ScienceDaily (July 19, 2012) — What do you get when you dissect 10 000 fruit-fly larvae? A team of researchers led by the EMBL-European Bioinformatics Institute (EMBL-EBI) in the UK and the Max Planck Institute of Immunobiology and Epigenetics (MPI) in Freiburg, Germany has discovered a way in which cells can adjust the activity of many different genes at once. Their findings, published in the journal Science, overturn commonly held views and reveal an important mechanism behind sex differences.
Asifa Akhtar’s laboratory, previously at EMBL now at MPI, studies precisely how flies regulate an important set of genes. Females have two X chromosomes while males have only one, so the genes on the female X chromosomes somehow need to be kept from producing twice as many proteins as those on the male X chromosome. Male fruit flies get around this by making their X chromosome’s genes work double time: an epigenetic enzyme doubles the output of thousands of different genes. But just how much that doubled output is can vary tremendously from one gene to the next.
“Imagine that you have thousands of half-filled glasses of all different sizes and shapes,” explains Nick Luscombe, who led the work at EMBL-EBI. “Now imagine that you have to fill them all up to the top at the same time. This is an incredibly complex mechanism.”
To see how genes are expressed, scientists try to pinpoint signals that show when a gene increases its output. In most studies of this kind, this output is increased by a factor of between 10 and 100 when a gene is being expressed. In this study, the signal involved is miniscule: an increase of only a factor of two.
Observing such a faint signal is a major challenge. But thanks to the painstaking fly-larvae dissection efforts of graduate student Thomas Conrad, combined with the detailed analytical efforts of Florence Cavalli and Juanma Vaquerizas, the team gathered enough material to measure this output and compare males and females directly.
The scientists found twice as many DNA-transcribing (reading) proteins — known as polymerases — attached to the male X chromosome as to the female version. This means that the difference between males and females is rooted in the beginning of the transcription process, when the polymerase first binds to the DNA. This goes against the commonly held view that the regulation mechanism is kicked off during transcription.
“A factor of two appears miniscule, so it is not easy to measure accurately,” says Akhtar. “We were really doing a bulk analysis of several hundred genes, and that required a lot of careful bioinformatics analysis. Our group would run experiments, Nick’s would analyse the data, and then we would decide on new experiments together to be sure that what we were seeing was real.”
Discovering the machinery that doubles the expression of male X-chromosome genes could well have implications that go far beyond the humble fly. Speaking more technically, Luscombe says: “This is the first direct, clear mechanism that links a histone modification and the activity of a polymerase across thousands of genes.”
Looking into future directions, Akhtar says: “We now need to look more deeply into what makes this kind of mass regulation possible, and how it fits in with other means cells may have to fine-tune their use of genetic information.”
- Conrad, T., Cavalli, F.M.G., Vaquerizas, J.M., Luscombe, N.M., Akhtar, A. Drosophila dosage compensation involves enhanced Pol II recruitment to male X-linked promoters. Science, 2012 DOI: 10.1126/science.1221428
European Molecular Biology Laboratory – European Bioinformatics Institute (2012, July 19). What 10,000 fruit flies have to tell us about differences between the sexes. ScienceDaily. Retrieved July 21, 2012, from http://www.sciencedaily.com /releases/2012/07/120719141806.htm
ScienceDaily (July 15, 2012) — Your genes determine much about you, but environment can have a strong influence on your genes even before birth, with consequences that can last a lifetime. In a study published online in Genome Research, researchers have for the first time shown that the environment experienced in the womb defines the newborn epigenetic profile, the chemical modifications to DNA we are born with, that could have implications for disease risk later in life.
Epigenetic tagging of genes by a chemical modification called DNA methylation is known to affect gene activity, playing a role in normal development, aging, and also in diseases such as diabetes, heart disease, and cancer. Studies conducted in animals have shown that the environment shapes the epigenetic profile across the genome, called the epigenome, particularly in the womb. An understanding of how the intrauterine environment molds the human epigenome could provide critical information about disease risk to help manage health throughout life.
Twin pairs, both monozygotic (identical) and dizygotic (fraternal), are ideal for epigenetic study because they share the same mother but have their own umbilical cord and amniotic sac, and in the case of identical twins, also share the same genetic make-up. Previous studies have shown that methylation can vary significantly at a single gene across multiple tissues of identical twins, but it is important to know what the DNA methylation landscape looks like across the genome.
In this report, an international team of researchers has for the first time analyzed genome-scale DNA methylation profiles of umbilical cord tissue, cord blood, and placenta of newborn identical and fraternal twin pairs to estimate how genes, the shared environment that their mother provides and the potentially different intrauterine environments experienced by each twin contribute to the epigenome. The group found that even in identical twins, there are widespread differences in the epigenetic profile of twins at birth.
“This must be due to events that happened to one twin and not the other,” said Dr. Jeffrey Craig of the Murdoch Childrens Research Institute (MCRI) in Australia and a senior author of the report. Craig added that although twins share a womb, the influence of specific tissues like the placenta and umbilical cord can be different for each fetus, and likely affects the epigenetic profile.
Interestingly, the team found that methylated genes closely associated with birth weight in their cohort are genes known to play roles in growth, metabolism, and cardiovascular disease, lending further support to a known link between low birth weight and risk for diseases such as diabetes and heart disease. The authors explained that their findings suggest the unique environmental experiences in the womb may have a more profound effect on epigenetic factors that influence health throughout life than previously thought.
Furthermore, an understanding of the epigenetic profile at birth could be a particularly powerful tool for managing future health. “This has potential to identify and track disease risk early in life, said Dr. Richard Saffery of the MCRI and a co-senior author of the study, “or even to modify risk through specific environmental or dietary interventions.
- Gordon L, Joo JE, Powell JE, Ollikainen M, Novakovic B, Li X, Andronikos R, Cruickshank MN, Conneely KN, Smith AK, Alisch RS, Morley R, Visscher PM, Craig JM, Saffery R. Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence. Genome Res, July 16, 2012 DOI: 10.1101/gr.136598.111
Cold Spring Harbor Laboratory (2012, July 15). Differences between human twins at birth highlight importance of intrauterine environment. ScienceDaily. Retrieved July 16, 2012, from http://www.sciencedaily.com /releases/2012/07/120715193843.htm