{Reference Type}: Journal Article
{Title}: Comprehensive network modeling approaches unravel dynamic enhancer-promoter interactions across neural differentiation.
{Author}: DeGroat W;Inoue F;Ashuach T;Yosef N;Ahituv N;Kreimer A;
{Journal}: Genome Biol
{Volume}: 25
{Issue}: 1
{Year}: 2024 Aug 14
暂无{DOI}: 10.1186/s13059-024-03365-w
{Abstract}: <B>BACKGROUND: </B>Increasing evidence suggests that a substantial proportion of disease-associated mutations occur in enhancers, regions of non-coding DNA essential to gene regulation. Understanding the structures and mechanisms of the regulatory programs this variation affects can shed light on the apparatuses of human diseases.<BR><B>RESULTS: </B>We collect epigenetic and gene expression datasets from seven early time points during neural differentiation. Focusing on this model system, we construct networks of enhancer-promoter interactions, each at an individual stage of neural induction. These networks serve as the base for a rich series of analyses, through which we demonstrate their temporal dynamics and enrichment for various disease-associated variants. We apply the Girvan-Newman clustering algorithm to these networks to reveal biologically relevant substructures of regulation. Additionally, we demonstrate methods to validate predicted enhancer-promoter interactions using transcription factor overexpression and massively parallel reporter assays.<BR><B>CONCLUSIONS: </B>Our findings suggest a generalizable framework for exploring gene regulatory programs and their dynamics across developmental processes; this includes a comprehensive approach to studying the effects of disease-associated variation on transcriptional networks. The techniques applied to our networks have been published alongside our findings as a computational tool, E-P-INAnalyzer. Our procedure can be utilized across different cellular contexts and disorders.