RESUMO
Understanding the biological roles of all genes only through experimental methods is challenging. A computational approach with reliable interpretability is needed to infer the function of genes, particularly for non-coding RNAs. We have analyzed genomic features that are present across both coding and non-coding genes like transcription factor (TF) and cofactor ChIP-seq (823), histone modifications ChIP-seq (n = 621), cap analysis gene expression (CAGE) tags (n = 255), and DNase hypersensitivity profiles (n = 255) to predict ontology-based functions of genes. Our approach for gene function prediction was reliable (>90% balanced accuracy) for 486 gene-sets. PubMed abstract mining and CRISPR screens supported the inferred association of genes with biological functions, for which our method had high accuracy. Further analysis revealed that TF-binding patterns at promoters have high predictive strength for multiple functions. TF-binding patterns at the promoter add an unexplored dimension of explainable regulatory aspects of genes and their functions. Therefore, we performed a comprehensive analysis for the functional-specificity of TF-binding patterns at promoters and used them for clustering functions to reveal many latent groups of gene-sets involved in common major cellular processes. We also showed how our approach could be used to infer the functions of non-coding genes using the CRISPR screens of coding genes, which were validated using a long non-coding RNA CRISPR screen. Thus our results demonstrated the generality of our approach by using gene-sets from CRISPR screens. Overall, our approach opens an avenue for predicting the involvement of non-coding genes in various functions.
RESUMO
The true benefits of large single-cell transcriptome and epigenome data sets can be realized only with the development of new approaches and search tools for annotating individual cells. Matching a single-cell epigenome profile to a large pool of reference cells remains a major challenge. Here, we present scEpiSearch, which enables searching, comparison, and independent classification of single-cell open-chromatin profiles against a large reference of single-cell expression and open-chromatin data sets. Across performance benchmarks, scEpiSearch outperformed multiple methods in accuracy of search and low-dimensional coembedding of single-cell profiles, irrespective of platforms and species. Here we also demonstrate the unconventional utilities of scEpiSearch by applying it on single-cell epigenome profiles of K562 cells and samples from patients with acute leukaemia to reveal different aspects of their heterogeneity, multipotent behavior, and dedifferentiated states. Applying scEpiSearch on our single-cell open-chromatin profiles from embryonic stem cells (ESCs), we identified ESC subpopulations with more activity and poising for endoplasmic reticulum stress and unfolded protein response. Thus, scEpiSearch solves the nontrivial problem of amalgamating information from a large pool of single cells to identify and study the regulatory states of cells using their single-cell epigenomes.
Assuntos
Cromatina , Transcriptoma , Humanos , Cromatina/metabolismo , Epigenoma , Células-Tronco Embrionárias/metabolismo , Análise de Célula ÚnicaRESUMO
Finding direct dependencies between genetic pathways and diseases has been the target of multiple studies as it has many applications. However, due to cellular heterogeneity and limitations of the number of samples for bulk expression profiles, such studies have faced hurdles in the past. Here, we propose a method to perform single-cell expression-based inference of association between pathway, disease and cell-type (sci-PDC), which can help to understand their cause and effect and guide precision therapy. Our approach highlighted reliable relationships between a few diseases and pathways. Using the example of diabetes, we have demonstrated how sci-PDC helps in tracking variation of association between pathways and diseases with changes in age and species. The variation in pathways-disease associations in mice and humans revealed critical facts about the suitability of the mouse model for a few pathways in the context of diabetes. The coherence between results from our method and previous reports, including information about the drug target pathways, highlights its reliability for multidimensional utility.
Assuntos
Doença , Perfil Genético , Animais , Doença/genética , Humanos , CamundongosRESUMO
BACKGROUND: The COVID-19 pandemic has affected the health, economic, and social fabric of many nations worldwide. Identification of individual-level susceptibility factors may help people in identifying and managing their emotional, psychological, and social well-being. OBJECTIVE: This study is focused on learning a ranked list of factors that could indicate a predisposition to a mental disorder during the COVID-19 pandemic. METHODS: In this study, we have used a survey of 17,764 adults in the United States from different age groups, genders, and socioeconomic statuses. Through initial statistical analysis and Bayesian network inference, we have identified key factors affecting mental health during the COVID-19 pandemic. Integrating Bayesian networks with classical machine learning approaches led to effective modeling of the level of mental health prevalence. RESULTS: Overall, females were more stressed than males, and people in the age group 18-29 years were more vulnerable to anxiety than other age groups. Using the Bayesian network model, we found that people with a chronic mental illness were more prone to mental disorders during the COVID-19 pandemic. The new realities of working from home; homeschooling; and lack of communication with family, friends, and neighbors induces mental pressure. Financial assistance from social security helps in reducing mental stress during the COVID-19-generated economic crises. Finally, using supervised machine learning models, we predicted the most mentally vulnerable people with ~80% accuracy. CONCLUSIONS: Multiple factors such as social isolation, digital communication, and working and schooling from home were identified as factors of mental illness during the COVID-19 pandemic. Regular in-person communication with friends and family, a healthy social life, and social security were key factors, and taking care of people with a history of mental disease appears to be even more important during this time.