RESUMO
Identifying new gene functions and pathways underlying diseases and biological processes are major challenges in genomics research. Particularly, most methods for interpreting the pathways characteristic of an experimental gene list defined by genomic data are limited by their dependence on assessing the overlapping genes or their interactome topology, which cannot account for the variety of functional relations. This is particularly problematic for pathway discovery from single-cell genomics with low gene coverage or interpreting complex pathway changes such as during change of cell states. Here, we exploited the comprehensive sets of molecular concepts that combine ontologies, pathways, interactions and domains to help inform the functional relations. We first developed a universal concept signature (uniConSig) analysis for genome-wide quantification of new gene functions underlying biological or pathological processes based on the signature molecular concepts computed from known functional gene lists. We then further developed a novel concept signature enrichment analysis (CSEA) for deep functional assessment of the pathways enriched in an experimental gene list. This method is grounded on the framework of shared concept signatures between gene sets at multiple functional levels, thus overcoming the limitations of the current methods. Through meta-analysis of transcriptomic data sets of cancer cell line models and single hematopoietic stem cells, we demonstrate the broad applications of CSEA on pathway discovery from gene expression and single-cell transcriptomic data sets for genetic perturbations and change of cell states, which complements the current modalities. The R modules for uniConSig analysis and CSEA are available through https://github.com/wangxlab/uniConSig.
Assuntos
Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Algoritmos , Linhagem Celular Tumoral , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Genômica , HumanosRESUMO
Basal-like breast cancer (BLBC) is an aggressive breast cancer subtype with features similar to the basal cells surrounding the mammary ducts. Treatment of patients with BLBC has been challenging due to the lack of well-defined molecular targets. Due to the clinical and pathological similarities of BLBC with BRCA-deficient breast cancers, the effectiveness of Poly (ADP-ribose) polymerase inhibitors (PARPi) has been tested in early phase clinical trials for patients with advanced BLBC, with limited clinical responses. Recently, it was reported that HORMAD1 overexpression sensitizes BLBC to HR-targeting agents by suppressing homologous recombination. Our independent analysis suggests that HORMAD1 is aberrantly overexpressed in about 80% of BLBC, and its expression in normal tissues is restricted to testis. Our experimental data suggests that HORMAD1 overexpression correlates with focal hypomethylation in BLBC. On the other hand, investigation of the Genomics of Drug Sensitivity in Cancer dataset revealed significantly reduced sensitivity of HORMAD1-overexpressing BLBC cell lines to Rucaparib, a commonly used PARPi. To further assess the role of HORMAD1 in PARPi sensitivity, we generated three HORMAD1-overexpressing xenograft models using the HORMAD1-low BLBC cell lines HCC1954, HCC1806, and BT20; we then subjected these xenograft models to Rucaparib treatment. Ectopic expression of HORMAD1 enhances tumor formations in two of these models, and significantly reduces sensitivity to Rucaparib in the HCC1954 model. Taken together, our data suggest that epigenetic activation of HORMAD1 by hypomethylation in BLBC may endow reduced sensitivity to Rucaparib treatment in some tumor models.