Transcriptional enhancers: functional insights and role in human disease

Abstract

In recent years, studies of cis-regulatory mechanisms have evolved from a predominant focus on promoter regions to the realization that spatial and temporal gene regulation is frequently driven by long-range enhancer clusters that operate within chromosomal compartments. This increased understanding of genome function, together with the emergence of technologies that enable whole-genome sequencing of patients' DNAs, open the prospect of dissecting the role of cis-regulatory defects in human disease. In this review we discuss how recent epigenomic studies have provided insights into the function of transcriptional enhancers. We then present examples that illustrate how integrative genomics can help uncover enhancer sequence variants underlying Mendelian and common polygenic human disease.

Figure 1

Integrative genomics reveals that isolated pancreas agenesis is caused by enhancer mutations. (a) Integration of whole genome sequences from two patients with pancreatic agenesis with maps of active enhancers profiled in human embryonic pancreatic progenitors identified causal recessive mutations. These mutations map to a previously unannotated enhancer 25 kb away from PTF1A, a transcription factor that is known to be essential for the embryonic development of the pancreas. (b) Schematic representation of the PTF1A locus harboring wild-type (A) and mutated (G) enhancer sequences. The newly identified enhancer (indented red box) establishes a physical interaction with the PTF1A promoter and is bound by regulatory factors such as FOXA2 (green teardrop). The presence of a single-nucleotide enhancer variant in some patients with pancreatic agenesis (g.23508437A > G) disrupts binding by FOXA2, abolishes enhancer activity and potentially alters the local chromatin structure of the enhancer cluster. A deletion of this enhancer region or other single base mutations that disrupt binding of FOXA2, PDX1 or an unidentified binding protein cause the same phenotype, thus highlighting a crucial role of this enhancer in the active conformation of the PTF1A locus.