Integrative pathway analysis with gene expression, miRNA, methylation and copy number variation for breast cancer subtypes.

Developments in biotechnologies enable multi-platform data collection for functional genomic units apart from the gene. Profiling of non-coding microRNAs (miRNAs) is a valuable tool for understanding the molecular profile of the cell, both for canonical functions and malignant behavior due to complex diseases. We propose a graphical mixed-effects statistical model incorporating miRNA-gene target relationships. We implement an integrative pathway analysis that leverages measurements of miRNA activity for joint analysis with multimodal observations of gene activity including gene expression, methylation, and copy number variation. We apply our analysis to a breast cancer dataset, and consider differential activity in signaling pathways across breast tumor subtypes. We offer discussion of specific signaling pathways and the effect of miRNA integration, as well as publish an interactive data visualization to give public access to the results of our analysis.

KARR-seq reveals cellular higher-order RNA structures and RNA-RNA interactions.

RNA fate and function are affected by their structures and interactomes. However, how RNA and RNA-binding proteins (RBPs) assemble into higher-order structures and how RNA molecules may interact with each other to facilitate functions remain largely unknown. Here we present KARR-seq, which uses N3-kethoxal labeling and multifunctional chemical crosslinkers to covalently trap and determine RNA-RNA interactions and higher-order RNA structures inside cells, independent of local protein binding to RNA. KARR-seq depicts higher-order RNA structure and detects widespread intermolecular RNA-RNA interactions with high sensitivity and accuracy. Using KARR-seq, we show that translation represses mRNA compaction under native and stress conditions. We determined the higher-order RNA structures of respiratory syncytial virus (RSV) and vesicular stomatitis virus (VSV) and identified RNA-RNA interactions between the viruses and the host RNAs that potentially regulate viral replication.

MODEL-BASED DISTANCE EMBEDDING WITH APPLICATIONS TO CHROMOSOMAL CONFORMATION BIOLOGY.

Recent development of high-throughput biotechnologies, such as Hi-C, have enabled genome-wide measurement of chromosomal conformation. The interaction signals among genomic loci are contaminated with noises. It remains largely unknown how well the underlying chromosomal conformation can be elucidated, based on massive and noisy measurements. We propose a new model-based distance embedding (MDE) framework, to reveal spatial organizations of chromosomes. The proposed framework is a general methodology, which allows us to link accurate probabilistic models, which characterize biological data properties, to efficiently recovering Euclidean distance matrices from noisy observations. The performance of MDE is shown through numerical experiments inspired by regular helix structure and random movement of chromosomes. The practical merits of MDE are also demonstrated by applications to real Hi-C data from both human and mouse cells which are further validated by gold standard benchmarks.