Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells

Abstract

Long-range cis-regulatory elements such as enhancers coordinate cell-specific transcriptional programmes by engaging in DNA looping interactions with target promoters. Deciphering the interplay between the promoter connectivity and activity of cis-regulatory elements during lineage commitment is crucial for understanding developmental transcriptional control. Here, we use Promoter Capture Hi-C to generate a high-resolution atlas of chromosomal interactions involving ~22,000 gene promoters in human pluripotent and lineage-committed cells, identifying putative target genes for known and predicted enhancer elements. We reveal extensive dynamics of cis-regulatory contacts upon lineage commitment, including the acquisition and loss of promoter interactions. This spatial rewiring occurs preferentially with predicted changes in the activity of cis-regulatory elements and is associated with changes in target gene expression. Our results provide a global and integrated view of promoter interactome dynamics during lineage commitment of human pluripotent cells.

DOI: http://dx.doi.org/10.7554/eLife.21926.001

eLife digest

Virtually every cell in the body contains the same set of DNA, which encodes thousands of genes. The activities of these genes vary between different types of cells and at different points in time. As a result, our DNA contains a complex array of molecular switches that instruct genes to switch on and off at the right time and in the right cells. These molecular switches, termed regulatory elements, are often a long way away from the genes that they control, and this can make it difficult to find out which switch controls which genes.

DNA is made up of several different building blocks known as bases and the order of these bases encodes specific information about the gene. Every human cell contains approximately two meters of DNA, which is highly folded in the cell nucleus. This three-dimensional folding allows regions that are far apart on the DNA thread to physically contact each other. To reach the genes they control, regulatory elements form loops on the DNA that are near-impossible to predict from looking at the sequence of bases alone. Mapping the locations of these loops can reveal the hidden circuitry within our DNA and help us to understand how unwanted changes (mutations) within regulatory elements may cause disease.

Freire-Pritchett, Schoenfelder et al. set out to reveal how loops between genes and their regulatory elements change as the stem cells specialise into immature brain cells. The experiments show that the pattern of DNA loops is extensively altered after the stem cells specialise into brain cells, that is, some loops are lost and new ones form. Furthermore, the regulatory elements themselves were often toggled between “on” and “off” states. These two processes tend to occur together, so that new loops are formed at the same time as the switch is activated.

Freire-Pritchett, Schoenfelder et al. also show that individual genes are often connected to many different regulatory elements. The next step is to understand how these multiple connections work together to coordinate gene activity, and whether this information could be used to control how stem cells specialise. This knowledge may lead to the development of stem cell-based therapies for stroke, Parkinson’s disease and other conditions.

DOI: http://dx.doi.org/10.7554/eLife.21926.002