Saturday, March 27, 2010

Insulin-like signal needed to keep stem cells alive in adult brain

Insulin-like signal needed to keep stem cells alive in adult brain

By Robert Sanders, Media Relations | 25 March 2010


BERKELEY — University of California, Berkeley, biologists have found a signal that keeps stem cells alive in the adult brain, providing a focus for scientists looking for ways to re-grow or re-seed stem cells in the brain to allow injured areas to repair themselves.

fruit fly nerve cellsMushroom bodies (red), which are the center of learning and memory in the brain, from two adult fruit flies. Normally, new neurons do not appear in the adult mushroom body. UC Berkeley biologists altered neural stem cells to allow them to persist for at least a month in the adult brain, and to give rise to newborn nerve cells (green) that send out axons to other areas of the mushroom body, just like normal neurons. (Sarah Siegrist/UC Berkeley)
The researchers discovered in fruit flies that keeping the insulin receptor revved up in the brain prevents the die-off of neural stem cells that occurs when most regions of the brain mature into their adult forms. Whether the same technique will work in humans is unknown, but the UC Berkeley team hopes to find out.

"This work doesn't point the way to taking an adult who has already lost stem cells and bringing them back mysteriously, but it suggests what mechanisms might be operating to get rid of them in the first place," said Iswar K. Hariharan, UC Berkeley professor of molecular and cell biology. "Plus, if you were able to introduce neural stem cells into an adult brain, this suggests what kinds of mechanisms you might need to have in place to keep them alive."

Hariharan noted that other researchers have gotten neural stem cells to persist by blocking genes that cause them to die. Yet this alone does not produce healthy, normal-looking neural stem cells that can make mature neurons. The UC Berkeley team's new finding shows that it also is necessary to provide an insulin-like signal. If stopping neural stem cell death is analogous to taking your foot off the brake, then providing an insulin-like signal is like stepping on the gas, he said. Both are essential.

Hariharan, post-doctoral researcher Sarah E. Siegrist and their colleagues published their findings today (Thursday, March 25) in the online version of the journal Current Biology. Their report will appear in the journal's April 13 print edition.

Most areas of the adult mammalian brain and fruit fly brain are devoid of neural stem cells, the only cells able to generate full-fledged neurons. Presumably, Hariharan said, the lack of neural stem cells is why the injured brain is unable to replace dead neurons.

In the new study, Siegrist showed that the stem cells present in the pupal stage of fruit flies are gone in the adult brain because they die off, rather than merely mature into neurons. The stem cells that persisted the longest were in the mushroom body, a region of the fly brain responsible for memory and learning that, in some ways, is like the hippocampus in humans.

In subsequent experiments, she attempted to prevent the death of neural stem cells in fruit flies by genetically blocking a process called programmed cell death (apoptosis). While this allowed the stem cells to survive longer, the cells were small and did not make many neurons. In fact, Siegrist said, they showed signs of impaired growth, suggestive of insulin withdrawal.

She then tried various genetic manipulations to mimic an insulin-type signal, this time using mutant fruit flies with their apoptosis genes also blocked. Amazingly, the neural stem cells persisted for at least a month and even generated many mature, apparently normal, nerve cells.

"These neural stem cells seem to behave properly, they express the proteins that you expect neural stem cells to express, they look like their normal counterparts, and most importantly, they spin off cells which become normal mature nerve cells that put out processes (axons) that, in some cases, seem to go where normal processes go," Siegrist said. "We don't know whether these cells function normally or whether they are electrically active. At least it is encouraging that we can get nerve cells made in a part of the (fruit fly) brain that normally cannot make nerve cells in the adult brain."

"Sarah had to do two manipulations together to keep these neural stem cells alive, and neither worked alone," Hariharan said. "One was to keep the insulin signal on, and one was to block programmed cell death. Each improved things a little bit, but when you did the two together, the neural stem cells survived for a month, at which time they were throwing off mature neurons or normal looking neurons that sent out processes."

Siegrist plans to continue her search through mutant fruit flies to find other genes that improve survival in the mushroom body and allow stem cells in other areas of the fly brain to persist. She also plans collaborations to explore similar mechanisms in mammals, to see if analogous manipulations could keep neural stem cells alive in the mammalian brain.

"In fruit flies, pathways downstream of the insulin receptor are important in keeping these neural stem cells alive," Siegrist said. "Mammals have the same genes downstream of their insulin receptors, so we may find the same response to insulin or insulin-like growth factors in mammals."

Other coauthors are former UC Berkeley undergraduate Najm Haque, now a technician in Hariharan's lab; Chun-Hong Chen of the National Health Research Institutes in Zhunan Town, Taiwan; and Bruce A. Hay of the California Institute of Technology (Caltech) in Pasadena, Calif.

The research is funded by the National Institutes of Health and the Damon Runyon Cancer Research Foundation.

Sunday, March 21, 2010

What counts is how genes are regulated

What counts is how genes are regulated

Once the human genome was sequenced in 2001, the hunt was on for the genes that make each of us unique. But scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and Yale and Stanford Universities in the USA, have found that we differ from each other mainly because of differences not in our genes, but in how they're regulated – turned on or off, for instance. In a study published today in Science, they are the first to compare entire human genomes and determine which changes in the stretches of DNA that lie between genes make gene regulation vary from one person to the next. Their findings hail a new way of thinking about ourselves and our diseases.

The technological advances of the past decade have been so great that scientists can now obtain the genetic sequences – or genomes – of several people in a fraction of the time and for a fraction of the cost it took to determine that first human genome. Moreover, these advances now enable researchers to understand how genes are regulated in humans.

A group of scientists led by Jan Korbel at EMBL and Michael Snyder initially at Yale and now in Stanford were the first to compare individually sequenced human genomes to look for what caused differences in gene regulation amongst ten different people. They focused on non-coding regions – stretches of DNA that lie between genes and, unlike genes, don't hold the instructions for producing proteins. These DNA sequences, which may vary from person to person, can act as anchors to which regulatory proteins, known as transcription factors, attach themselves to switch genes on or off.

Korbel, Snyder, and colleagues found that up to a quarter of all human genes are regulated differently in different people, more than there are genetic variations in genes themselves. The scientists found that many of these differences in how regulatory proteins act are due to changes in the DNA sequences they bind to. In some cases, such changes can be a difference in a single letter of the genetic code, while in others a large section of DNA may be altered. But surprisingly, they discovered even more variations could not be so easily explained. They reasoned that some of these seemingly inexplicable differences might arise if regulatory proteins didn't act alone, but interacted with each other.

"We developed a new approach which enabled us to identify cases where a protein's ability to turn a gene on or off can be affected by interactions with another protein anchored to a nearby area of the genome," Korbel explains. "With it, we can begin to understand where such interactions happen, without having to study every single regulatory protein out there."

The scientists found that even if different people have identical copies of a gene – for instance ORMDL3, a gene known to be involved in asthma in children – the way their cells regulate that gene can vary from person to person.

"Our findings may help change the way we think of ourselves, and of diseases", Snyder concludes: "as well as looking for disease genes, we could start looking at how genes are regulated, and how individual variations in gene regulation could affect patients' reactions."

Finally, Korbel, Snyder and colleagues compared the information on humans with that from a chimpanzee, and found that with respect to gene regulation there seems to be almost as much variation between humans as between us and our primate cousins – a small margin in which may lie important clues both to how we evolved and to what makes us humans different from one another.

In a study published online in Nature yesterday, researchers led by Snyder in the USA and Lars Steinmetz at EMBL in Heidelberg have found that similar differences in gene regulation also occur in an organism which is much farther from us in the evolutionary tree: baker's yeast.

Friday, March 19, 2010

Transcription Factors May Dictate Differences Between Individuals

March 18, 2010
Transcription Factors May Dictate Differences Between Individuals

Researchers are only beginning to understand how individual variation in gene regulation can have a lasting impact on one’s health and susceptibility to certain diseases. Now, an ambitious survey of the human genome has identified differences in the binding of master regulators called transcription factors to DNA that affect how genes are expressed in different people.

The study, which is published in the March 18, 2010, issue of Science, looked at two common transcription factors. HHMI medical research fellow Maya Kasowski and her colleagues in the laboratory of molecular biologist Michael Snyder at Yale University conducted the work with Jan Korbel at the European Molecular Biology Laboratory. Snyder has since joined the faculty at Stanford University.

“We know there are differences in gene expression between people. Understanding the differences in how genes are regulated could help us understand human diversity. ”
Maya Kasowski

Transcription factors account for as much as 10 percent of the coding genome in humans and other organisms. When activated, transcription factors switch on or off hundreds or thousands of genes, a cascade that programs cells to grow or divide. “The activity of transcription factors determines what a cell is doing at any given moment,” says Kasowski, who was a medical student at Yale when she received her HHMI medical research fellowship. She has since decided to pursue an M.D./Ph.D. degree.

Despite their large numbers and critical role, many aspects of transcription factor biology remain poorly understood. Until now, no one had looked at whether there was any variability in the targets of transcription factors from one person to the next. The current study found a “number of differences between individuals” in the binding sites of two transcription factors, Snyder says.

Transcription factors bind to the human genome within areas of the genome still viewed as a black box—vast stretches of DNA sequence between known genes. Gradually, biologists have found that much of this DNA performs a vital function—helping turn genes on and off in specific situations. Some of the regulatory regions, known as binding regions, serve as handholds for transcription factors.

“We know there are differences in gene expression between people.” Kasowski says. “Understanding the differences in how genes are regulated could help us understand human diversity. But identifying the regulatory DNA that controls expression is much more difficult than looking for differences in the regions of the genome that code for genes.”

For the current study, Kasowski, Snyder, and their colleagues examined two important transcription factors: RNA polymerase II and NFkappaB. RNA polymerase II, which is active in all cells, transcribes DNA into RNA. NFkappaB is activated by stress, plays a key role in immune responses to infections, and has been implicated in several diseases, including cancer.

The team mapped every binding region for these two factors inside the genomes of 10 individuals. To do so, they deployed a new technology that uses chemicals to freeze transcription factors as they bind to the genome. The scientists then sequenced the segment of DNA to which the transcription factor bound. After the team combined the data from all 10 individuals, they found around 19,000 binding regions for RNA polymerase II and another 15,500 binding regions for NFkappaB.

They discovered that the number of transcription factors binding at the different sites often varied near different genes, which in many cases influenced how much of the gene was expressed. Hence, variation in transcription factor binding can help explain why one person may make more of a certain gene product than another, Snyder says. Among any two individuals, the team found that 25 percent of the RNA polymerase II binding regions varied in time or frequency, as did 7.5 percent of the NFkappaB binding regions.

Closer examination of these variable binding regions showed that single-letter differences in the genome—called SNPs—accounted for some of the difference in transcription factor binding. That is, in some of individuals, a single letter change at a certain binding region influenced the likelihood that the transcription factor would bind there. “We found that differences in DNA sequence contributed to differences in transcription factor binding,” Kasowski says. “The more SNPs we found in a particular binding region, the more variation in binding we saw.”

Other, larger differences in the genome, called structural variation, also accounted for a number of the differences in transcription factor binding. Structural variation happens when large segments of the genome are deleted, duplicated, or inverted. It varies widely among humans, and the role of such variability in human biology is not well understood.

But the new study shows that SNPs and structural variation can either increase or decrease transcription factor binding, and, hence, the amount of a protein that gets made from a particular gene. “We found that about one third of the differences in binding was caused by SNPs and structural variation,” Snyder says. “This is the first time anyone has shown that SNPs and structural variation affect large number of regulatory elements that control gene expression. Normally, people look at differences in the gene themselves rather than in the regulatory regions, because they are difficult to identify.”

The study also reports differences in binding of RNA polymerase II and NFkappaB near genes implicated in many major diseases, including type 1 diabetes, lupus, chronic lymphatic leukemia, schizophrenia, asthma, Crohn’s disease, and rheumatoid arthritis. “Variation in the regulation of genes might eventually help account for some of the varying susceptibility to diseases we see in the population,” Kasowski says.

In addition to looking at humans, Kasowski, Snyder and their colleagues looked at transcription factor binding for a single chimpanzee. The study shows that 32 percent of RNA polymerase II binding regions differed between the humans in the study and the chimp. Snyder says that he included the chimp out of curiosity to see how transcription factor binding might account for differences between ourselves and our closest genetic cousin. But the 32 percent difference between chimps and humans was not that much larger than the 25 percent difference in RNA polymerase II binding found among two individuals.

Still, Snyder says that the study opens a new genomic frontier for biologists. “Only about two percent of our DNA codes for genes,” he says. “Studying the rest of the genome, including gene regulation and transcription factors, is the next wave in understanding human variation.”

Tuesday, March 16, 2010

SeqTrim: a high-throughput pipeline for pre-processing any type of sequence read

SeqTrim: a high-throughput pipeline for pre-processing any type of sequence read

Juan Falgueras1 email, Antonio J Lara2 email, Noé Fernández-Pozo3 email, Francisco R Cantón3 email, Guillermo Pérez-Trabado2,4 email and M Gonzalo Claros2,3 email

1 Departamento de Lenguajes y Ciencias de la Computación, Universidad de Málaga, Málaga, Spain

2 Plataforma Andaluza de Bioinformática, Universidad de Málaga, 29071 Málaga, Spain

3 Departamento de Biología Molecular y Bioquímica, Universidad de Málaga, 29071 Málaga, Spain

4 Departamento de Arquitectura de Computadores, Universidad de Málaga, Málaga, Spain

author email corresponding author email

BMC Bioinformatics 2010, 11:38doi:10.1186/1471-2105-11-38
Published: 20 January 2010

High-throughput automated sequencing has enabled an exponential growth rate of sequencing data. This requires increasing sequence quality and reliability in order to avoid database contamination with artefactual sequences. The arrival of pyrosequencing enhances this problem and necessitates customisable pre-processing algorithms.

SeqTrim has been implemented both as a Web and as a standalone command line application. Already-published and newly-designed algorithms have been included to identify sequence inserts, to remove low quality, vector, adaptor, low complexity and contaminant sequences, and to detect chimeric reads. The availability of several input and output formats allows its inclusion in sequence processing workflows. Due to its specific algorithms, SeqTrim outperforms other pre-processors implemented as Web services or standalone applications. It performs equally well with sequences from EST libraries, SSH libraries, genomic DNA libraries and pyrosequencing reads and does not lead to over-trimming.

SeqTrim is an efficient pipeline designed for pre-processing of any type of sequence read, including next-generation sequencing. It is easily configurable and provides a friendly interface that allows users to know what happened with sequences at every pre-processing stage, and to verify pre-processing of an individual sequence if desired. The recommended pipeline reveals more information about each sequence than previously described pre-processors and can discard more sequencing or experimental artefacts.

Saturday, March 13, 2010

Small RNAs: An epigenetic silencing influence

Small RNAs: An epigenetic silencing influence
SOURCE: Nature Reviews Genetics
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New evidence has emerged that in moss, miRNAs can silence gene expression at the transcriptional level by interacting with DNA, leading to methylation.

MicroRNAs (miRNAs) regulate gene expression by base pairing with target RNAs, leading to their cleavage in plants or translational inhibition in animals. Now evidence has emerged that in moss, miRNAs can also silence gene expression at the transcriptional level by interacting with DNA, leading to methylation. This discovery broadens the regulatory influence of miRNAs, and the mechanism may also be applicable to other organisms.


Khraiwesh et al. examined the role of Dicer proteins in the moss Physcomitrella patens, which has four Dicers (DICER-LIKE 1a (DCL1a), DCL1b, DCL3 and DCL4). They chose P. patens because the dual functions of Dicers in miRNA biogenesis and target cleavage are separable in this species. Using targeted knockout-mutants of P. patens, the authors showed that DCL1a is required for miRNA biogenesis and DCL1b is required for miRNA-induced target RNA cleavage.

Intriguingly, DCL1b-null mutants had reduced levels of miRNA target transcripts despite the absence of miRNA-guided cleavage. How do miRNAs regulate their targets in DCL1b knockouts? The authors found that the genes that encode miRNA targets were methylated in DCL1b knockouts, but were not methylated in wild-type controls. They then showed that there was a reduced rate of transcription of miRNA target genes compared with unmethylated non-miRNA-target genes in DCL1b knockouts, indicating that the observed methylation leads to transcriptional silencing of genes that encode miRNA targets.

The authors suggested that in DCL1b-null mutants, miRNAs form stable duplexes with mRNAs within an RNA-induced transcriptional silencing complex. Consistent with this model, the miRNA targets primed cDNA synthesis without the addition of exogenous primers, supporting the existence of miRNA–mRNA duplexes. Do the levels of miRNAs, and therefore the levels of these duplexes, influence DNA methylation? Khraiwesh et al. created transgenic P. patens lines that expressed different levels of an artificial miRNA (amiRNA) and found that with increased expression of the amiRNA, there was increased silencing of the amiRNA target. Moreover, methylation and silencing were not restricted to DCL1b knockouts — they also occurred when high levels of amiRNA were expressed in wild-type P. patens lines.

As transcriptional silencing was also observed in non-transgenic P. patens, the authors investigated whether this pathway could also operate in wild-type P. patens under physiological conditions. Treatment of P. patens with the plant hormone abscisic acid (ABA) led to reduced levels of an miRNA target transcript (bHLH) that encodes a basic helix–loop–helix transcription factor, which in turn led to increased levels of the cognate miRNA (miR1026) and methylation of the bHLH gene. As ABA is a mediator of stress signalling, these results suggest that miRNAs might epigenetically regulate stress-responsive genes.

The physiological regulation of this epigenetic miRNA-induced silencing pathway and the conservation of miRNA pathway components among species suggest that this mechanism might be generally applicable — a topic for future investigation.

Meera Swami

Thursday, March 11, 2010

Discovery of cellular 'switch' may provide new means of triggering cell death, treating disease

Discovery of cellular 'switch' may provide new means of triggering cell death, treating disease

A research team led by the University of Colorado at Boulder has discovered a previously unknown cellular "switch" that may provide researchers with a new means of triggering programmed cell death, findings with implications for treating cancer.

TA-65 - The revolutionary molecule that makes cells young again -

The new results are a big step forward in understanding programmed cell death, or apoptosis, a cell suicide process that involves a series of biochemical events leading to changes like cell body shrinkage, mitochondria destruction and chromosome fragmentation, said CU-Boulder Professor Ding Xue. But unlike traumatic cell death from injury, programmed cell death is a naturally occurring aspect of animal development that may help prevent human diseases like cancer and autoimmune disorders, said Xue, lead author on the new study.

In the new study, Xue and his team found that a well-known cellular molecule called caspase - known as the "executioner enzyme" for apoptosis because of its primary role of cutting up and destroying cellular proteins -- has an entirely different effect on a particular enzyme called Dicer. The team found that when caspase cleaves Dicer, it does not kill it but instead changes its function, causing Dicer to break up chromosomes -- pieces of coiled DNA containing thousands of genes -- and kill the cells that house them.

"This finding was totally unexpected," said Xue of CU-Boulder's molecular, cellular and developmental biology department. "We believe that by understanding this mechanism, we may be able to develop a new way to trigger cell death in a controlled manner as a way to treat disease."

A paper on the subject appears in the March 12 issue of Science. Co-authors on the study included CU-Boulder postdoctoral researchers Akihisa Nakagawa and Yong Shi and Tokyo Women's Medical University researchers Eriko Kage-Nakadai and Shohei Mitani.

The normal function of Dicer is to snip strands of RNA into smaller pieces that attach to messenger RNA molecules -- which carry DNA's genetic messages from the nucleus of cells to make specific proteins in cell cytoplasm -- and silence their activity, said Xue. But when caspase comes in contact with Dicer, it takes away Dicer's ability to cleave RNA and it replaces it with the ability to snip up and destroy DNA-laden chromosomes.

Wednesday, March 10, 2010

The primary transcriptome of the major human pathogen Helicobacter pylori

Nature 464, 250-255 (11 March 2010) | doi:10.1038/nature08756; Received 6 August 2009; Accepted 14 December 2009; Published online 17 February 2010

The primary transcriptome of the major human pathogen Helicobacter pylori

Cynthia M. Sharma1, Steve Hoffmann2, Fabien Darfeuille3,4, Jérémy Reignier3,4, Sven Findeiß2, Alexandra Sittka1, Sandrine Chabas3,4, Kristin Reiche5, Jörg Hackermüller5, Richard Reinhardt6, Peter F. Stadler2,5,7,8,9 & Jörg Vogel1,10

1. Max Planck Institute for Infection Biology, RNA Biology Group, D-10117 Berlin, Germany
2. University of Leipzig, Department of Computer Science & Interdisciplinary Centre for Bioinformatics, D-04107 Leipzig, Germany
3. INSERM U869 and,
4. Université de Bordeaux, F-33076 Bordeaux Cedex, France
5. Fraunhofer Institute for Cell Therapy and Immunology, RNomics Group, D-04103 Leipzig, Germany
6. Max Planck Institute for Molecular Genetics, D-14195 Berlin, Germany
7. Max Planck Institute for the Mathematics in Sciences, D-04103 Leipzig, Germany
8. University of Vienna, Institute for Theoretical Chemistry, A-1090 Vienna, Austria
9. The Santa Fe Institute, Santa Fe, 87501 New Mexico, USA
10. University of Würzburg, Institute for Molecular Infection Biology, D-97080 Würzburg, Germany

Correspondence to: Jörg Vogel1,10 Correspondence and requests for materials should be addressed to J.V. (Email:

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Genome sequencing of Helicobacter pylori has revealed the potential proteins and genetic diversity of this prevalent human pathogen, yet little is known about its transcriptional organization and noncoding RNA output. Massively parallel cDNA sequencing (RNA-seq) has been revolutionizing global transcriptomic analysis. Here, using a novel differential approach (dRNA-seq) selective for the 5′ end of primary transcripts, we present a genome-wide map of H. pylori transcriptional start sites and operons. We discovered hundreds of transcriptional start sites within operons, and opposite to annotated genes, indicating that complexity of gene expression from the small H. pylori genome is increased by uncoupling of polycistrons and by genome-wide antisense transcription. We also discovered an unexpected number of ~60 small RNAs including the ϵ-subdivision counterpart of the regulatory 6S RNA and associated RNA products, and potential regulators of cis- and trans-encoded target messenger RNAs. Our approach establishes a paradigm for mapping and annotating the primary transcriptomes of many living species.

Wednesday, March 3, 2010

Surprising mtDNA diversity

Surprising mtDNA diversity
Posted by Jef Akst at
[Entry posted at 3rd March 2010 06:00 PM GMT]
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Mitochondrial genomes are not uniform across cells of the body as previously believed, but vary between different tissue types, according to a study published online today (March 3) in Nature.

The findings may affect forensics and the search for biomarkers, both of which utilize mitochondrial DNA.

"I was surprised," said molecular cell biologist Hans Spelbrink of the University of Tampere, Finland, who was not involved in the research. "Mostly the assumption is that from the start of life individuals are homoplasmic," meaning that within an individual, mitochondrial DNA (mtDNA) is the same. However, the results of this study demonstrate "that each individual is a mosaic of multiple [mt]DNA types in various frequencies in different tissues," he said.

Previous studies have documented some degree of heteroplasmy -- variation in mtDNA in an individual -- but these findings were limited and mostly restricted to people with mitochondrial disorders, "where one would expect" to find such variation, Spelbrink said. "This is the first time [mitochondrial variation] was properly documented" in normal individuals.

Using high throughput sequencing technology, molecular geneticist Nickolas Papadopoulos of the Ludwig Center for Cancer Genetic and Therapeutics and the Johns Hopkins Kimmel Cancer Center in Baltimore and his colleagues analyzed the mitochondrial genomes of a variety of tissues in 2 different people and the lining of the colon in 10 others. In every individual, the researchers found at least 1 allele that differed between tissues, and one individual had as many as 14 heteroplasmies.

"That was a surprise when we saw the results," Papadopoulos said. "There's more than one mitochondrial genome present in each one of us. In addition to that, there were variations from tissue to tissue [in the levels of heteroplasmy observed], which may have implications in embryogenesis." The findings may also affect more practical applications in forensics science and the development of biomarkers for certain diseases, which often utilize mtDNA because it is abundant and easy to amplify, he added.

"When you look for biomarkers, you want to establish what the normal tissue looks like" in order to have a reference with which to compare the disease state, Papadopoulos said. With the recognition that mitochondrial genomes are quite variable even in normal tissues, "now we have to keep in mind [that] some of the changes we see may not really be [disease-related] mutations."

Thus, to use mitochondrial mutations as potential biomarkers, future studies "will have to investigate a lot of carefully determine the normal control range," molecular biologist Ian Holt of the Mitochondrial Biology Unit of the Medical Research Council in Cambridge, UK, wrote in an email to The Scientist. "Also, there is a big question mark about how early this increase in mtDNA variation appears in the blood. If it's only apparent once the cancer is well established then it isn't much use as a biomarker."

With regard to forensics, the normal variation in mtDNA "complicates things a little bit," Papadopoulos said. Because the mtDNA in one tissue might vary from another tissue, caution must be used when comparing a hair sample, for example, to blood. "The positive side is that, in principle, you could even distinguish monozygous twins, if you can characterize their heteroplasmy pattern," added molecular evolutionary biologist Nicolas Galtier of the Université Montpellier 2 in an email.

It's unclear why mtDNA is so variable. One reason may be that mitochondria have a higher mutation rate than nuclear DNA, said pediatrician and clinical geneticist Richard Boles of the Keck School of Medicine of University of Southern California. "It's really sitting in the heat of the furnace where it's likely to get damaged," Boles said, referring to the free radicals and other byproducts of energy metabolism that takes place in the mitochondria. Alternatively, it could be that the mitochondria have less effective DNA repair mechanisms.

These findings are likely to spur future studies to further characterize the diversity in mitochondrial genomes and determine the mechanism underlying the variation, Boles said. "This is certainly going to raise a lot of eyebrows."

Read more: Surprising mtDNA diversity - The Scientist - Magazine of the Life Sciences

Monday, March 1, 2010

KDM7 is a dual demethylase for histone H3 Lys 9 and Lys 27 and functions in brain development

Published in Genes & Development

1. Yu-ichi Tsukada1,2,3,
2. Tohru Ishitani4 and
3. Keiichi I. Nakayama1,2,5

+ Author Affiliations

1.1Division of Cell Biology, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan;
2.2CREST, Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan;
3.3PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan;
4.4Division of Cell Regulation Systems, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan


Methylation of histone H3 Lys 9 and Lys 27 (H3K9 and H3K27) is associated with transcriptional silencing. Here we show that KDM7, a JmjC domain-containing protein, catalyzes demethylation of both mono- or dimethylated H3K9 and H3K27. Inhibition of KDM7 orthologs in zebrafish resulted in developmental brain defects. KDM7 interacts with the follistatin gene locus, and KDM7 depletion in mammalian neuronal cells suppressed follistatin gene transcription in association with increased levels of dimethylated H3K9 and H3K27. Our findings identify KDM7 as a dual demethylase for H3K9 and H3K27 that functions as an eraser of silencing marks on chromatin during brain development.