April 13, 2022
Enhancer-promoter interactions — distance matters
When and where a gene is transcribed in a living organism often depends on its physical interactions with distal genomic regulatory regions called enhancers. Researchers in the group of Luca Giorgetti have thrown light on how such interactions control transcription thanks to a novel ingenious experimental approach combined with mathematical modelling. They found that gene expression levels depend on interaction frequencies with an enhancer. Their study establishes general principles for the role of chromosome structure in long-range transcriptional regulation.
Transcription is the process by which the information contained in a section of DNA encoding a protein — a gene — is copied into messenger RNA (mRNA). This process occurs when specific proteins bind to a stretch of DNA located right before the gene to be transcribed, namely a promoter. Many promoters only become activated at the right time, in the right place and at the right level, when they work in concert with other regulatory regions called enhancers. Enhancers can be located up to millions of base pairs away from their target promoter.
Although genetic variation within enhancer sequences is a major driver of evolution and is causal to genetic disorders and human diseases, the way enhancers control gene expression is still shrouded in mystery. It is thought that the relationship requires enhancers and promoters to be in close physical proximity and that the three-dimensional structure of chromosomes allows DNA regions that are far apart to get closer by looping out intervening DNA (see picture 1). But how these physical interactions contribute to the process of gene regulation and determine the promoter transcriptional output is unclear.
Jessica Zuin dedicated her postdoctoral work in the laboratory of Luca Giorgetti to a better understanding of how an enhancer functions in the context of the three-dimensional structure of chromosomes. With the support of colleagues in the Giorgetti lab, she conducted ingenious and technically daunting experiments allowing to move an enhancer around on the DNA, therefore changing its relative position to a fixed promoter. This enabled the researchers to measure transcriptional outputs, or the number of mRNA molecules produced by the promoter, relative to hundreds of different enhancer-promoter distances. Using this large amount of quantitative data, Gregory Roth, a mathematician supporting research labs at the FMI, developed a physical model of enhancer-promoter communication which suggests a molecular mechanism that could explain their main findings.
The study, co-authored by Zuin and Roth and published in the journal Nature, sparked an enormous amount of interest in the research community. It shows for the first time that the transcription levels generated by an enhancer depend on its genomic distance from its target promoter: the closer the enhancer is to the promoter along the DNA — and therefore the more likely they are to interact — the more mRNA is produced (see picture 2). This relationship, which is not linear, allows to explain why a promoter can only be activated by an enhancer when both are located within the same topologically associating domain (TAD). TADs are genomic regions within which DNA sequences interact with each other more frequently. They have often been suggested to constrain enhancer-promoter communication, which Zuin, Roth and their colleagues now formally prove.
Gene expression is a fundamental process in biology and this study contributes to elucidate one of the most fundamental ways it is regulated.
Picture 1: Chromatin loops bring in physical proximity the enhancer (red) with the target promoter (blue).
Picture 2: Transcription output depends on enhancer-promoter genomic distance and the enhancer action is constrained by TAD boundaries.
Jessica Zuin*, Gregory Roth*, Yinxiu Zhan, Julie Cramard, Josef Redolfi, Ewa Piskadlo, Pia Mach, Mariya Kryzhanovska, Gergely Tihanyi, Hubertus Kohler, Mathias Eder, Christ Leemans, Bas van Steensel, Peter Meister, Sebastien Smallwood, Luca Giorgetti Nonlinear control of transcription through enhancer-promoter interactions. Nature (2022). Advance online publication
ABOUT THE FIRST AUTHORS
Jessica Zuin was born in Padova, Italy, where she studied Medical Biotechnology. After her master’s, she moved to Rotterdam, the Netherlands for her PhD. Since one of her principal research interests is to understand how the 3D chromatin organization regulates gene transcription, she joined the lab of Luca Giorgetti in Nov. 2015 as a postdoctoral fellow. Her goal was to study the mechanism underlying enhancer-promoter communication in mouse embryonic stem cells. In 2017, she was awarded a Marie Curie fellowship.
Gregory Roth was born in Neuchatel, Switzerland. He studied mathematics at the University of Neuchatel where he also did his PhD at the interface of dynamical systems and probability theories. He then joined the group of Sebastian Schreiber at the University of California, Davis and later the group of Hal Caswell at the University of Amsterdam where he developed mathematical models for ecological population dynamics. In 2018, he joined the FMI as a staff scientist to support different research groups in developing mathematical and physical models for molecular and cellular processes.