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Schiavone D.,Medical Research Council | Guilbaud G.,Medical Research Council | Murat P.,University of Cambridge | Papadopoulou C.,Medical Research Council | And 5 more authors.
EMBO Journal | Year: 2014

REV1-deficient chicken DT40 cells are compromised in replicating G quadruplex (G4)-forming DNA. This results in localised, stochastic loss of parental chromatin marks and changes in gene expression. We previously proposed that this epigenetic instability arises from G4-induced replication fork stalls disrupting the accurate propagation of chromatin structure through replication. Here, we test this model by showing that a single G4 motif is responsible for the epigenetic instability of the BU-1 locus in REV1-deficient cells, despite its location 3.5 kb from the transcription start site (TSS). The effect of the G4 is dependent on it residing on the leading strand template, but is independent of its in vitro thermal stability. Moving the motif to more than 4 kb from the TSS stabilises expression of the gene. However, loss of histone modifications (H3K4me3 and H3K9/14ac) around the transcription start site correlates with the position of the G4 motif, expression being lost only when the promoter is affected. This supports the idea that processive replication is required to maintain the histone modification pattern and full transcription of this model locus. © 2014 MRC Laboratory of Molecular Biology. Published under the terms of the CC BY 4.0 license.

News Article | December 22, 2015

The world of epigenetics – where molecular ‘switches’ attached to DNA turn genes on and off – has just got bigger with the discovery by a team of scientists from the University of Cambridge of a new type of epigenetic modification. Published in the journal Nature Structural and Molecular Biology, the discovery suggests that many more DNA modifications than previously thought may exist in human, mouse and other vertebrates. DNA is made up of four ‘bases’: molecules known as adenine, cytosine, guanine and thymine – the A, C, G and T letters. Strings of these letters form genes, which provide the code for essential proteins, and other regions of DNA, some of which can regulate these genes. Epigenetics (epi - the Greek prefix meaning ‘on top of’) is the study of how genes are switched on or off. It is thought to be one explanation for how our environment and behavior, such as our diet or smoking habit, can affect our DNA and how these changes may even be passed down to our children and grandchildren. Epigenetics has so far focused mainly on studying proteins called histones that bind to DNA. Such histones can be modified, which can result in genes being switched on or of. In addition to histone modifications, genes are also known to be regulated by a form of epigenetic modification that directly affects one base of the DNA, namely the base C. More than 60 years ago, scientists discovered that C can be modified directly through a process known as methylation, whereby small molecules of carbon and hydrogen attach to this base and act like switches to turn genes on and off, or to ‘dim’ their activity. Around 75 million (one in ten) of the Cs in the human genome are methylated. Now, researchers at the Wellcome Trust-Cancer Research UK Gurdon Institute and the Medical Research Council Cancer Unit at the University of Cambridge have identified and characterized a new form of direct modification – methylation of the base A – in several species, including frogs, mouse and humans. Methylation of A appears to be far less common that C methylation, occurring on around 1,700 As in the genome, but is spread across the entire genome. However, it does not appear to occur on sections of our genes known as exons, which provide the code for proteins. “These newly-discovered modifiers only seem to appear in low abundance across the genome, but that does not necessarily mean they are unimportant,” said Dr. Magdalena Koziol from the Gurdon Institute. “At the moment, we don’t know exactly what they actually do, but it could be that even in small numbers they have a big impact on our DNA, gene regulation and ultimately human health.” More than two years ago, Dr. Koziol made the discovery while studying modifications of RNA. There are 66 known RNA modifications in the cells of complex organisms. Using an antibody that identifies a specific RNA modification, Dr. Koziol looked to see if the analogous modification was also present on DNA, and discovered that this was indeed the case. Researchers at the MRC Cancer Unit then confirmed that this modification was to DNA, rather than from any RNA contaminating the sample. “It’s possible that we struck lucky with this modifier,” said Dr. Koziol, “but we believe it is more likely that there are many more modifications that directly regulate our DNA. This could open up the field of epigenetics.” The research was funded by the Biotechnology and Biological Sciences Research Council, Human Frontier Science Program, Isaac Newton Trust, Wellcome Trust, Cancer Research UK and the Medical Research Council.

Jain D.,Cancer Research UK Research Institute | Hebden A.K.,Imperial College London | Nakamura T.M.,University of Illinois at Chicago | Miller K.M.,Gurdon Institute | Cooper J.P.,Cancer Research UK Research Institute
Nature | Year: 2010

The notion that telomeres are essential for chromosome linearity stems from the existence of two chief dangers: inappropriate DNA damage response (DDR) reactions that mistake natural chromosome ends for double-strand DNA breaks (DSBs), and the progressive loss of DNA from chromosomal termini due to the end replication problem. Telomeres avert the former peril by binding sequence-specific end-protection factors that control the access of DDR activities1,2. The latter threat is tackled by recruiting telomerase, a reverse transcriptase that uses an integral RNA subunit to template the addition of telomere repeats to chromosome ends3. Here we describe an alternative mode of linear chromosome maintenance in which canonical telomeres are superseded by blocks of heterochromatin. We show that in the absence of telomerase, Schizosaccharomyces pombe cells can survive telomere sequence loss by continually amplifying and rearranging heterochromatic sequences. Because the heterochromatin assembly machinery is required for this survival mode, we have termedit 'HAATI' (heterochromatin amplification-mediated and telomerase-independent). HAATI uses the canonical end-protection protein Pot1 (ref. 4) and its interacting partner Ccq1 (ref. 5) to preserve chromosome linearity. The data suggest a model in which Ccq1 is recruited by the amplified heterochromatin and provides an anchor for Pot1, which accomplishes its end-protection function in the absence of its cognate DNA-binding sequence. HAATI resembles the chromosome end-maintenance strategy found in Drosophila melanogaster, which lacks specific telomere sequences but nonetheless assembles terminal heterochromatin structures that recruit end-protection factors. These findings reveal a previously unrecognized mode by which cancer cells might escape the requirement for telomerase activation, and offer a tool for studying genomes that sustain unusually high levels of heterochromatinization. © 2010 Macmillan Publishers Limited. All rights reserved.

Conduit P.T.,University of Oxford | Brunk K.,Gurdon Institute | Dobbelaere J.,Gurdon Institute | Dobbelaere J.,Research Institute of Molecular Pathology | And 5 more authors.
Current Biology | Year: 2010

Background: Centrosomes are major microtubule organizing centers in animal cells, and they comprise a pair of centrioles surrounded by an amorphous pericentriolar material (PCM). Centrosome size is tightly regulated during the cell cycle, and it has recently been shown that the two centrosomes in certain stem cells are often asymmetric in size. There is compelling evidence that centrioles influence centrosome size, but how centrosome size is set remains mysterious. Results: We show that the conserved Drosophila PCM protein Cnn exhibits an unusual dynamic behavior, because Cnn molecules only incorporate into the PCM closest to the centrioles and then spread outward through the rest of the PCM. Cnn incorporation into the PCM is driven by an interaction with the conserved centriolar proteins Asl (Cep152 in humans) and DSpd-2 (Cep192 in humans). The rate of Cnn incorporation into the PCM is tightly regulated during the cell cycle, and this rate influences the amount of Cnn in the PCM, which in turn is an important determinant of overall centrosome size. Intriguingly, daughter centrioles in syncytial embryos only start to incorporate Cnn as they disengage from their mothers; this generates a centrosome size asymmetry, with mother centrioles always initially organizing more Cnn than their daughters. Conclusions: Centrioles can control the amount of PCM they organize by regulating the rate of Cnn incorporation into the PCM. This mechanism can explain how centrosome size is regulated during the cell cycle and also allows mother and daughter centrioles to set centrosome size independently of one another. © 2010 Elsevier Ltd. All rights reserved.

Stevens N.R.,Gurdon Institute | Stevens N.R.,University of Oxford | Dobbelaere J.,Gurdon Institute | Brunk K.,Gurdon Institute | And 4 more authors.
Journal of Cell Biology | Year: 2010

In Caenorhabditis elegans, five proteins are required for centriole duplication: SPD-2, ZYG-1, SAS-5, SAS-6, and SAS-4. Functional orthologues of all but SAS-5 have been found in other species. In Drosophila melanogaster and humans, Sak/Plk4, DSas-6/hSas-6, and DSas-4/CPAP - orthologues of ZYG-1, SAS-6, and SAS-4, respectively - are required for centriole duplication. Strikingly, all three fly proteins can induce the de novo formation of centriole-like structures when overexpressed in unfertilized eggs. Here, we find that of eight candidate duplication factors identified in cultured fly cells, only two, Ana2 and Asterless (Asl), share this ability. Asl is now known to be essential for centriole duplication in flies, but no equivalent protein has been found in worms. We show that Ana2 is the likely functional orthologue of SAS-5 and that it is also related to the vertebrate STIL/SIL protein family that has been linked to microcephaly in humans. We propose that members of the SAS-5/Ana2/STIL family of proteins are key conserved components of the centriole duplication machinery. © 2010 Stevens et al.

Pines J.,Gurdon Institute | Hagan I.,Paterson Institute for Cancer Research
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

Orson Welles might have been a little unfair on the Swiss, after all cuckoo clocks were developed in the Schwartzwald, but, more importantly, Swiss democracy gives remarkably stable government with considerable decision-making at the local level. The alternative is the battling city-states of Renaissance Italy: culturally rich but chaotic at a higher level of organization. As our understanding of the cell cycle improves, it appears that the cell is organized more along the lines of Switzerland than Renaissance Italy, and one major challenge is to determine how local decisions are made and coordinated to produce the robust cell cycle mechanisms that we observe in the cell as a whole. © 2011 The Royal Society.

Tessarz P.,Gurdon Institute | Tessarz P.,Max Planck Institute for Biology of Ageing | Kouzarides T.,Gurdon Institute
Nature Reviews Molecular Cell Biology | Year: 2014

Post-translational modifications of histones regulate all DNA-templated processes, including replication, transcription and repair. These modifications function as platforms for the recruitment of specific effector proteins, such as transcriptional regulators or chromatin remodellers. Recent data suggest that histone modifications also have a direct effect on nucleosomal architecture. Acetylation, methylation, phosphorylation and citrullination of the histone core may influence chromatin structure by affecting histone-histone and histone-DNA interactions, as well as the binding of histones to chaperones. © 2014 Macmillan Publishers Limited. All rights reserved.

News Article | October 26, 2016

Starting with skin cells rather than egg cells, Japanese researchers say they have generated eggs that led to healthy mouse pups capable of living normal lives and reproducing. Mammals, of course, have always reproduced via the sperm of one animal combining with the egg cell of another. But the new research started instead with a skin cell from a mouse’s tail and transformed it into egg cells, then matured those eggs in a laboratory dish and finally fertilized them and implanted them into a female mouse. Although only 1 percent of the cells led to live births, the animals that were born alive were healthy, fertile, and lived a normal lifespan, says Katsuhiko Hayashi, a stem cell biologist at Kyushu University in Fukuoka, Japan, and the senior author of a paper on the research, published Monday in Nature. Although this process likely remains decades away from a stage at which it could work in people, the research suggests it may someday be possible for women who lack eggs, or for men without sperm, to get replacement cells made from their own skin. If that becomes possible it could extend the age of human fertility by decades, help preserve endangered animal species and someday perhaps allow same-sex couples to have their own genetic children. In the meantime, several experts say they are highly impressed by the new study. “This is quite an amazing piece of research,” says Azim Surani at the Gurdon Institute in Cambridge, UK. He was not involved in the latest work, but he supervised Hayashi’s postdoctoral fellowship there. “People might have thought this was science fiction, but it does work,” Surani adds. In an earlier study published in Cell, Hayashi and his colleagues had shown that they could generate healthy mouse pups by maturing skin-cell-derived eggs inside the mouse mother. In the new work the maturation took place entirely in a lab dish, making it much closer to a process that could one day be used in people. “That’s quite a remarkable feat, actually,” Surani says. Shinya Yamanaka won a 2012 Nobel Prize for his 2006 work transforming skin cells into stem cells that are theoretically capable of becoming any cells in the body. But Hayashi is one of just a few scientists worldwide trying to make germline cells from these so-called induced pluripotent stem (or iPS) cells. To transform a stem cell into a primordial egg cell, the researchers had to design an environment that recapitulated cell signaling and promoted development through several stages, says Shoukhrat Mitalipov, a reproductive and developmental biologist at Oregon Health & Science University, who was not involved in the study. “This is a tremendous amount of work. I have to congratulate the team. It’s such a huge accomplishment,” Mitalipov says. Hayashi says his next step will be to try to repeat this process in a non-human primate, which will be much more complicated. To help mature the mouse egg cells he simply took supporting cells from the mother's ovaries. In a primate he will first need to generate these supportive cells from stem cells—something that has never been done before. Hayashi says the mouse research has taken him four years, and he expects it would take at least twice that long to achieve the same results in people. It is far too early to try that, he says. “At the moment I must say that this kind of system should not be used for the human, because there are big risks,” he warns, adding that the process might lead to abnormal or seriously ill offspring. It may be possible to eventually make it safer by using a combination of technical improvements and advances in genetic analyses of embryos, he says. In a mouse it is ethically allowable to examine a large number of the embryos generated by research, and to accept the possibility—though not yet seen—that the pups might have genetic defects. Similar studies would not be possible in human research. “In mice we can also work directly on the organism itself. We can look at events in vivo, introduce mutations and see what happens,” Surani says. “In humans we need a culture system to study the germ line, because we can’t do the kinds of experiments we can do in mice.” Surani admits there will be challenges to getting this type of reproduction to work in people, and suspects the process could take a long time—possibly one to two decades. But Hayashi’s achievements so far make him confident of eventual success. “Sometimes when you know something is possible, it takes off the mental barriers you might have. You start being more optimistic,” he explains. “I wouldn’t say it’s impossible. I think it is possible.”

News Article | November 22, 2016

Dr. Meritxell Huch, from Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge - UK, is the winner of the Hamdan International Award for Medical Research Excellence for the topic of Liver Disorders, according to an official announcement that was given recently in Dubai. H.H. Sheikh Hamdan bin Rashid al Maktoum, Deputy Ruler of Dubai, the UAE Minister of Finance and the Patron of the Award, will honor Dr. Huch in a grand ceremony to be held in Dubai, United Arab Emirates, on 14 December, alongside with 14 prestigious personalities and organizations from USA, France, Australia, United Arab Emirates, Saudi Arabia, and Morocco. "Dr. Meritxell Huch's research is focused on the contribution of stem cells to the regeneration of adult liver and pancreas tissues as well as on the development of organoid cultures for these endodermal organs (stomach, liver and pancreas).  She has established a new culture system that maintains the self-renewal status of liver stem cells in vitro, while differentiation towards functional liver cells can be induced by modulating key signaling pathways", as mentioned in a report recently issued by the Hamdan Medical Award. "Dr. Huch and colleagues located the specific type of stem cells responsible for this regeneration. By isolating these cells and placing them in a culture medium, the researchers were able to grow organoids. Dr. Huch is now moving on to testing it with human cells, which would not only be more relevant to research into human disease, but would also lead to the development of a patient's own liver tissue for transplantation", the report said. Beside Dr. Huch, 2 US scientists won the Hamdan International Award for Medical Research Excellence namely; Professor Sanford Markowitz, Case Western Reserve University, School of Medicine, Cleveland Ohio, for the topic of Colon Disorders, and Professor David Tuveson, Deputy Director of the Cold Spring Harbor Laboratory Cancer Centre, New York, for the topic of Pancreatic Diseases. Notably, Sheikh Hamdan bin Rashid Al Maktoum Award for Medical Sciences is a non-profit organization that honors researchers around the world who carry out distinguished medical research to serve mankind at large. Also, the Award works towards stimulating scientific interaction and enriching scientific research among doctors within the UAE and overseas.

Scientists studied the whole-genome sequences of 146 small fish in the 700m-wide Lake Massoko in Tanzania in order to answer two of the most debated questions in evolutionary biology: is sympatric speciation possible and, if so, what are the genetic and physical traits that drive this form of evolution (sexual attraction or specialisation in lifestyle, diet or other ecological factors)? Senior author, Professor George Turner of the School of Biological Sciences, Bangor University said: "The idea of sympatric speciation has divided evolutionary opinion for a long time. It has been difficult to substantiate that new species can arise when genetic variations can be exchanged easily between the two evolving groups. But we have caught this form of evolution in the act by identifying two different forms of cichlid fish that are separating from each other within a lake that is only 700m wide." Cichlid fish are a valuable model of evolution. In nearby Lake Malawi, many hundreds of cichlid species have been found, differentiated by size, shape, colour, feeding habits and ecological preferences such as living towards the surface of the lake or at the bottom. Because of this vast diversity the lake is known as 'Darwin's Pond'. In contrast Lake Massoko is 'Darwin's puddle': a much simpler place with many fewer species and fewer factors to drive speciation. In the lake, researchers discovered two significantly different forms (ecomorphs) of a common species of cichlid fish. One ecomorph – known as littoral – has yellow-green males and lives towards the shores of the lake. The other form – benthic – has dark blue-black males and lives towards the bottom of the lake where the light levels are much lower. There are many other measurable differences between the ecomorphs, for example in body shape, jaws and diet. These differences are reflected in the genetic differences observed when whole genomes from the two ecomorphs were sequenced and compared. The majority of significant genetic variation lay in a small number of genomic regions associated with sight (such as rhodopsin and other twilight-associated genes), hormone signalling, size and shape. First author Dr Milan Malinsky of the Wellcome Trust Sanger Institute and the Gurdon Institute, University of Cambridge said: "One of the most striking characteristics of this diversification is that less than 1 per cent of the genome appears to be involved. Previous expectations were that speciation involved changes across the whole genome. However, in this example of nascent sympatric speciation, we find that the differences are confined to localised regions of the genome – known as genomic islands – that are associated with specific traits." Confusingly, no single factor – either genetic or physical – seems to separate the two morphs: although they prefer different depths, the yellow and blue fish are frequently found together. One theoretical model for sympatric speciation is that sexual selection can reinforce differences via mate preference. The investigators also carried out mate-choice experiments between the ecomorphs in a controlled laboratory setting and found some differences, but again not enough to explain the separation by themselves. Senior author, Dr Martin Genner of Bristol's School of Biological Sciences said: "We seem to be seeing a complex combination of ecological separation and mate-choice preference that jointly has allowed the two ecomorphs to separate even in the presence of some genetic exchange. These fish have much to tell us." An exciting prospect is that these findings in a simple system will be relevant to understanding the much richer and more dramatic evolutionary radiation in Lake Malawi and the other African great lakes, and indeed beyond. Senior author, Dr Richard Durbin from the Sanger Institute said: "The same genes are found in many species, both in fish and in other vertebrates. So the mechanisms at work in Lake Massoko are likely to have been involved in speciation more widely over history, driving evolution in which species can separate genetically to exploit new ecological niches even when there is no physical separation." More information: M. Malinsky et al. Genomic islands of speciation separate cichlid ecomorphs in an East African crater lake, Science (2015). DOI: 10.1126/science.aac9927

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