Genome re-wiring during neural cell development
Researchers at the Babraham Institute have mapped the changes in the three-dimensional shape of DNA that occur as human stem cells specialise towards becoming developing neural cells, the cells that make up the nervous system. These changes in DNA shape rewire the circuitry that connects genes with their control switches, which instruct them to turn on or off during neural development. These findings open up new ways to improve the efficiency of driving stem cells to become different types of cell, which is a prerequisite for many stem cell-based therapies. The research also provides new insights into which genes are inappropriately turned on or off in developmental disorders due to mutations in their control switches.
Our DNA contains a complex array of molecular control switches that instruct genes to turn on and off at the right time and in the right cells. These switches, termed regulatory elements, are often a long way away from the genes that they control, and knowing which switch controls which genes is nearly impossible to predict from just looking at the DNA sequence. To enable to regulatory elements to reach their target genes in three-dimensional space, the DNA forms loops to bring the regulatory element and gene into close physical contact.
In the current research that was published today in the journal eLife, the scientists set out to reveal how loops between genes and their regulatory elements change as human stem cells develop into neural cells. They mapped the loops between genes and their regulatory elements in unspecialised human embryonic stem cells and in stem cells in the process of developing into neural cells. The scientists uncovered widespread remodelling with the DNA loops being extensively rewired after the stem cells specialised into neural cells (i.e. loops were formed and lost). Also the regulatory elements were frequently toggled between “active” and “inactive”.
Dr Peter Rugg-Gunn, group leader in the Institute’s Epigenetics research programme and a senior co-author on the paper, explains: “We wanted to understand how changes to the loops and to the activity of the molecular switches work together to turn the correct genes on and off, which enables the cells to develop normally. Excitingly, changes in regulatory element activity and looping interactions tended to occur together, so that new loops were formed at the same time as the switch was activated.”
Dr Mikhail Spivakov, group leader in the Institute’s Nuclear Dynamics research programme and another senior co-author, said: “One of the most striking findings from our research was that individual genes are often connected to many different regulatory elements. We would now like to understand how these multiple connections collectively coordinate gene activity, and whether we can use this information to control stem cell specialisation more effectively, which has potential future applications in regenerative medicine.”
This research was funded by grants to Dr Peter Rugg-Gunn by the Wellcome Trust and the Medical Research Council (MRC) and to Dr Peter Fraser from the European Research Council (ERC). The Babraham Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC).
The connections (arcs) mapped between the SOX2 gene (black arrow) and its potential control switch regions in human embryonic stem cells.
Affiliated authors (in author order):
Paula Freire-Pritchett, visiting scientist, (Spivakov lab), Nuclear Dynamics Programme, now at the MRC Laboratory of Molecular Biology
Stefan Schoenfelder, senior postdoc researcher (Fraser lab), Nuclear Dynamics Programme
Csilla Várnai, postdoc researcher (Fraser lab), Nuclear Dynamics Programme
Steven Wingett, research scientist (Fraser lab), Nuclear Dynamics Programme
Jonathan Cairns, postdoc researcher (Fraser lab), Nuclear Dynamics Programme
Amanda Collier, PhD student (Rugg-Gunn lab), Epigenetics Programme
Raquel García-Vílchez, visiting student (Rugg-Gunn lab), Epigenetics Programme
Mayra Furlan-Magaril, postdoc researcher (Fraser lab), Nuclear Dynamics Programme, now at the Cellular Physiology Institute (IFC-UNAM)
Cameron Osborne, group leader, Babraham Institute, now at Department of Genetics & Molecular Medicine, King's College London
Peter Fraser, group leader, Nuclear Dynamics Programme
Peter Rugg-Gunn, group leader, Epigenetics Programme
Mikhail Spivakov, group leader, Nuclear Dynamics Programme
Freire-Pritchett and Schoenfelder et al. (2017) Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells. eLife DOI: http://dx.doi.org/10.7554/eLife.21926