Single gene central to Circadian Rhythms in plants, animals  

Both plants and animals have complicated genetic circuitry that controls circadian rhythms that control the waxing and waning of hundreds of biological processes throughout a day. These cycles appear to have evolved independently, with just a few circadian genes in common between plants and animals.  

Now, a pair of Howard Hughes Medical Institute international research scholars at the University of Buenos Aires in Argentina has discovered a deep connection between the circadian clocks of plants and animals. The shared piece of machinery is known as PRMT5, a gene involved in creating alternative forms of circadian rhythm-related proteins in the nucleus of the cell.

PRMT5 is regulated by other circadian genes in fruit flies and in a plant commonly used to study genetics, the mustard plant Arabidopsis thaliana. This regulation sets up a feedback loop that likely controls the daily fluctuations of thousands of plant genes.  

“We think the PRMT5 gene lies at the heart of the circadian systems in both plants and animals,” says Marcelo Yanovsky, who led the work, which is published 20 October 2010, in Nature. “Circadian clocks most likely evolved independently in plants and animals, but in the way these clocks control physiologic processes, plants and animals use the same tool, PRMT5.”  

Alberto Kornblihtt, the second HHMI international research scholar who contributed to the work, agrees. “It is very interesting to see that one of the key regulators of circadian rhythms is conserved in evolution among plants and insects. But because the actual genes carrying out the actions of circadian clock are different, we think this is an example of convergent evolution.”  

Yanovsky has been striving to dissect the biology behind circadian clocks for 15 years, and he chose to use plants as a tool for working out the genetics underlying the phenomenon. After all, the ancient Greeks knew about circadian cycles in plants 2,500 years ago, when Greek writers noted that leaves move in a predictable pattern throughout the day. Also, the genetics of Arabidopsis, a relative of mustard and a plant commonly used in laboratory research, are easy to manipulate.  

For this study, Yanovsky and his colleagues introduced random genetic mutations into hundreds of Arabidopsis plants and then looked for tell-tale signs of defects in the plants’ circadian patterns. One such sign was easy to pick out – the appearance of unusually tall plants. Abnormally tall plants might result from mutations affecting circadian clock genes because cell elongation is under control of the circadian clock. After picking out one particularly tall plant, Yanovsky’s team set up a camera to take pictures of its leaves every two hours. The leaves turned not in a 24-hour pattern, as they should, but in a 27-hour cycle. A screen of the plant’s genome revealed a mutation in PRMT5, a gene that had never been implicated in circadian rhythms before. A review of genetics databases showed that PRMT5 exists in every organism from yeast to man, and that it creates an enzyme that operates as a catalyst within a cell’s nucleus. The specific job of the enzyme is to add a chemical tag to certain proteins. Specifically, the enzyme adds that tag to a group of proteins in the nucleus that controls alternative splicing of RNA, the process by which a single gene can produce variations of the same protein.  

Yanovksy and his colleagues then enlisted Kornblihtt, who has been studying alternative splicing for 20 years. A series of experiments showed that the enzyme made by PRMT5 rises and falls in a regular rhythm during the day – suggesting that the gene is involved in the circadian cycle. Furthermore, the mutated form of PRMT5 in Arabidopsis produced alternative splices of one of the key circadian clock genes, known as PRR9. The mutation in the PRMT5 enzyme also produced alternative versions of many other proteins.  

Yanovsky and Kornblihtt concluded that circadian clock genes – sometimes called the circadian oscillator – were controlling the amount of PRMT5 enzyme made during the day, which in turn produced alternative versions of many proteins. “The PRMT5 enzyme has regulatory activities that not only to help regulate the circadian clock itself, but also are key to linking the circadian oscillator to hundreds of biological processes,” Yanovsky says.  
To see if PRMT5 also impacted circadian rhythms in animals, Yanovsky’s team, in collaboration with Fernanda Ceriani, a former HHMI international research scholar at Leloir Institute Foundation, obtained fruit flies with mutated PRMT5 genes. And indeed, instead of displaying a normal pattern of activity during the day – active in the morning, resting in the afternoon, and active again in the evening – the mutant flies displayed the same amount of activity across the entire day. That suggested that PRMT5 was also important in circadian rhythms in the flies. And, again, Konblihtt found that the mutant PRMT5 enzyme produced alternative splices of clock- related genes, as well as many other genes, in the flies.

Researchers identify genetic elements influencing risk of type 2 diabetes

A team led by researchers at the US-based National Human Genome Research Institute (NHGRI) has captured the most comprehensive snapshot to date of DNA regions that regulate genes in human pancreatic islet cells, a subset of which produces insulin.

The study highlights the importance of genome regulatory sequences in human health and disease, particularly type 2 diabetes, which affects more than 200 million people worldwide. The findings appear in the 3 November 2010 issue of Cell Metabolism.  

“This study applies the power of epigenomics to a common disease with both inherited and environmental causes,” said NHGRI scientific director Daniel Kastner, MD, PhD “Epigenomic studies are exciting new avenues for genomic analysis, providing the opportunity to peer deeper into genome function, and giving rise to new insights about our genome's adaptability and potential.”  

Epigenomic research focuses on the mechanisms that regulate the expression of genes in the human genome. The researchers used DNA sequencing technology to search the chromatin of islet cells for specific histone modifications and other signals marking regulatory DNA. Computational analysis of the large amounts of DNA sequence data generated in this study identified different classes of regulatory DNA.  

“This study gives us an encyclopedia of regulatory elements in islet cells of the human pancreas that may be important for normal function and whose potential dysfunction can contribute to disease,” said senior author and US NIH Director Francis S. Collins, MD, PhD. “These elements represent an important component of the uncharted genetic underpinnings of type-2 diabetes that is outside of protein-coding genes.”  

Among the results, the researchers detected about 18,000 promoters, which are regulatory sequences immediately adjacent to the start of genes. Promoters are like molecular on-off switches and more than one switch can control a gene. Several hundred of these were previously unknown and found to be highly active in the islet cells.  

“Along the way, we also hit upon some unexpected but fascinating findings,” said co-lead author Praveen Sethupathy, PhD, NHGRI postdoctoral fellow. “For example, some of the most important regulatory DNA in the islet, involved in controlling hormones such as insulin, completely lacked typical histone modifications, suggesting an unconventional mode of gene regulation.”

The researchers also identified at least 34,000 distal regulatory elements, so called because they are farther away from the genes. Many of these were bunched together, suggesting they may cooperate to form regulatory modules. These modules may be unique to islets and play an important role in the maintenance of blood glucose levels.

“Genome-wide association studies have told us there are genetic differences between type 2 diabetic and non-diabetic individuals in specific regions of the genome, but substantial efforts are required to understand how these differences contribute to disease,” said co-lead author Michael Stitzel, PhD, NHGRI postdoctoral fellow. “Defining regulatory elements in human islets is a critical first step to understanding the molecular and biological effects for some of the genetic variants statistically associated with type 2 diabetes.”  

The researchers also found that 50 single nucleotide polymorphisms, or genetic variants, associated with islet-related traits or diseases are located within or very close to non-promoter regulatory elements. Variants associated with type 2 diabetes are present in six such elements that function to boost gene activity. These results suggest that regulatory elements may be a key component to understanding the molecular defects that contribute to type 2 diabetes.

Scientists discover key gene mutation in Acute Myeloid Leukemia

Researchers have discovered mutations in a particular gene that affects the treatment prognosis for some patients with acute myeloid leukemia (AML), an aggressive blood cancer that kills thousands around the world every year. The research is published in the 11 November 2010 online issue of The New England Journal of Medicine. The Washington University School of Medicine in St. Louis team initially discovered a mutation by completely sequencing the genome of a single AML patient. They then used targeted DNA sequencing on nearly 300 additional AML patient samples to confirm that mutations discovered in one gene correlated with the disease. Although genetic changes previously were found in AML, this work shows that newly discovered mutations in a single gene, called DNA methyltransferase 3A or DNMT3A, appear responsible for treatment failure in a significant number of AML patients. The finding should prove rapidly useful in treating patients and which may provide a molecular target against which to develop new drugs.

“This is a wonderful example of the ability of the unbiased application of whole- genome, DNA sequencing to discover a frequently mutated gene in cancer that was previously unknown to be correlated with prognosis,” said Eric D. Green, MD, PhD, director of the National Human Genome Research Institute (NHGRI). “This may quickly lead to a change in medical care because physicians may now screen for these mutations in patients and adjust their treatment accordingly.”

“Cancer is a genetic disease,” said Harold Varmus, MD, US National Cancer Institute director. “Every discovery teaches us more and more about the many ways genes can be deranged in a tumour cell to make it grow out of control. While we generally describe some 200 types of cancer based on where they originate in the body, genetics may show us that there are thousands of different types, each requiring different treatments. Fortunately, we are now acquiring the tools we need to understand them and to make important progress.”  

“This work represents the culmination of years of collaborative research that has focused on cataloging the mutations involved in AML,” says co-author John Dipersio, MD, PhD, chief of the division of oncology and deputy director of the Siteman Cancer Center. “This work provides a pathway and a foundation for doing the same in all other malignancies that could potentially lead to more effective, targeted therapies.”  

Researchers show stem cells may be able to reverse damage caused by MS  

Researchers from the Universities of Cambridge and Edinburgh have identified a mechanism essential for regenerating insulating layers – myelin sheaths – that protect nerve fibres in the brain. In additional studies in rodents, they showed how this mechanism can be exploited to make the brain's own stem cells better able to regenerate new myelin.  

In multiple sclerosis, loss of myelin leads to the nerve fibres in the brain becoming damaged. These nerve fibres are important as they send messages to other parts of the body.  

The scientists believe that this research will help in identifying drugs to encourage myelin repair in multiple sclerosis patients.

Professor Robin Franklin, Director of the MS Society’s Cambridge Centre for Myelin Repair at the University of Cambridge, said: “Therapies that repair damage are the missing link in treating multiple sclerosis. In this study we have identified a means by which the brain's own stem cells can be encouraged to undertake this repair, opening up the possibility of a new regenerative medicine for this devastating disease.”  

The study, funded by the MS Society in the UK and the National Multiple Sclerosis Society in America, is published in Nature Neuroscience.

Professor Charles ffrench-Constant, of the University of Edinburgh's MS Society Centre for Multiple Sclerosis Research, said: “The aim of our research is to slow the progression of multiple sclerosis with the eventual aim of stopping and reversing it. This discovery is very exciting as it could potentially pave the way to find drugs that could help repair damage caused to the important layers that protect nerve cells in the brain.”  

                                   
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