Integrative ceRNA network analysis identifies unique and shared molecular signatures in Bipolar Disorder and Schizophrenia.

Bipolar Disorder (BPD) and Schizophrenia (SCZ) are complex psychiatric disorders with shared symptomatology and genetic risk factors. Understanding the molecular mechanisms underlying these disorders is crucial for refining diagnostic criteria and guiding targeted treatments. In this study, publicly available RNA-seq data from post-mortem samples of the basal ganglia's striatum were analyzed using an integrative computational approach to identify differentially expressed (DE) transcripts associated with SCZ and BPD. The analysis aimed to reveal both shared and distinct genes and long non-coding RNAs (lncRNAs) and to construct competitive endogenous RNA (ceRNA) networks within the striatum. Furthermore, the functional implications of these identified transcripts are explored, alongside their presence in established databases such as BipEx and SCHEMA. A significant outcome of our analysis was the identification of 21 DEmRNAs and 1 DElncRNA shared between BPD and SCZ across the Caudate, Putamen, and Nucleus Accumbens. Another noteworthy finding was the identification of Hub nodes within the ceRNA networks that were linked to major psychosis. Particularly, MED19, HNRNPC, MAGED4B, KDM5A, GOLGA7, CHASERR, hsa-miR-4778-3p, hsa-miR-4739, and hsa-miR-4685-5p emerged as potential biomarkers. These findings shed light on the common and unique molecular signatures underlying BPD and SCZ, offering significant potential for the advancement of diagnostic and therapeutic strategies tailored to these psychiatric disorders.

UICPC: Centrality-based clustering for scRNA-seq data analysis without user input.

scRNA-seq data analysis enables new possibilities for identification of novel cells, specific characterization of known cells and study of cell heterogeneity. The performance of most clustering methods especially developed for scRNA-seq is greatly influenced by user input. We propose a centrality-clustering method named UICPC and compare its performance with 9 state-of-the-art clustering methods on 11 real-world scRNA-seq datasets to demonstrate its effectiveness and usefulness in discovering cell groups. Our method does not require user input. However, it requires settings of threshold, which are benchmarked after performing extensive experiments. We observe that most compared approaches show poor performance due to high heterogeneity and large dataset dimensions. However, UICPC shows excellent performance in terms of NMI, Purity and ARI, respectively. UICPC is available as an R package and can be downloaded by clicking the link https://sites.google.com/view/hussinchowdhury/software.

An Integrative Systems Biology Approach Identifies Molecular Signatures Associated with Gallbladder Cancer Pathogenesis.

Gallbladder cancer (GBC) has a lower incidence rate among the population relative to other cancer types but is a major contributor to the total number of biliary tract system cancer cases. GBC is distinguished from other malignancies by its high mortality, marked geographical variation and poor prognosis. To date no systemic targeted therapy is available for GBC. The main objective of this study is to determine the molecular signatures correlated with GBC development using integrative systems level approaches. We performed analysis of publicly available transcriptomic data to identify differentially regulated genes and pathways. Differential co-expression network analysis and transcriptional regulatory network analysis was performed to identify hub genes and hub transcription factors (TFs) associated with GBC pathogenesis and progression. Subsequently, we assessed the epithelial-mesenchymal transition (EMT) status of the hub genes using a combination of three scoring methods. The identified hub genes including, CDC6, MAPK15, CCNB2, BIRC7, L3MBTL1 were found to be regulators of cell cycle components which suggested their potential role in GBC pathogenesis and progression.

Rank-preserving biclustering algorithm: a case study on miRNA breast cancer.

Effective biomarkers aid in the early diagnosis and monitoring of breast cancer and thus play an important role in the treatment of patients suffering from the disease. Growing evidence indicates that alteration of expression levels of miRNA is one of the principal causes of cancer. We analyze breast cancer miRNA data to discover a list of biclusters as well as breast cancer miRNA biomarkers which can help to understand better this critical disease and take important clinical decisions for treatment and diagnosis. In this paper, we propose a pattern-based parallel biclustering algorithm termed Rank-Preserving Biclustering (RPBic). The key strategy is to identify rank-preserved rows under a subset of columns based on a modified version of all substrings common subsequence (ALCS) framework. To illustrate the effectiveness of the RPBic algorithm, we consider synthetic datasets and show that RPBic outperforms relevant biclustering algorithms in terms of relevance and recovery. For breast cancer data, we identify 68 biclusters and establish that they have strong clinical characteristics among the samples. The differentially co-expressed miRNAs are found to be involved in KEGG cancer related pathways. Moreover, we identify frequency-based biomarkers (hsa-miR-410, hsa-miR-483-5p) and network-based biomarkers (hsa-miR-454, hsa-miR-137) which we validate to have strong connectivity with breast cancer. The source code and the datasets used can be found at http://agnigarh.tezu.ernet.in/~rosy8/Bioinformatics_RPBic_Data.rar . Graphical Abstract.

POPBic: Pathway-Based Order Preserving Biclustering Algorithm Towards the Analysis of Gene Expression Data.

To understand the underlying biological mechanisms of gene expression data, it is important to discover the groups of genes that have similar expression patterns under certain subsets of conditions. Biclustering algorithms have been effective in analyzing large-scale gene expression data. Recently, traditional biclustering has been improved by introducing biological knowledge along with the expression data during the biclustering process. In this paper, we propose the Pathway-based Order Preserving Biclustering (POPBic) algorithm by incorporating Kyoto Encyclopedia of Genes and Genomes (KEGG) based on the hypothesis that two genes sharing similar pathways are likely to be similar. The basic principle of the POPBic approach is to apply the concept of Longest Common Subsequence between a pair of genes which have a high number of common pathways. The algorithm identifies the expression patterns from data using two major steps: (i) selection of significant seed genes and (ii) extraction of biclusters. We performe exhaustive experimentation with the POPBic algorithm using synthetic dataset to evaluate the bicluster model, finding its robustness in the presence of noise and identifying overlapping biclusters. We demonstrate that POPBic is able to discover biologically significant biclusters for four cancer microarray gene expression datasets. POPBic has been found to perform consistently well in comparison to its closest competitors.

Differential Expression Analysis of RNA-seq Reads: Overview, Taxonomy, and Tools.

Analysis of RNA-sequence (RNA-seq) data is widely used in transcriptomic studies and it has many applications. We review RNA-seq data analysis from RNA-seq reads to the results of differential expression analysis. In addition, we perform a descriptive comparison of tools used in each step of RNA-seq data analysis along with a discussion of important characteristics of these tools. A taxonomy of tools is also provided. A discussion of issues in quality control and visualization of RNA-seq data is also included along with useful tools. Finally, we provide some guidelines for the RNA-seq data analyst, along with research issues and challenges which should be addressed.

(Differential) Co-Expression Analysis of Gene Expression: A Survey of Best Practices.

Analysis of gene expression data is widely used in transcriptomic studies to understand functions of molecules inside a cell and interactions among molecules. Differential co-expression analysis studies diseases and phenotypic variations by finding modules of genes whose co-expression patterns vary across conditions. We review the best practices in gene expression data analysis in terms of analysis of (differential) co-expression, co-expression network, differential networking, and differential connectivity considering both microarray and RNA-seq data along with comparisons. We highlight hurdles in RNA-seq data analysis using methods developed for microarrays. We include discussion of necessary tools for gene expression analysis throughout the paper. In addition, we shed light on scRNA-seq data analysis by including preprocessing and scRNA-seq in co-expression analysis along with useful tools specific to scRNA-seq. To get insights, biological interpretation and functional profiling is included. Finally, we provide guidelines for the analyst, along with research issues and challenges which should be addressed.

Integrative network analysis identifies differential regulation of neuroimmune system in Schizophrenia and Bipolar disorder.

Background: Neuropsychiatric disorders such as Schizophrenia (SCZ) and Bipolar disorder (BPD) pose a broad range of problems with different symptoms mainly characterized by some combination of abnormal thoughts, emotions, behaviour, etc. However, in depth molecular and pathophysiological mechanisms among different neuropsychiatric disorders have not been clearly understood yet. We have used RNA-seq data to investigate unique and overlapping molecular signatures between SCZ and BPD using an integrative network biology approach. Methods: RNA-seq count data were collected from NCBI-GEO database generated on post-mortem brain tissues of controls (n = 24) and patients of BPD (n = 24) and SCZ (n = 24). Differentially expressed genes (DEGs) were identified using the consensus of DESeq2 and edgeR tools and used for downstream analysis. Weighted gene correlation networks were constructed to find non-preserved (NP) modules for SCZ, BPD and control conditions. Topological analysis and functional enrichment analysis were performed on NP modules to identify unique and overlapping expression signatures during SCZ and BPD conditions. Results: We have identified four NP modules from the DEGs of BPD and SCZ. Eleven overlapping genes have been identified between SCZ and BPD networks, and they were found to be highly enriched in inflammatory responses. Among these eleven genes, TNIP2, TNFRSF1A and AC005840.1 had higher sum of connectivity exclusively in BPD network. In addition, we observed that top five genes of NP module from SCZ network were downregulated which may be a key factor for SCZ disorder. Conclusions: Differential activation of the immune system components and pathways may drive the common and unique pathogenesis of the BPD and SCZ.

Biomarker Identification for Cancer Disease Using Biclustering Approach: An Empirical Study.

This paper presents an exhaustive empirical study to identify biomarkers using two approaches: frequency-based and network-based, over seventeen different biclustering algorithms and six different cancer expression datasets. To systematically analyze the biclustering algorithms, we perform enrichment analysis, subtype identification and biomarker identification. Biclustering algorithms such as C&C, SAMBA and Plaid are useful to detect biomarkers by both approaches for all datasets except prostate cancer. We detect a total of 102 gene biomarkers using frequency-based method out of which 19 are for blood cancer, 36 for lung cancer, 25 for colon cancer, 13 for multi-tissue cancer and 9 for prostate cancer. Using the network-based approach we detect a total of 41 gene biomarkers of which 15 are from blood cancer, 12 from lung cancer, 6 from colon cancer, 7 from multi-tissue cancer and 1 from prostate cancer dataset. We further extend our network analysis over some biclusters and detect some gene biomarkers not detected earlier by both frequency-based or network-based approach. We expand our work on breast cancer miRNA expression data to evaluate the performance of the biclustering algorithms. We detect 19 breast cancer biomarkers by frequency-based method and 5 by network-based method for the miRNA dataset.

FUMET: a fuzzy network module extraction technique for gene expression data.

Construction of co-expression network and extraction of network modules have been an appealing area of bioinformatics research. This article presents a co-expression network construction and a biologically relevant network module extraction technique based on fuzzy set theoretic approach. The technique is able to handle both positive and negative correlations among genes. The constructed network for some benchmark gene expression datasets have been validated using topological internal and external measures. The effectiveness of network module extraction technique has been established in terms of well-known p-value, Q-value and topological statistics.

Shifting-and-Scaling Correlation Based Biclustering Algorithm.

The existence of various types of correlations among the expressions of a group of biologically significant genes poses challenges in developing effective methods of gene expression data analysis. The initial focus of computational biologists was to work with only absolute and shifting correlations. However, researchers have found that the ability to handle shifting-and-scaling correlation enables them to extract more biologically relevant and interesting patterns from gene microarray data. In this paper, we introduce an effective shifting-and-scaling correlation measure named Shifting and Scaling Similarity (SSSim), which can detect highly correlated gene pairs in any gene expression data. We also introduce a technique named Intensive Correlation Search (ICS) biclustering algorithm, which uses SSSim to extract biologically significant biclusters from a gene expression data set. The technique performs satisfactorily with a number of benchmarked gene expression data sets when evaluated in terms of functional categories in Gene Ontology database.