Comprehensive gene regulatory networks to uncover the interplay of diverse pathways in ocular development and disease

Over the past two decades, genetic perturbation analyses in distinct animal models have significantly expanded the molecular basis of vertebrate lens development. We hypothesized that this wealth of functional data can be represented as a systems-level resource, to serve as a core base for assembly of comprehensive co-expression based gene regulatory networks (GRNs). Toward this goal, we curated genetic perturbation evidences from the lens literature on several distinct lens development stages representing early events during initiation, differentiation through post-natal development. Furthermore, other publicly available high-throughput datasets such as those containing protein-protein interaction data were systematically integrated to this core “evidence-based” network to identify gene regulatory modules in the lens. This condition-dependent network reveals several major regulatory modules. In a module representing early development, known regulators such as Pax6, Six3, Foxe3 and Hmx1 are represented. On the other hand, in a module representing late development, lens structural and refractive proteins such as bead filament proteins and crystallins were represented. Several new candidates are also identified by this analysis.  For example, a transcription factor Sall4 that is involved in early sensory placode development and Dmrta2, belonging to the doublesex and mab-3 related transcription factor like family A2 are identified as promising candidate. Conclusively, in present study we build on published perturbation studies and lens gene expression data to derive condition-dependent gene networks, that informs on regulatory interactions in the lens at specific stages, and makes new predictions of promising transcription factors candidates in early stages of lens development.