Histone Modification Controls Development: Chemical Tags On Histones Regulate Gene Activity

Feb. 8, 2013 — Every gene in the nucleus of an animal or plant cell is packaged into a beads-on-a-string like structure called nucleosomes: the DNA of the gene forms the string and a complex of proteins called histones forms the beads around which the DNA is wrapped. Scientists of the Max Planck Institute of Biochemistry in Martinsried near Munich, Germany, have now established that adding chemical tags on histones is critical for regulating gene activity during animal development.

Top image, No PRC2. Bottom image, altered histone. (Credit: Image courtesy of Max Planck Institute of Biochemistry)

Studies over the past two decades revealed that many proteins that control the activity of genes are enzymes that add small chemical tags on histone proteins but also on a variety of other proteins. With their studies the researchers have now shown that it is the tags on the histones that control if genes are active or inactive.

Their results were published in the journal Science.

Histone proteins can be modified by a number of different chemical tags at very specific sites. The researchers in the Research Group ‘Chromatin Biology’ of Jürg Müller focused on the histone tag that is added by an enzyme called Polycomb Repressive Complex 2 (PRC2). PRC2 is essential for a variety of different cell fate decisions in animals and plants. PRC2 functions to keep genes inactive in cells and at times where they should remain inactive.

Using the model organismDrosophila — the fruit fly — the scientists now generated animals with cells expressing an altered histone protein to which PRC2 can no longer add the tag. These cells cannot keep genes inactive anymore and many cell fate decisions go awry, exactly like in cells that lack the PRC2 enzyme.

“This observation demonstrates that the business end is the tag on the histone and not on some other protein” says Ana Pengelly, the PhD student who conducted the experiments. Her colleague Omer Copur adds: “The approach we used permits us to now also investigate the function of other tags on histone proteins that have a different chemical nature.” The insight gained from the work on PRC2 provides a strong impetus to figure how this tag alters the beads-on-a-string structure of genes and thereby controls gene activity.

Story Source:

The above story is reprinted from materials provided byMax Planck Institute of Biochemistry.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

  1. A. R. Pengelly, O. Copur, H. Jackle, A. Herzig, J. Muller. A Histone Mutant Reproduces the Phenotype Caused by Loss of Histone-Modifying Factor PolycombScience, 2013; 339 (6120): 698 DOI: 10.1126/science.1231382
Max Planck Institute of Biochemistry (2013, February 8). Histone modification controls development: Chemical tags on histones regulate gene activity. ScienceDaily. Retrieved February 10, 2013, from http://www.sciencedaily.com/releases/2013/02/130208105720.htm

Early-Onset Puberty in Females Explained

Jan. 29, 2013 — New research from Oregon Health & Science University has provided significant insight into the reasons why early-onset puberty occurs in females. The research, which was conducted at OHSU’s Oregon National Primate Research Center, is published in the current early online edition of the journalNature Neuroscience.

The paper explains how OHSU scientists are investigating the role of epigenetics in the control of puberty. Epigenetics refers to changes in gene activity linked to external factors that do not involve changes to the genetic code itself. The OHSU scientists believe improved understanding of these complex protein/gene interactions will lead to greater understanding of both early-onset (precocious) puberty and delayed puberty, and highlight new therapy avenues.

To conduct this research, scientists studied female rats, which like their human counterparts, go through puberty as part of their early aging process. These studies revealed that a group of proteins, called PcG proteins, regulate the activity of a gene called the Kiss1 gene, which is required for puberty to occur. When these PcG proteins diminish, Kiss1 is activated and puberty begins.

PcG proteins are produced by another set of genes that act as a biological switch during the embryonic stage of life. The role of these proteins is to turn off specific downstream genes at key developmental stages.

OHSU scientists found that both the activity of these “master” genes and their ability to turn off puberty are impacted by two forms of epigenetic control: a chemical modification of DNA known as DNA methylation, and changes in the composition of histones, a specialized set of proteins that modify gene activity by interacting with DNA.

Using this new information, researchers were then able to delay puberty in female rats. They accomplished this by increasing PcG protein levels in the hypothalamus of the brain using a targeted gene therapy approach so that Kiss1 activation failed to occur at the normal time in life. The hypothalamus is a region of the brain that controls reproductive development.

“While it was always understood that an organism’s genes determine the timing of puberty, the role of epigenetics in this process has never been recorded until now,” said Alejandro Lomniczi, Ph.D., a scientist in the Division of Neuroscience at the OHSU Oregon National Primate Research Center.

“Because epigenetic changes are driven by environmental, metabolic and cell-to-cell influences, these findings raise the possibility that a significant percentage of precocious and delayed puberty cases occurring in humans may be the result of environmental factors and other alterations in epigenetic control,” said Sergio Ojeda, D.V.M., who is also a scientist in the Division of Neuroscience at the OHSU ONPRC.

“There is also much more to be learned about the way that epigenetic factors may link environmental factors such as nutrition, human-made chemicals, social interactions and other day-today influences to the timing and completion of normal puberty.”

Story Source:

The above story is reprinted from materials provided byOregon Health & Science University.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

  1. Alejandro Lomniczi, Alberto Loche, Juan Manuel Castellano, Oline K Ronnekleiv, Martha Bosch, Gabi Kaidar, J Gabriel Knoll, Hollis Wright, Gerd P Pfeifer, Sergio R Ojeda. Epigenetic control of female pubertyNature Neuroscience, 2013; DOI: 10.1038/nn.3319
Oregon Health & Science University (2013, January 29). Early-onset puberty in females explained. ScienceDaily. Retrieved January 31, 2013, from http://www.sciencedaily.com/releases/2013/01/130129130947.htm

Scientists Discover How Epigenetic Information Could Be Inherited: Mechanism of Epigenetic Reprogramming Revealed

Jan. 24, 2013 — New research reveals a potential way for how parents’ experiences could be passed to their offspring’s genes. The research was published January, 25 in the journal Science.


Epigenetics is a system that turns our genes on and off. The process works by chemical tags, known as epigenetic marks, attaching to DNA and telling a cell to either use or ignore a particular gene.

The most common epigenetic mark is a methyl group. When these groups fasten to DNA through a process called methylation they block the attachment of proteins which normally turn the genes on. As a result, the gene is turned off.

Scientists have witnessed epigenetic inheritance, the observation that offspring may inherit altered traits due to their parents’ past experiences. For example, historical incidents of famine have resulted in health effects on the children and grandchildren of individuals who had restricted diets, possibly because of inheritance of altered epigenetic marks caused by a restricted diet.

However, it is thought that between each generation the epigenetic marks are erased in cells called primordial gene cells (PGC), the precursors to sperm and eggs. This ‘reprogramming’ allows all genes to be read afresh for each new person — leaving scientists to question how epigenetic inheritance could occur.

The new Cambridge study initially discovered how the DNA methylation marks are erased in PGCs, a question that has been under intense investigation over the past 10 years. The methylation marks are converted to hydroxymethylation which is then progressively diluted out as the cells divide. This process turns out to be remarkably efficient and seems to reset the genes for each new generation. Understanding the mechanism of epigenetic resetting could be exploited to deal with adult diseases linked with an accumulation of aberrant epigenetic marks, such as cancers, or in ‘rejuvenating’ aged cells.

However, the researchers, who were funded by the Wellcome Trust, also found that some rare methylation can ‘escape’ the reprogramming process and can thus be passed on to offspring — revealing how epigenetic inheritance could occur. This is important because aberrant methylation could accumulate at genes during a lifetime in response to environmental factors, such as chemical exposure or nutrition, and can cause abnormal use of genes, leading to disease. If these marks are then inherited by offspring, their genes could also be affected.

Dr Jamie Hackett from the University of Cambridge, who led the research, said: “Our research demonstrates how genes could retain some memory of their past experiences, revealing that one of the big barriers to the theory of epigenetic inheritance — that epigenetic information is erased between generations — should be reassessed.”

“It seems that while the precursors to sperm and eggs are very effective in erasing most methylation marks, they are fallible and at a low frequency may allow some epigenetic information to be transmitted to subsequent generations. The inheritance of differential epigenetic information could potentially contribute to altered traits or disease susceptibility in offspring and future descendants.”

“However, it is not yet clear what consequences, if any, epigenetic inheritance might have in humans. Further studies should give us a clearer understanding of the extent to which heritable traits can be derived from epigenetic inheritance, and not just from genes. That could have profound consequences for future generations.”

Professor Azim Surani from the University of Cambridge, principal investigator of the research, said: “The new study has the potential to be exploited in two distinct ways. First, the work could provide information on how to erase aberrant epigenetic marks that may underlie some diseases in adults. Second, the study provides opportunities to address whether germ cells can acquire new epigenetic marks through environmental or dietary influences on parents that may evade erasure and be transmitted to subsequent generations, with potentially undesirable consequences.”


Story Source:

The above story is reprinted from materials provided byUniversity of Cambridge, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

  1. J. A. Hackett, R. Sengupta, J. J. Zylicz, K. Murakami, C. Lee, T. A. Down, M. A. Surani. Germline DNA Demethylation Dynamics and Imprint Erasure Through 5-HydroxymethylcytosineScience, 2012; DOI:10.1126/science.1229277
University of Cambridge (2013, January 24). Scientists discover how epigenetic information could be inherited: Mechanism of epigenetic reprogramming revealed. ScienceDaily. Retrieved January 29, 2013, from http://www.sciencedaily.com/releases/2013/01/130124150808.htm

In Epigenomics, Location Is Everything: Researchers Exploit Gene Position to Test ‘Histone Code’

Jan. 3, 2013 — In a novel use of gene knockout technology, researchers at the University of California, San Diego School of Medicine tested the same gene inserted into 90 different locations in a yeast chromosome — and discovered that while the inserted gene never altered its surrounding chromatin landscape, differences in that immediate landscape measurably affected gene activity.

This is an X-ray micrograph of a yeast cell, Saccharomyces cerevisiae, as it buds before dividing. (Credit: Carolyn Larabell, UC San Francisco, Lawrence Berkeley National Laboratory and the National Institute of General Medical Sciences.)


The findings, published online in the Jan. 3 issue of Cell Reports, demonstrate that regulation of chromatin — the combination of DNA and proteins that comprise a cell’s nucleus — is not governed by a uniform “histone code” but by specific interactions between chromatin and genetic factors.

“One of the main challenges of epigenetics has been to get a handle on how the position of a gene in chromatin affects its expression,” said senior author Trey Ideker, PhD, chief of the Division of Genetics in the School of Medicine and professor of bioengineering in UC San Diego’s Jacobs School of Engineering. “And one of the major elements of that research has been to look for a histone code, a general set of rules by which histones (proteins that fold and structure DNA inside the nucleus) bind to and affect genes.”

The Cell Report findings indicate that there is no singular universal code, according to Ideker. Rather, the effect of epigenetics on gene expression or activity depends not only on the particular mix of histones and other epigenetic material, but also on the identity of the gene being expressed.

To show this, the researchers exploited an overlooked feature of an existing resource. The widely-used gene knockout library for yeast, originally created to see what happens when a particular gene is missing, was built by systematically inserting the same reporter gene into different locations. Ideker and colleagues focused on this reporter gene and observed what happens to gene expression at different locations along yeast chromosome 1.

“If epigenetics didn’t matter — the state of histones and DNA surrounding the gene — the expression of a gene would be the same regardless of where on the chromosome that gene is positioned,” said Ideker. But in every case, gene expression was measurably influenced by interaction with nearby epigenetic players.

Ideker said the work provides a new tool for more deeply exploring how and why genes function, particularly in relation to their location.

Co-authors are first author Menzies Chen, UCSD Department of Bioengineering; Katherine Licon, UCSD Department of Medicine and UCSD Institute for Genomic Medicine; Rei Otsuka and Lorraine Pillus, UCSD Department of Molecular Biology and UCSD Moores Cancer Center.

Funding for this research came, in part, from NIH grants R21HG005232, R01GM084279, P50GM085764 and P30CA023100.


Story Source:

The above story is reprinted from materials provided byUniversity of California, San Diego Health Sciences. The original article was written by Scott LaFee.


Journal Reference:

  1. Menzies Chen, Katherine Licon, Rei Otsuka, Lorraine Pillus, Trey Ideker. Decoupling Epigenetic and Genetic Effects through Systematic Analysis of Gene Position.Cell Reports, 2013; DOI: 10.1016/j.celrep.2012.12.003


University of California, San Diego Health Sciences (2013, January 3). In epigenomics, location is everything: Researchers exploit gene position to test ‘histone code’. ScienceDaily. Retrieved January 9, 2013, from http://www.sciencedaily.com/releases/2013/01/130103130756.htm

Acute Stress Alters Control of Gene Activity: Researchers Examine DNA Methylation

ScienceDaily (Aug. 15, 2012) — Acute stress alters the methylation of the DNA and thus the activity of certain genes. This is reported by researchers at the Ruhr-Universität Bochum together with colleagues from Basel, Trier and London for the first time in the journal Translational Psychiatry. “The results provide evidence how stress could be related to a higher risk of mental or physical illness,” says Prof. Dr. Gunther Meinlschmidt from the Clinic of Psychosomatic Medicine and Psychotherapy at the LWL University Hospital of the RUB. The team looked at gene segments which are relevant to biological stress regulation.

In stressful social situations, the methylation patterns (bright spheres) of the DNA change. (Credit: Illustration: Christoph Unternährer and Christian Horisberger)

Epigenetics — the “second code” — regulates gene activity

Our genetic material, the DNA, provides the construction manual for the proteins that our bodies need. Which proteins a cell produces depends on the cell type and the environment. So-termed epigenetic information determines which genes are read, acting quasi as a biological switch. An example of such a switch is provided by methyl (CH3) groups that attach to specific sections of the DNA and can remain there for a long time — even when the cell divides. Previous studies have shown that stressful experiences and psychological trauma in early life are associated with long-term altered DNA methylation. Whether the DNA methylation also changes after acute psychosocial stress, was, however, previously unknown.

Two genes tested

To clarify this issue, the research group examined two genes in particular: the gene for the oxytocin receptor, i.e. the docking site for the neurotransmitter oxytocin, which has become known as the “trust hormone” or “anti-stress hormone”; and the gene for the nerve growth factor Brain-Derived Neurotrophic Factor (BDNF), which is mainly responsible for the development and cross-linking of brain cells. The researchers tested 76 people who had to participate in a fictitious job interview and solve arithmetic problems under observation — a proven means for inducing acute stress in an experiment. For the analysis of the DNA methylation, they took blood samples from the subjects before the test as well as ten and ninety minutes afterwards.

DNA methylation changes under acute psychosocial stress

Stress had no effect on the methylation of the BDNF gene. In a section of the oxytocin receptor gene, however, methylation already increased within the first ten minutes of the stressful situation. This suggests that the cells formed less oxytocin receptors. Ninety minutes after the stress test, the methylation dropped below the original level before the test. This suggests that the receptor production was excessively stimulated.

Possible link between stress and disease

Stress increases the risk of physical or mental illness. The stress-related costs in Germany alone amount to many billions of Euros every year. In recent years, there have been indications that epigenetic processes are involved in the development of various chronic diseases such as cancer or depression. “Epigenetic changes may well be an important link between stress and chronic diseases” says Prof. Meinlschmidt, Head of the Research Department of Psychobiology, Psychosomatics and Psychotherapy at the LWL University Hospital. “We hope to identify more complex epigenetic stress patterns in future and thus to be able to determine the associated risk of disease. This could provide information on new approaches to treatment and prevention.” The work originated within the framework of an interdisciplinary research consortium with the University of Trier, the University of Basel and King’s College London. The German Research Foundation and the Swiss National Science Foundation supported the study.

Story Source:

The above story is reprinted from materials provided byRuhr-Universitaet-Bochum. 

Journal Reference:

  1. E Unternaehrer, P Luers, J Mill, E Dempster, A H Meyer, S Staehli, R Lieb, D H Hellhammer, G Meinlschmidt.Dynamic changes in DNA methylation of stress-associated genes (OXTR, BDNF ) after acute psychosocial stressTranslational Psychiatry, 2012; 2 (8): e150 DOI: 10.1038/tp.2012.77

Ruhr-Universitaet-Bochum (2012, August 15). Acute stress alters control of gene activity: Researchers examine DNA methylation.ScienceDaily. Retrieved August 16, 2012, from http://www.sciencedaily.com/releases/2012/08/120815082709.htm

What 10,000 Fruit Flies Have to Tell Us About Differences Between the Sexes

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.”



Journal Reference:

  1. 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