Jaclyn N Taroni | Search bioRxiv

bioRxiv2016

Integrative networks illuminate biological factors underlying gene-disease associations

A.Integrative networks combine multiple layers of biological data into a model of how genes work together to carry out cellular processes. Such networks become more valuable as they become more context specific, for example, by capturing how genes work together in a certain tissue or cell type. Once constructed, these networks provide the means to identify broad biological patterns underlying genes associated with complex traits and diseases. In this review, we discuss the different types of integrative networks that currently exist and how such networks that encompass multiple biological layers are constructed. We highlight how specificity can be incorporated into the reconstruction of different types of biomolecular interactions between genes, using tissue-specificity as a motivating example. We identify examples of cases where networks have been applied to study human diseases and discuss opportunities for new applications.

Bioinformatics↗

bioRxiv2016

A Novel Multi-network Approach Reveals Tissue-specific Cellular Modulators of Fibrosis in Systemic Sclerosis, Pulmonary Fibrosis and Pulmonary Arterial Hypertension

We have used integrative genomics to determine if a common molecular mechanism underlies different clinical manifestations in systemic sclerosis (SSc), and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH). We identified a common pathogenic gene expression signature - an immune-fibrotic axis-indicative of pro-fibrotic macrophages in multiple affected tissues (skin, lung, esophagus and PBMCs) of SSc, PF, and PAH. We used this disease-associated signature to query tissue-specific functional genomic networks. This allowed us to identify common and tissue-specific pathology of SSc and related conditions. We rigorously contrasted the lung- and skin-specific gene-gene interaction networks to identify a distinct lung resident macrophage signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct macrophages alternative activation transcriptional programs in SSc-PF lung and in the skin of patients with an \"inflammatory\" SSc gene expression signature. Our results suggest that the innate immune system is central to SSc disease processes, but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases.

Systems Biology↗