Stem cell differentiation involves several regulatory waves that lead to activation of cell type-specific genes and silencing of stem cell-specific genes. This has been shown to involve considerable changes in the activity of transcriptional enhancers, remodeling of the chromatin structure at the nucleosome level, and rewiring of promoter-to-enhancer interactions. However, the degree to which transcriptional enhancers interact and cooperate has not yet been explored.
In a collaborative project, spear-headed by PhD Jesper Grud Skat Madsen, who was recently appointed Assistant Professor in the Center for Functional Genomics and Tissue Plasticity (ATLAS), the Mandrup group performed enhancer capture Hi-C (ECHi-C), an adaptation of capture Hi-C, to capture enhancer-based interactions at different time points during the differentiation of human mesenchymal stem cells towards the adipocyte and osteoblast lineages. The results show that enhancers integrate signals across enhancer-to-enhancer interactions, and that enhancers form large enhancer communities where many different enhancers interact with each other and with promoters. The most highly connected enhancer communities act as key drivers of cell type-specific gene programs. This work has important implications for the understanding of transcriptional regulation and the control of cellular fate in both health and disease.
The paper is published in Nature Genetics and the abstract as well as link to the full text version can be found here.