Daily Archives: April 7, 2017

April 6, 2017 A depiction of the double helical structure of DNA. Its four coding units (A, T, C, G) are color-coded in pink, orange, purple and yellow. Credit: NHGRI

The DNA molecules in each one of the cells in a person's body, if laid end to end, would measure approximately two metres in length. Remarkably, however, cells are able to fold and compact their genetic material in the confined space of the nucleus, which spans only a few micrometres. Importantly, the compaction and arrangement of the genome inside the nucleus needs to be achieved in an ordered fashion that still allows cells to access the genetic information appropriately, for example to produce messenger RNAs for specific proteins, or to replicate the genetic material prior to cell division. When mutations occur that disrupt features associated with the spatial organisation of the genome, this leads to developmental disorders and cancer.

Scientists have had a long-standing interest in examining the spatial organisation of the genome in the cell's nucleus, mostly using microscopy techniques. Recent advances in genomic techniques to measure the 3D organisation of the genome have allowed for an increased resolution of this organisation. However, when the genome gains 3D organisation during development is not known. Now, using early development fruit fly embryos and genomic techniques to measure 3D genome organisation, scientists of the Research Group 'Regulatory Genomics' at the Max Planck Institute for Molecular Biomedicine in Muenster have shown that the 3D organisation of the genome emerges when the early embryo switches on its own genetic programme.

A common image of the cell's genetic material is the rod-like structures of mitotic chromosomes. However, those only exist while cells are undergoing cell division. The rest of the time, the genetic material is found in the form of chromatin fibres - DNA molecules densely wrapped around histone proteins - which are less densely compacted than mitotic chromosomes and occupy the nuclear space.

"One could think of this as a plate of spaghetti, where each individual piece of pasta would correspond to the DNA molecule in each chromosome", says Juanma Vaquerizas, head of the Max Planck Research Group 'Regulatory Genomics' at the Max Planck Institute for Molecular Biomedicine, who led the study. "A fundamental question in the field was whether each spaghetti would randomly mingle with other pieces of pasta or whether they would occupy a defined space within the plate."

Using microscopy approaches, scientists had determined before that the location of chromatin in the nucleus was not random, and recent advances in our ability to measure chromatin architecture have shown that finer structures, called topologically associating domains (TADs), form part of the basic functional units that determine the 3D organisation of the genome. However, a very puzzling observation has been that when the TAD organisation of the genome is examined in different cell types in an organism or in conserved regions of the DNA between species, this seems to be very similar across samples, despite different parts of the genome being actively used in different cell types. This prompted Clemens Hug and Juanma Vaquerizas to address the question of when during organismal development chromatin architecture is established.

The team turned to early development of fruit flies to perform their experiments. "An amazing feature about fruit fly embryonic development is that upon fertilization, the nuclei synchronously divide every 10-15 minutes for thirteen times without gene activation", says Vaquerizas. Maternally deposited mRNAs and proteins make sure that differentiation and development occur during those initial nuclear cycles. Then, at nuclear cycle 14 - only 2,5 hours after fertilization - the embryonic genome is activated. "Thus, in fruit flies, we can accurately study early chromatin organization at a high temporal resolution", says Vaquerizas.

The choice of organism and its developmental timing proved critical for the researchers' experiments, since this allowed them to examine 3D genome organisation in nuclei at a stage when transcription is naturally not occurring, and by doing so, decouple genome organisation from the effects of transcription.

By using state-of the-art genomic analyses, the scientists were able to study chromatin organization at a very high spatial resolution. Clemens Hug, PhD student and first author of the study, explains the method they used: "The so-called in situ Hi-C technique allows us to accurately identify those parts of the DNA that interact with each other in the three-dimensional nuclear space and the extent of interaction throughout the genome. We are therefore able to capture the 3D organization of the chromatin at a certain time point and can reveal changes in organisation across early development stages." Strikingly, the team found that at early stages of development the genome lacks defined higher-order chromatin organisation, and that 3D architecture progressively emerges in later stages.

"We found that TAD boundaries - defining functionally distinct chromatin units - arise when the first zygotic genes are transcribed. The number of TAD boundaries reaches a plateau when the complete zygotic genome has been activated", says Hug. "These boundaries are occupied by housekeeping genes that are constantly transcribed in all cell types. Once established, these are maintained throughout development." This is an important finding since it helps explain why the TAD organisation of genomes is similar across tissue types and evolutionary conserved regions between species.

However, the scientists could demonstrate that the establishment of TAD boundaries is independent of transcription itself, despite being associated with transcriptionally active regions. "This is of interest since it suggests that the machinery or mechanisms leading to transcription might play a role in TAD boundary establishment", says Hug. The scientists observed that Zelda, a pioneer transcription factor protein that opens the chromatin so that the transcription machinery can access the DNA, is necessary to establish some TAD boundaries. "We therefore think that Zelda and maybe other proteins with a similar function, in concert with RNA Pol II, create the TAD boundaries and thus are responsible for the 3D chromatin architecture", says Hug.

"When the proteins that determine TAD boundaries - and thus are critical for the chromatin architecture - are disrupted, this can result in distinct developmental disorders and cancer", says Vaquerizas. "Our newly gained insights into how the 3D chromatin architecture is established and maintained will thus have a major impact on further studies looking at its impact on gene expression during development and disease."

Explore further: Scientists reveal hidden structures in bacterial DNA

More information: Clemens B. Hug, Alexis G. Grimaldi, Kai Kruse and Juan M. Vaquerizas. Chromatin architecture emerges during zygotic genome activation independent of transcription. Cell 169: 216-228, April 6th, 2017, DOI: 10.1016/j.cell.2017.03.024

Journal reference: Cell

Provided by: Max Planck Society

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Nuclear architecture emerges at the awakening of the genome - Phys.Org

Octopus, squid, and cuttlefish are famous for engaging in complex behavior, from unlocking an aquarium tank and escaping to instantaneous skin camouflage to hide from predators. A new study suggests their evolutionary path to neural sophistication includes a novel mechanism: Prolific RNA editing at the expense of evolution in their genomic DNA.

The study, led by Joshua J.C. Rosenthal of the Marine Biological Laboratory (MBL), Woods Hole and Eli Eisenberg and Noa Liscovitch-Brauer of Tel Aviv University, is published this week in Cell.

The research builds on the scientists' prior discovery that squid display an extraordinarily high rate of editing in coding regions of their RNA -- particularly in nervous system cells -- which has the effect of diversifying the proteins that the cells can produce. (More than 60 percent of RNA transcripts in the squid brain are recoded by editing, while in humans or fruit flies, only a fraction of 1 percent of their RNAs have a recoding event.)

In the present study, the scientists found similarly high levels of RNA editing in three other "smart" cephalopod species (two octopus and one cuttlefish) and identified tens of thousands of evolutionarily conserved RNA recoding sites in this class of cephalopods, called coleoid. Editing is especially enriched in the coleoid nervous system, they found, affecting proteins that are the key players in neural excitability and neuronal morphology.

In contrast, RNA editing in the more primitive cephalopod Nautilus and in the mollusk Aplysia occurs at orders of magnitude lower levels than in the coleoids, they found. "This shows that high levels of RNA editing is not generally a molluscan thing; it's an invention of the coleoid cephalopods," Rosenthal says. In mammals, very few RNA editing sites are conserved; they are not thought to be under natural selection. "There is something fundamentally different going on in these cephalopods where many of the editing events are highly conserved and show clear signs of selection," Rosenthal says.

The scientists also discovered a striking trade-off between high levels of RNA recoding and genomic evolution in these cephalopods. The most common form of RNA editing is carried out by ADAR enzymes, which require large structures (dsRNA) flanking the editing sites. These structures, which can span hundreds of nucleotides, are conserved in the coleoid genome along with the editing sites themselves. The genetic mutation rate in these flanking regions is severely depressed, the team reported.

"The conclusion here is that in order to maintain this flexibility to edit RNA, the coleoids have had to give up the ability to evolve in the surrounding regions -- a lot," Rosenthal says. "Mutation is usually thought of as the currency of natural selection, and these animals are suppressing that to maintain recoding flexibility at the RNA level."

Rosenthal and colleagues at the MBL are currently developing genetically tractable cephalopod model systems to explore the mechanisms and functional consequences of their prolific RNA editing. "When do they turn it on, and under what environmental influences? It could be something as simple as temperature changes or as complicated as experience, a form of memory," he says.

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Materials provided by Marine Biological Laboratory. Original written by Diana Kenney. Note: Content may be edited for style and length.

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Octopuses, Squid Defy Genetics' 'Central Dogma' - Science Daily

Amongst the potential causes for the decline in honey bee colonies, pathogens and parasites of the honey bee, particularly mites, are considered major threats to honey bee health and colonies. Now scientists at the University of Liverpool and Xian Jiaotong-Liverpool University (XJTLU) have sequenced the genome of the bee mite Tropilaelaps mercedesae to assess the interaction between the parasite and host. The results provide resources for control developing gene-based control strategies, determining the weak points for conventional methods, and identifying new targets for biological control.

T. mercedesae is a honey bee parasite prevalent in most Asian countries, and has a similar impact on bee colonies that the globally-present bee mite Varroa destructor has. More, T. mercedesae and V. destructor typically co-exist in Asian bee colonies and with the global trade of honey bees T. mercedesae is likely to become established world-wide.

Dr Alistair Darby, from the Universitys Centre for Genomic Research where said: The genome sequence data and research findings provide useful resources for understanding mite biology and identifying potential gene-based mite control strategies.

Of particular interest, the team found that the mite does not rely on sensing stimulatory chemicals to affect their behaviour, meaning that current control methods targeted to gustatory, olfactory and ionotropic receptors are not effective. The researchers also found that T. mercedesae is enriched with detoxifying enzymes and pumps for the toxic xenobiotics, which means the mite can quickly acquire miticide resistance.

Relevant to this, the researchers investigated the bacteria that infect the bee mite, of which little is known. The scientists discovered that the symbiotic Rickettsiella grylli-like bacteria is commonly present in T. mercedesae and suggest that manipulating this bacteria could help in the development of novel control strategiesin the battle to save bee colonies.

The extent of honey bee colony destruction remains a complex problem, but one that has an extensive impact on crop productivity since honey bees are needed for pollination of a variety of plants. The findings, genome, transcriptome, and proteome data from this T. mercedesae study add an important new resource in the battle to save bee colonies.

Draft genome of the honey bee ectoparasite mite, Tropilaelaps mercedesae, is shaped by the parasitic life history is published in GigaScience.

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