% (439/701) of Chr. 8-coded protein-coding genes. Interestingly, we found that the missing proteins exhibited a tendency to form a cluster region in chromosomes, such as two ß-defensins clusters in Chr. 8, caused perhaps by their inflammation-related features. For the 41 Chr. 8-coded proteins being weakly or barely identified previously, we have performed an immunohistochemical (IHC) verification in 30 pairs of carcinoma/para-carcinoma HCC and 20 noncancerous liver tissues and confirmed their expressional evidence and occurrence proportions in tissue samples. We also verified 13 Chr. 8-coded HCC tumorigenesis-associated depleting or deficient proteins reported in CCPD 1.0 using IHC and screened 16 positive and 24 negative HCC metastatic potential-correlated proteins from large-scale label-free proteome quantitation data of CCPD 2013. Our results suggest that the selection of proper samples and the methodology to look for targeted missing proteins should be carefully considered in further verifications for the remaining Chr. 8-coded proteins.


Subject(s)
Chromosomes, Human, Pair 8 , Proteome , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , China , Humans , Immunohistochemistry , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Protein Biosynthesis , Transcriptome
17.
J Proteome Res ; 12(1): 151-61, 2013 Jan 04.
Article in English | MEDLINE | ID: mdl-23252959

ABSTRACT

Under the guidance of the Chromosome-centric Human Proteome Project (C-HPP), (1, 2) we conducted a systematic survey of the expression status of genes located at human chromosome 20 (Chr.20) in three cancer tissues, gastric, colon, and liver carcinoma, and their representative cell lines. We have globally profiled proteomes in these samples with combined technology of LC-MS/MS and acquired the corresponding mRNA information upon RNA-seq and RNAchip. In total, 323 unique proteins were identified, covering 60% of the coding genes (323/547) in Chr.20. With regards to qualitative information of proteomics, we overall evaluated the correlation of the identified Chr.20 proteins with target genes of transcription factors or of microRNA, conserved genes and cancer-related genes. As for quantitative information, the expression abundances of Chr.20 genes were found to be almost consistent in both tissues and cell lines of mRNA in all individual chromosome regions, whereas those of Chr.20 proteins in cells are different from tissues, especially in the region of 20q13.33. Furthermore, the abundances of Chr.20 proteins were hierarchically evaluated according to tissue- or cancer-related distribution. The analysis revealed several cancer-related proteins in Chr.20 are tissue- or cell-type dependent. With integration of all the acquired data, for the first time we established a solid database of the Chr.20 proteome.


Subject(s)
Chromosomes, Human, Pair 20 , Neoplasms , Proteins , Proteome , Cell Line, Tumor , Chromosomes, Human, Pair 20/genetics , Chromosomes, Human, Pair 20/metabolism , Colon/metabolism , Colon/pathology , Gastric Mucosa/metabolism , Gene Expression Regulation, Neoplastic , Genome, Human , Humans , Liver/metabolism , Liver/pathology , Mass Spectrometry , Neoplasms/genetics , Neoplasms/metabolism , Proteins/classification , Proteins/genetics , Proteins/metabolism , Proteome/genetics , Proteome/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Stomach/pathology
18.
Mol Biosyst ; 7(7): 2278-85, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21584303

ABSTRACT

The filamentous fungus Neurospora crassa is a leading model organism for circadian clock studies. Computational identification of a protein-protein interaction (PPI) network (also known as an interactome) in N. crassa can provide new insights into the cellular functions of proteins. Using two well-established bioinformatics methods (the interolog method and the domain interaction-based method), we predicted 27,588 PPIs among 3006 N. crassa proteins. To the best of our knowledge, this is the first identified interactome for N. crassa, although it remains problematic because of incomplete interactions and false positives. In particular, the established PPI network has provided clues to further decipher the molecular mechanism of circadian rhythmicity. For instance, we found that clock-controlled genes (ccgs) are more likely to act as bottlenecks in the established PPI network. We also identified an important module related to circadian oscillators, and some functional unknown proteins in this module may serve as potential candidates for new oscillators. Finally, all predicted PPIs were compiled into a user-friendly database server (NCPI), which is freely available at .


Subject(s)
Fungal Proteins/metabolism , Neurospora crassa/metabolism , Protein Interaction Mapping/methods , Circadian Clocks/physiology , Circadian Rhythm/physiology , Databases, Protein , Internet , Neurospora crassa/physiology , Protein Binding , Reproducibility of Results , Signal Transduction
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