Making connections: enhancers in cellular differentiation

Deciphering the process by which hundreds of distinct cell types emerge from a single zygote to form a complex multicellular organism remains one of the greatest challenges in biological research. Enhancers are known to be central to cell type-specific gene expression, yet many questions regarding how these genomic elements interact both temporally and spatially with other cis- and trans-acting factors to control transcriptional activity during differentiation and development remain unanswered. Here, we review our current understanding of the role of enhancers and their interactions in this context and highlight recent progress achieved with experimental methods of unprecedented resolution. Topologically associating domains constrain the interactions of cis-regulatory elements and are at least partially dynamic during differentiation.Enhancer–promoter interactions are highly cell type specific and associated with gene expression, yet apparently not always sufficient to induce transcriptional activation.Enhancers could be involved in different steps of the transcription cycle, most likely transcriptional initiation and/or transcriptional elongation.Transcription factors are determinants of enhancer identity and potentially involved in establishing and maintaining close physical contact between enhancers and promoters.The cell cycle can be used as a tool to study the hierarchical organisation of the genome and its relation to gene expression.