scholarly journals Mapping the Germline and Somatic Mutation Interaction Landscape in Indolent and Aggressive Prostate Cancers

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Tarun Karthik Kumar Mamidi ◽  
Jiande Wu ◽  
Chindo Hicks
Keyword(s):  
Signaling Pathways ◽  
Somatic Mutation ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Multiple Gene ◽  
Gene Regulatory ◽  
Aggressive Tumors ◽  
Prostate Cancers ◽  
Mutation Information

Background. A majority of prostate cancers (PCas) are indolent and cause no harm even without treatment. However, a significant proportion of patients with PCa have aggressive tumors that progress rapidly to metastatic disease and are often lethal. PCa develops through somatic mutagenesis, but emerging evidence suggests that germline genetic variation can markedly contribute to tumorigenesis. However, the causal association between genetic susceptibility and tumorigenesis has not been well characterized. The objective of this study was to map the germline and somatic mutation interaction landscape in indolent and aggressive tumors and to discover signatures of mutated genes associated with each type and distinguishing the two types of PCa. Materials and Methods. We integrated germline mutation information from genome-wide association studies (GWAS) with somatic mutation information from The Cancer Genome Atlas (TCGA) using gene expression data from TCGA on indolent and aggressive PCas as the intermediate phenotypes. Germline and somatic mutated genes associated with each type of PCa were functionally characterized using network and pathway analysis. Results. We discovered gene signatures containing germline and somatic mutations associated with each type and distinguishing the two types of PCa. We discovered multiple gene regulatory networks and signaling pathways enriched with germline and somatic mutations including axon guidance, RAR, WINT, MSP-RON, STAT3, PI3K, TR/RxR, and molecular mechanisms of cancer, NF-kB, prostate cancer, GP6, androgen, and VEGF signaling pathways for indolent PCa and MSP-RON, axon guidance, RAR, adipogenesis, and molecular mechanisms of cancer and NF-kB signaling pathways for aggressive PCa. Conclusion. The investigation revealed germline and somatic mutated genes associated with indolent and aggressive PCas and distinguishing the two types of PCa. The study revealed multiple gene regulatory networks and signaling pathways dysregulated by germline and somatic alterations. Integrative analysis combining germline and somatic mutations is a powerful approach to mapping germline and somatic mutation interaction landscape.

scholarly journals Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer

2019 ◽  
Vol 16 (6) ◽  
pp. 1055 ◽  
Author(s):  
Jiande Wu ◽  
Tarun Mamidi ◽  
Lu Zhang ◽  
Chindo Hicks
Keyword(s):  
Breast Cancer ◽  
Somatic Mutation ◽  
Triple Negative Breast Cancer ◽  
Somatic Mutations ◽  
Triple Negative ◽  
Germline Mutations ◽  
Biological Pathways ◽  
Molecular Networks ◽  
Increased Risk ◽  
Mutation Information

Recent advances in high-throughput genotyping and the recent surge of next generation sequencing of the cancer genomes have enabled discovery of germline mutations associated with an increased risk of developing breast cancer and acquired somatic mutations driving the disease. Emerging evidence indicates that germline mutations may interact with somatic mutations to drive carcinogenesis. However, the possible oncogenic interactions and cooperation between germline and somatic alterations in triple-negative breast cancer (TNBC) have not been characterized. The objective of this study was to investigate the possible oncogenic interactions and cooperation between genes containing germline and somatic mutations in TNBC. Our working hypothesis was that genes containing germline mutations associated with an increased risk developing breast cancer also harbor somatic mutations acquired during tumorigenesis, and that these genes are functionally related. We further hypothesized that TNBC originates from a complex interplay among and between genes containing germline and somatic mutations, and that these complex array of interacting genetic factors affect entire molecular networks and biological pathways which in turn drive the disease. We tested this hypothesis by integrating germline mutation information from genome-wide association studies (GWAS) with somatic mutation information on TNBC from The Cancer Genome Atlas (TCGA) using gene expression data from 110 patients with TNBC and 113 controls. We discovered a signature of 237 functionally related genes containing both germline and somatic mutations. We discovered molecular networks and biological pathways enriched for germline and somatic mutations. The top pathways included the hereditary breast cancer and role of BRCA1 in DNA damage response signaling pathways. In conclusion, this is the first large-scale and comprehensive analysis delineating possible oncogenic interactions and cooperation among and between genes containing germline and somatic mutations in TNBC. Genetic and somatic mutations, along with the genes discovered in this study, will require experimental functional validation in different ethnic populations. Functionally validated genetic and somatic variants will have important implications for the development of novel precision prevention strategies and discovery of prognostic markers in TNBC.

scholarly journals Comprehensive Assessment and Network Analysis of the Emerging Genetic Susceptibility Landscape of Prostate Cancer

2013 ◽  
Vol 12 ◽  
pp. CIN.S12128 ◽  
Author(s):  
Chindo Hicks ◽  
Lucio Miele ◽  
Tejaswi Koganti ◽  
Srinivasan Vijayakumar
Keyword(s):  
Prostate Cancer ◽  
Genetic Susceptibility ◽  
Pathway Analysis ◽  
Gene Regulatory Networks ◽  
Genetic Variants ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Comprehensive Assessment ◽  
Increased Risk ◽  
Gene Regulatory

Background Recent advances in high-throughput genotyping have made possible identification of genetic variants associated with increased risk of developing prostate cancer using genome-wide associations studies (GWAS). However, the broader context in which the identified genetic variants operate is poorly understood. Here we present a comprehensive assessment, network, and pathway analysis of the emerging genetic susceptibility landscape of prostate cancer. Methods We created a comprehensive catalog of genetic variants and associated genes by mining published reports and accompanying websites hosting supplementary data on GWAS. We then performed network and pathway analysis using single nucleotide polymorphism (SNP)-containing genes to identify gene regulatory networks and pathways enriched for genetic variants. Results We identified multiple gene networks and pathways enriched for genetic variants including IGF-1, androgen biosynthesis and androgen signaling pathways, and the molecular mechanisms of cancer. The results provide putative functional bridges between GWAS findings and gene regulatory networks and biological pathways.

scholarly journals Unique expression patterns of multiple key genes associated with the evolution of mammalian flight

2014 ◽  
Vol 281 (1783) ◽  
pp. 20133133 ◽  
Author(s):  
Zhe Wang ◽  
Mengyao Dai ◽  
Yao Wang ◽  
Kimberly L. Cooper ◽  
Tengteng Zhu ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Genetic Changes ◽  
Multiple Gene ◽  
Membrane Growth ◽  
Complex Integration ◽  
Key Genes ◽  
Bat Wing

Bats are the only mammals capable of true flight. Critical adaptations for flight include a pair of dramatically elongated hands with broad wing membranes. To study the molecular mechanisms of bat wing evolution, we perform genomewide mRNA sequencing and in situ hybridization for embryonic bat limbs. We identify seven key genes that display unique expression patterns in embryonic bat wings and feet, compared with mouse fore- and hindlimbs. The expression of all 5′HoxD genes ( Hoxd9–13 ) and Tbx3 , six known crucial transcription factors for limb and digit development, is extremely high and prolonged in the elongating wing area. The expression of Fam5c , a tumour suppressor, in bat limbs is bat-specific and significantly high in all short digit regions (the thumb and foot digits). These results suggest multiple genetic changes occurred independently during the evolution of bat wings to elongate the hand digits, promote membrane growth and keep other digits short. Our findings also indicate that the evolution of limb morphology depends on the complex integration of multiple gene regulatory networks and biological processes that control digit formation and identity, chondrogenesis, and interdigital regression or retention.

scholarly journals Chip-seq and gene expression data for the identification of functional sub-pathways: a proof of concept in lung cancer

2020 ◽  
Author(s):  
Xanthoula Atsalaki ◽  
Lefteris Koumakis ◽  
George Potamias ◽  
Manolis Tsiknakis
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Systems Biology ◽  
Gene Expression Data ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Integrative Approach ◽  
Expression Data ◽  
Gene Regulatory

AbstractHigh-throughput technologies, such as chromatin immunoprecipitation (ChIP) with massively parallel sequencing (ChIP-seq) have enabled cost and time efficient generation of immense amount of genome data. The advent of advanced sequencing techniques allowed biologists and bioinformaticians to investigate biological aspects of cell function and understand or reveal unexplored disease etiologies. Systems biology attempts to formulate the molecular mechanisms in mathematical models and one of the most important areas is the gene regulatory networks (GRNs), a collection of DNA segments that somehow interact with each other. GRNs incorporate valuable information about molecular targets that can be corellated to specific phenotype.In our study we highlight the need to develop new explorative tools and approaches for the integration of different types of -omics data such as ChIP-seq and GRNs using pathway analysis methodologies. We present an integrative approach for ChIP-seq and gene expression data on GRNs. Using public microarray expression samples for lung cancer and healthy subjects along with the KEGG human gene regulatory networks, we identified ways to disrupt functional sub-pathways on lung cancer with the aid of CTCF ChIP-seq data, as a proof of concept.We expect that such a systems biology pipeline could assist researchers to identify corellations and causality of transcription factors over functional or disrupted biological sub-pathways.

scholarly journals Evolution of abbreviated development in Heliocidaris erythrogramma dramatically re-wired the highly conserved sea urchin developmental gene regulatory network to decouple signaling center function from ultimate fate

2019 ◽  
Author(s):  
Allison Edgar ◽  
Maria Byrne ◽  
David R. McClay ◽  
Gregory A. Wray
Keyword(s):  
Early Development ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Sea Urchins ◽  
Stabilizing Selection ◽  
Developmental Gene ◽  
Heliocidaris Erythrogramma ◽  
Signaling Center ◽  
Gene Regulatory ◽  
Ultimate Fate

AbstractDevelopmental gene regulatory networks (GRNs) describe the interactions among gene products that drive the differential transcriptional and cell regulatory states that pattern the embryo and specify distinct cell fates. GRNs are often deeply conserved, but whether this is the product of constraint inherent to the network structure or stabilizing selection remains unclear. We have constructed the first formal GRN for early development in Heliocidaris erythrogramma, a species with dramatically accelerated, direct development. This life history switch has important ecological consequences, arose rapidly, and has evolved independently many times in echinoderms, suggesting it is a product of selection. We find that H. erythrogramma exhibits dramatic differences in GRN topology compared with ancestral, indirect-developing sea urchins. In particular, the GRN sub-circuit that directs the early and autonomous commitment of skeletogenic cell precursors in indirect developers appears to be absent in H. erythrogramma, a particularly striking change in relation to both the prior conservation of this sub-circuit and the key role that these cells play ancestrally in early development as the embryonic signaling center. These results show that even highly conserved molecular mechanisms of early development can be substantially reconfigured in a relatively short evolutionary time span, suggesting that selection rather than constraint is responsible for the striking conservation of the GRN among other sea urchins.

scholarly journals Single cell and single nucleus RNA-Seq reveal cellular heterogeneity and homeostatic regulatory networks in adult mouse stria vascularis

2019 ◽  
Author(s):  
Soumya Korrapati ◽  
Ian Taukulis ◽  
Rafal Olszewski ◽  
Madeline Pyle ◽  
Shoujun Gu ◽  
...  
Keyword(s):  
Single Cell ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Stria Vascularis ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Genetic Mechanisms ◽  
Single Nucleus ◽  
Gene Regulatory

AbstractThe stria vascularis (SV) generates the endocochlear potential (EP) in the inner ear and is necessary for proper hair cell mechanotransduction and hearing. While channels belonging to SV cell types are known to play crucial roles in EP generation, relatively little is known about gene regulatory networks that underlie the ability of the SV to generate and maintain the EP. Using single cell and single nucleus RNA-sequencing, we identify and validate known and rare cell populations in the SV. Furthermore, we establish a basis for understanding molecular mechanisms underlying SV function by identifying potential gene regulatory networks as well as druggable gene targets. Finally, we associate known deafness genes with adult SV cell types. This work establishes a basis for dissecting the genetic mechanisms underlying the role of the SV in hearing and will serve as a basis for designing therapeutic approaches to hearing loss related to SV dysfunction.

scholarly journals Unraveling the Genomic-Epigenomic Interaction Landscape in Triple Negative and Non-Triple Negative Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1559
Author(s):  
Jiande Wu ◽  
Tarun Karthik Kumar Mamidi ◽  
Lu Zhang ◽  
Chindo Hicks
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Signaling Pathways ◽  
Somatic Mutation ◽  
Gene Expression Data ◽  
Triple Negative Breast Cancer ◽  
Somatic Mutations ◽  
Triple Negative ◽  
Expression Data ◽  
Gene Expression Signatures

Background: The recent surge of next generation sequencing of breast cancer genomes has enabled development of comprehensive catalogues of somatic mutations and expanded the molecular classification of subtypes of breast cancer. However, somatic mutations and gene expression data have not been leveraged and integrated with epigenomic data to unravel the genomic-epigenomic interaction landscape of triple negative breast cancer (TNBC) and non-triple negative breast cancer (non-TNBC). Methods: We performed integrative data analysis combining somatic mutation, epigenomic and gene expression data from The Cancer Genome Atlas (TCGA) to unravel the possible oncogenic interactions between genomic and epigenomic variation in TNBC and non-TNBC. We hypothesized that within breast cancers, there are differences in somatic mutation, DNA methylation and gene expression signatures between TNBC and non-TNBC. We further hypothesized that genomic and epigenomic alterations affect gene regulatory networks and signaling pathways driving the two types of breast cancer. Results: The investigation revealed somatic mutated, epigenomic and gene expression signatures unique to TNBC and non-TNBC and signatures distinguishing the two types of breast cancer. In addition, the investigation revealed molecular networks and signaling pathways enriched for somatic mutations and epigenomic changes unique to each type of breast cancer. The most significant pathways for TNBC were: retinal biosynthesis, BAG2, LXR/RXR, EIF2 and P2Y purigenic receptor signaling pathways. The most significant pathways for non-TNBC were: UVB-induced MAPK, PCP, Apelin endothelial, Endoplasmatic reticulum stress and mechanisms of viral exit from host signaling Pathways. Conclusion: The investigation revealed integrated genomic, epigenomic and gene expression signatures and signing pathways unique to TNBC and non-TNBC, and a gene signature distinguishing the two types of breast cancer. The study demonstrates that integrative analysis of multi-omics data is a powerful approach for unravelling the genomic-epigenomic interaction landscape in TNBC and non-TNBC.

scholarly journals nSARS-Cov-2, pulmonary edema and thrombosis: possible molecular insights using miRNA-gene circuits in regulatory networks

ExRNA ◽  
2020 ◽  
Vol 2 (1) ◽  
Author(s):  
P. Khurana ◽  
A. Gupta ◽  
R. Sugadev ◽  
Y. K. Sharma ◽  
R. Varshney ◽  
...  
Keyword(s):  
Pulmonary Edema ◽  
Antigen Presentation ◽  
Signaling Pathways ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Mirna Gene ◽  
Protein Stabilization ◽  
Molecular Signature ◽  
Potential Candidate ◽  
Regulatory Circuits

Abstract Background Given the worldwide spread of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (nSARS-CoV-2) infection pandemic situation, research to repurpose drugs, identify novel drug targets, vaccine candidates have created a new race to curb the disease. While the molecular signature of nSARS-CoV-2 is still under investigation, growing literature shows similarity among nSARS-CoV-2, pulmonary edema, and thromboembolic disorders due to common symptomatic features. A network medicine approach is used to to explore the molecular complexity of the disease and to uncover common molecular trajectories of edema and thrombosis with nSARS-CoV-2. Results and conclusion A comprehensive nSARS-CoV-2 responsive miRNA: Transcription Factor (TF): gene co-regulatory network was built using host-responsive miRNAs and it’s associated tripartite, Feed-Forward Loops (FFLs) regulatory circuits were identified. These regulatory circuits regulate signaling pathways like virus endocytosis, viral replication, inflammatory response, pulmonary vascularization, cell cycle control, virus spike protein stabilization, antigen presentation, etc. A unique miRNA-gene regulatory circuit containing a consortium of four hub FFL motifs is proposed to regulate the virus-endocytosis and antigen-presentation signaling pathways. These regulatory circuits also suggest potential correlations/similarity in the molecular mechanisms during nSARS-CoV-2 infection, pulmonary diseases and thromboembolic disorders and thus could pave way for repurposing of drugs. Some important miRNAs and genes have also been proposed as potential candidate markers. A detailed molecular snapshot of TGF signaling as the common pathway, that could play an important role in controlling common pathophysiologies among diseases, is also put forth.

The Genetics of Evolutionary Novelties

2014 ◽  
Author(s):  
Günter P. Wagner
Keyword(s):  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Regulatory Elements ◽  
Complex Problem ◽  
Micro Rnas ◽  
Sex Comb ◽  
Gene Regulatory ◽  
Transcription Factor Proteins ◽  
Evolutionary Novelties

This chapter examines the molecular genetics of evolutionary novelties. In particular, it investigates which molecular mechanisms might be involved in the origination of novel gene regulatory networks (and, thus, character identity networks) and what these mechanisms imply for the origin of novel characters. The chapter begins with a discussion of the complex problem of the evolution of transcriptional regulation by focusing on the evolution of cis-regulatory elements (CREs) and the evolution of transcription factor proteins. It then asks whether novel pigment spots, such as the Drosophila wing spots, are novelties. It also explores an evolutionary novelty known as sex comb and the role of transposable elements in the origin of novel CREs. Finally, it considers the role of gene duplications, the evolution of micro-RNAs (miRNAs), and the possibility of a mechanistic difference between adaptation and innovation.

scholarly journals Comparative analyses of saprotrophy in Salisapilia sapeloensis and diverse plant pathogenic oomycetes reveal lifestyle-specific gene expression

2020 ◽  
Vol 96 (11) ◽  
Author(s):  
Sophie de Vries ◽  
Jan de Vries ◽  
John M Archibald ◽  
Claudio H Slamovits
Keyword(s):  
Gene Expression ◽  
Regulatory Networks ◽  
Plant Pathogens ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Reference Points ◽  
Global Perspective ◽  
Specific Gene ◽  
Gene Regulatory ◽  
Specific Array

ABSTRACT Oomycetes include many devastating plant pathogens. Across oomycete diversity, plant-infecting lineages are interspersed by non-pathogenic ones. Unfortunately, our understanding of the evolution of lifestyle switches is hampered by a scarcity of data on the molecular biology of saprotrophic oomycetes, ecologically important primary colonizers of dead tissue that can serve as informative reference points for understanding the evolution of pathogens. Here, we established Salisapilia sapeloensis as a tractable system for the study of saprotrophic oomycetes. We generated multiple transcriptomes from S. sapeloensis and compared them with (i) 22 oomycete genomes and (ii) the transcriptomes of eight pathogenic oomycetes grown under 13 conditions. We obtained a global perspective on gene expression signatures of oomycete lifestyles. Our data reveal that oomycete saprotrophs and pathogens use similar molecular mechanisms for colonization but exhibit distinct expression patterns. We identify a S. sapeloensis-specific array and expression of carbohydrate-active enzymes and putative regulatory differences, highlighted by distinct expression levels of transcription factors. Salisapilia sapeloensis expresses only a small repertoire of candidates for virulence-associated genes. Our analyses suggest lifestyle-specific gene regulatory signatures and that, in addition to variation in gene content, shifts in gene regulatory networks underpin the evolution of oomycete lifestyles.

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