New insight into how genes are switched on in the developing embryo
All forms of life undergo a process known as transcription, which sees genetic information transferred from DNA to RNA, marking the beginning of gene expression. The ‘on-switch’ or core promoter is a nearby stretch of DNA that signals all the necessary units needed to initiate transcription to come together. Now, in a collaborative discovery that unites computational, experimental and advancing gene technology platforms, scientists prove the existence of new overlapping core promoters, and revolutionise the field of promoter biology.
Published in Nature, the CSC’s Boris Lenhard (Computational Regulatory Genomics) teamed up with developmental genes expert, Ferenc Muller (School of Clinical and Experimental Medicine, University of Birmingham), and Division of Genomics Technologies Director at the RIKEN Center for Life Science Technologies, Piero Carninci. The team began monitoring promoter activity during very early stages of development in Zebrafish – a model organism in vertebrate developmental biology.
High-resolution snapshots to monitor and map promoter activity were taken using a technique pioneered by Piero Carninci, known as Cap Analysis Gene Expression (CAGE). CAGE captures and sequences the very beginning of transcribed RNA molecules revealing their exact position in the genome and frequency of their transcription initiation. The result: a genome-wide and single base-pair resolution map of transcription start sites that reflects both promoter activity and structure.
The team explored promoter activity, genome-wide, at various time points within the maternal to zygotic transition (MZT) – a stage in embryonic development that represents the most drastic changes within the repertoire of transcribed RNA molecules. “When we analysed the whole dataset, we noticed something striking,” explains Boris. “Oocyte (egg cell) transcription systematically began at a fixed distance downstream from a particular sequence motif, while, in the early embryo, transcription initiation was determined by the position of the first downstream nucleosome, suggesting that the transcription start site in the oocyte stage and then later in the embryo are chosen according to different rules.”
What’s more, even promoters active in both oocyte and embryo, as is the case for the majority of the so-called housekeeping genes (genes required for basic cell maintenance), contained overlapping sequence signals that would switch accordingly to become active and guide transcription accordingly. “It used to be thought housekeeping genes have generic or ubiquitously open promoters, but our paper shows that there are at least two differently regulated promoters in one,” adds Boris.
This revelation sets the framework for future studies within the realms of developmental biology and sheds light on the long-standing difficulty in establishing a universal core promoter code. “Although we haven’t conducted these experiments on mammalian systems, it’s likely that the same rules apply,” speculates Boris. “From now, investigators analysing promoters will have to take into account signals from a mixture of determinants – not just one – which will need to be disentangled before understanding the functional elements responsible for transcription in a particular biological context.”
YJ
Reference: Haberle, V., Li, N., Hadzhiev, Y., Plessy, C., Previti, C., Nepal, C., Gehrig, J., Dong, X., Akalin, A., Suzuki, A. M. M., van IJcken, W. F., Armant, O., Ferg, M., Strähle, U., Carninci, P., Müller, F., & Lenhard, B. (2014). Two independent transcription initiation codes overlap on vertebrate core promoters. Nature, 507 (7492), 381-385.
This work was supported by the Medical Research Council, Norwegian Research Council (YFF) and the Bergen Research Foundation.
The Medical Research Council has been at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Twenty-nine MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. www.mrc.ac.uk
