In a ground-breaking discovery that will have a major impact on our understanding of the regulation and function of our genes and DNA – our genetic blueprint – a group of scientists in South Africa is the first to show that when genes interact in three dimensions, or engage in so-called ‘gene kissing’, this has a major impact on how genes are switched on inside the cell. This landmark finding appears in the 24 October 2013 issue of the journal Cell, one of the world’s most prestigious research publications.
This is only the fifth South African-affiliated article that has ever been published in Cell, and one of just two articles in three decades to feature an all-South African-based cast.
A long-standing question in biology is whether ‘gene kissing’ is a cause – or simply correlated – with gene activation. This question was finally answered when a team led by Dr Musa Mhlanga, CSIR gene expression and biophysics research group leader, together with a collaborator at the University of the Witwatersrand faculty of Health Sciences, performed ground-breaking experiments to show that ‘gene kissing’ can switch genes on. The discovery sheds light on how genes change from inactive to active states, and how different genes can coordinate their activity simultaneously.
Within each of our cells lies an incredible 1.2 metres of tightly coiled DNA, shrunk to a size one fiftieth that of a grain of sand. These genes encode our physical traits, such as eye colour or blood type. However, DNA also codes for genes that function constantly to keep us alive. These need to be switched ‘on’ and ‘off’ by the cell as needed. How gene activity is regulated has been the subject of intense study for many years, and scientists have suspected for some time that the physical contact between genes, or ‘gene kissing’ could play a role.
“DNA is coiled and tangled like spaghetti inside the cell,” explains Prof Marc Weinberg from the University of the Witwatersrand and co-author of the study. “So, there are many places where the DNA touches and intersects. These interactions could be crucial to how the information in the DNA is read and interpreted by the cell, but this had never been shown before.”
State-of-the-art microscopes, which were custom-built in South Africa by Dr Mhlanga’s group, were an important tool in being able to achieve single-molecule resolution in imaging this gene activity by peering deep into the nucleus of cells. These tools enabled them to see the activity of even a single gene, among the 30 000 human genes. Then, using DNA nucleases – nicknamed ‘molecular scissors’ – they were able to cut DNA at precise locations to prevent genes from making contact.
According to lead author and Claude Leon postdoctoral fellow, Dr Stephanie Fanucchi, “being able to alter the genetic code in this manner is the ‘holy grail’ of molecular biology, but has only recently been made possible”. In this way, some genes were shown to ‘kiss’ in order to be switched ‘on’ and surprisingly in this instance, one gene acts as a master gene to orchestrate the activity of other genes. Co-author and Claude Leon postdoctoral fellow, Dr Youtaro Shibayama, remarks, “We jumped on the technology of producing efficient ‘molecular scissors’ as soon as it became available last year, and our integrated expertise in microscopy and molecular biology, combined with creative thinking, gave us a unique advantage over our peers in conducting this study.”
The group is focusing some of its efforts on what this work could mean for human health. In late 2011, Dr Mhlanga’s laboratory at the CSIR was the first in Africa to generate induced pluripotent stem cells, a type of stem cells which could hold the key to growing new tissue to replace that which is diseased – and can even be used to create disease models ‘in a dish’. This occurred several years after the initial breakthrough in this respect in Japan. Combined with the knowledge to alter the genetic code and control gene activity, exciting novel experiments and therapeutic avenues can be envisaged for the future. Scientists will gain a deeper understanding of cancer, chronic diseases such as diabetes, allergy responses and a host of other diseases and important cellular processes. This important research, which has now been published, gives scientists across the globe new knowledge and tools about how genes behave and how to direct them, paving the way for future discoveries.
Senior author, Dr Mhlanga, is passionate about what this discovery means, globally and to South Africa: “This work germinated from a desire to answer a fundamental long-standing question in gene regulation. Our goal is that scientists in Africa should not simply be consumers of fundamental scientific discoveries; rather they should be active contributors and producers to this body of basic scientific knowledge. We would like to train the next generation of scientists in Africa to become excellent scientists who routinely produce ground-breaking work. In this endeavour, we are very grateful for the continued support we receive from the Department of Science and Technology Emerging Research Area programme for several aspects of this work over the last few years.”
The Minister of Science and Technology, Mr Derek Hanekom says this achievement makes the country proud.
“We are proud of this achievement made through the pioneering research of the CSIR and its partners. We are confident that this important finding will shed light on and give scientists and researchers greater understanding of the treatment of a number of diseases, as well as insight into important cellular processes,” says Hanekom.
The paper is titled, Chromosomal Contact Permits Transcription between Coregulated Genes, and is authored by Stephanie Fanucchi, Youtaro Shibayama, Shaun Burd, Marc S Weinberg, and Musa M Mhlanga.
Story by: T. Tsedu, CSIR media release, October 2013