Cancer genomics: Modelling instability

Glitter of gold traps microparticles, Gene copy number and risk of autoimmunity, A red-letter day for brain connectivity, Skin barrier formation and caspase-14, Control of all fates, The dual role of BRCA2 in DNA repair, Deciphering the histone code


For papers that will be published online on 21 May 2007

This press release is copyrighted to the Nature journals mentioned below.

This press release contains:

· Summaries of newsworthy papers:

Cancer genomics: Modelling instability – Nature

Glitter of gold traps microparticles – Nature Physics

Gene copy number and risk of autoimmunity – Nature Genetics

A red-letter day for brain connectivity – Nature Neuroscience

Skin barrier formation and caspase-14 – Nature Cell Biology

Control of all fates – Nature Cell Biology

The dual role of BRCA2 in DNA repair – Nature Structural and Molecular Biology

Deciphering the histone code – Nature Methods

· Mention of papers to be published at the same time with the same embargo

· Geographical listing of authors

PDFs of all the papers mentioned on this release can be found in the relevant journal’s section of Press contacts for the Nature journals are listed at the end of this release.

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[1] Cancer genomics: Modelling instability

DOI: 10.1038/nature05886

A mouse model that for the first time mimics the levels of genomic instability in human cancers is presented online in Nature this week. The authors show that mouse and human tumours show similar genetic alterations, and suggest that future research should use this mouse model to understand the genetics of human cancer better.

Ronald DePinho and colleagues engineered lymphoma-prone mice with chromosomal instability to assess the usefulness of mouse models in cancer gene discovery. Using a comparative genomics approach they identified mutated genes in the model that are also altered in human T-cell acute lymphoblastic lymphomas and/or in a diverse range of other tumours. The researchers demonstrate a complexity and comparability in the human and mouse oncogenes that they believe means mouse models of tumours with a high degree of genomic instability will be a valuable resource for investigating complex human cancer genomes.

Author contact:

Ronald A DePinho (Dana Farber Cancer Institute, Boston, MA, USA)
Tel: +1 617 632 6085; E-mail: [email protected]

Other papers from Nature to be published online at the same time and with the same embargo:

[2] Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance

DOI: 10.1038/nature05894

[3] Rewiring cellular morphology pathways with synthetic guanine nucleotide exchange factors

DOI: 10.1038/nature05851

************************NATURE PHYSICS*****************************************

[4] Glitter of gold traps microparticles

DOI: 10.1038/nphys624

A simple technique for trapping suspended microparticles with a laser-illuminated array of gold microdots is demonstrated by Romain Quidant and colleagues online this week in Nature Physics. The technique could prove useful for manipulating living cells in ‘lab-on-a-chip’ microfluidic systems.

Until now, the most promising approach to controlling cells and other micrometre-sized particles suspended in a liquid has been with so-called optical tweezers. These devices exploit the fact that such particles are attracted to and can be trapped by a focused light field. But one of their drawbacks is that they are bulky and complex devices to set up.

The technique demonstrated by Quidant and colleagues is much simpler. It relies on the fact that when a gold microdot or other metallic microstructure is illuminated with light, it will concentrate the optical field in its vicinity, similar in effect to the focusing power of a lens. By setting out an array of gold microdots on a glass slide and illuminating it with a laser, the authors effectively create an array of optical tweezers, which they use to trap microparticles suspended in a fluid droplet placed on the slide. Moreover, they show that they can use the array to selectively trap particles of a specific size from a collection of two different sizes, by controlling the size of the gold dots.

Author contact:

Romain Quidant (Institut de Ciencies Fotoniques, Barcelona, Spain)

Tel: +34 93 55 34 076; E-mail: [email protected]

Other papers from Nature Physics to be published online at the same time and with the same embargo:

[5] Order-by-disorder and spiral spin liquid in frustrated diamond-lattice antiferromagnets

DOI: 10.1038/nphys622

*************************NATURE GENETICS **************************************

[6] Gene copy number and risk of autoimmunity

DOI: 10.1038/ng2046

Individuals with fewer than two copies of the gene FCGR3B are more susceptible to a variety of autoimmune disorders, including lupus, according to a study to be published online this week in Nature Genetics.

Evidence is accumulating that, in addition to gene mutations, variation in the actual number of copies of individual genes can influence susceptibility to common diseases. It was previously shown that variation in the copy number of FCGR3B, a cell-surface receptor that contributes to the protective functions of the immune system, is associated with susceptibility to a kidney disease called glomerulonephritis. Timothy Aitman and colleagues now report that FCGR3B copy number variation is associated more broadly with autoimmune disorders, including lupus, microscopic polyangiitis, and Wegener’s granulomatosis. The small group of individuals who have no copies of FCGR3B have a dramatically elevated risk of autoimmune disease. This is among the first demonstrations that common naturally occurring variation in gene copy number can influence human susceptibility to disease.

Author contact:

Timothy Aitman (Imperial College, London, UK)

Tel: +44 208 383 4253; E-mail: [email protected]

Other papers from Nature Genetics to be published online at the same time and with the same embargo:

[7] Tissue-specific transcriptional regulation has diverged significantly between human and mouse

DOI: 10.1038/ng2047

***********************NATURE NEUROSCIENCE ***********************************

[8] A red-letter day for brain connectivity

DOI: 10.1038/nn1906

Insights into grapheme-colour synesthesia are presented in a paper in the June issue of Nature Neuroscience. People with this condition – who see a cascade of colours associated with individual letters when looking at a page of text – appear to have more neural connections in areas of the brain involved in word processing and binding perceptions together.

Romke Rouw and Steven Scholte used a technique called diffusion tensor imaging (DTI) to look at brain differences between grapheme-colour synesthetes and healthy controls without this condition. DTI allows non-invasive visualisation of the white matter tracts, or axons, connecting neural cell bodies. The researchers found that synesthetes had more axons connecting three brain areas: the right fusiform gyrus, near regions involved in word and colour processing, and the left intraparietal sulcus and frontal cortex, both part of a network of regions involved in binding and consciousness.

The study also found differences among the synesthetes, according to how they perceived the association between words and colours. Some synesthetes, known as projectors, report stronger experiences that are projected into the external world, while others, known as associators, report weaker experiences that appear in their ‘mind’s eye’. The degree of structural connectivity in a region known as the right temporal cortex was correlated with the strength of the synesthetic experience. These results suggest a two-stage model of synesthesia, with increased connectivity in some areas being important for generating perceptual binding, and connectivity in other areas determining the intensity of the resultant perceptions.

Author contact:

Romke Rouw (University of Amsterdam, The Netherlands)
Tel: +31 20 525 6742; E-mail: [email protected]

Additional contact for comment on paper:

Edward Hubbard (INSERM, Gif-Sur-Yvette, France)
Tel: +33 1 69 86 78 48; E-mail: [email protected]

Other papers from Nature Neuroscience to be published online at the same time and with the same embargo:

[9] BDNF induces transport of PSD-95 to dendrites through PI3K-AKT signaling after NMDA receptor activation
DOI: 10.1038/nn1903

[10] Multiple climbing fibers signal to molecular layer interneurons exclusively via glutamate spillover
DOI: 10.1038/nn1907

[11] Supralinear increase of recurrent inhibition during sparse activity in the somatosensory cortex
DOI: 10.1038/nn1909

[12] Shape conveyed by visual-to-auditory sensory substitution activates the lateral occipital complex
DOI: 10.1038/nn1912

**********************NATURE CELL BIOLOGY ************************************

[13] Skin barrier formation and caspase-14

DOI: 10.1038/ncb1597

A protein known as caspase-14 has been identified as the enzyme involved in the protection of the skin against UVB damage and water loss, according to a study published online this week in Nature Cell Biology.

The involvement of caspase-family members in programmed cell death and inflammation is well understood but, a function for caspase-14 had previously not been identified. Using caspase-14 knockout mice, Wim Declercq and colleagues show that caspase-14 is responsible for the initial processing of profillagrin to fillagrin. Fillagrin is responsible for aggregating keratin and other proteins in the upper layers of the epidermis to form the stratum corneum – a layer of flattened dead-cell remnants that creates a protective barrier for the skin. The controlled processing of profillagrin to produce fillagrin ultimately maintains the integrity of the epidermis. In mice lacking caspase-14, their skin exhibits a defective stratum corneum and is more sensitive to water loss and UVB photodamage.

The identification of caspase-14 and its role in skin-barrier formation opens avenues for the pharmaceutical manipulation of this process to prevent the damage induced by UVB, the primary agent responsible for sunburn and skin ageing.

Author contact:

Wim Declercq (Ghent University, Belgium)

Tel: +32 9 33 13 660; E-mail: [email protected]

[14] Control of all fates

DOI: 10.1038/ncb1589

A study in the June issue of Nature Cell Biology investigates how pluripotency, the ability of a stem cell to differentiate into every cell type of the adult organism, is regulated.

Understanding how stem cells maintain their pluripotent state has involved the characterisation of a multitude of transcription factors – the proteins that determine whether a specific gene is expressed or not. Pluripotency in embryonic stem cells was thought to be controlled primarily by the transcription factors Oct3/4 and Sox2, as these proteins were believed to activate Oct-Sox enhancers – regulatory regions that determine the expression of pluripotent stem cell-specific genes. Shinji Masui and colleagues used mutant mice lacking the Sox2 gene to show that although Sox2 is needed for stem cell pluripotency, it is not required for the enhancers to function and in fact governs the expression of Oct3/4. The authors went on to show that this regulation is indirect, as Sox2 controls the expression of a number of transcription factors that in turn regulate Oct3/4 expression.

This study illustrates the precise regulation of pluripotency by key proteins, and reorders the hierarchy of these factors with Sox2 as the master regulator — another small step towards a complete understanding of stem cell biology.

Author contact:

Shinji Masui (International Medical Centre of Japan, Tokyo, Japan)
Tel: +81 3 3202 7181; E-mail: [email protected]

Other papers from Nature Cell Biology to be published online at the same time and with the same embargo:

[15] Rad3-dependent phosphorylation of the checkpoint clamp regulates repair-pathway choice

DOI: 10.1038/ncb1600

****************NATURE STRUCTURAL AND MOLECULAR BIOLOGY************************

[16] & [17] The dual role of BRCA2 in DNA repair

DOI: 10.1038/nsmb1245

DOI: 10.1038/nsmb1251

The dual role of the gene BRCA2 in DNA repair is described in two independent studies in the June issue of Nature Structural & Molecular Biology. The studies from Stephen West’s and Luca Pellegrini’s groups shed light on the role of the gene, mutations of which result in predisposition to breast cancer and other malignancies.

The protein encoded by BRCA2 is involved in homologous recombination, a process whereby damaged DNA is repaired using an intact copy of DNA as a template. This process also includes the protein RAD51, which interacts directly with two different regions of BRCA2, called BRC and TR2. The BRC region had been previously suggested to be involved in terminating homologous recombination. Data from the two present studies indicate that the TR2 region can oppose the activity of BRC, suggesting that BRCA2 contains regions that both favor and disrupt homologous recombination. These activities might operate at different stages of DNA repair.

Both reports also provide insight into how the opposing activities of BRCA2 can be regulated – a phosphorylation event at TR2 results in the loss of its interaction with RAD51, acting as a turn-off switch. These findings advance our knowledge of BRCA2’s role in genetic stability, and contribute to our understanding of why mutations in BRCA2 increase the likelihood of cancer.

Author contacts:

Stephen West (Cancer Research UK, London, UK) Author paper [16]

Tel: +44 1707 625 868; E-mail: [email protected]

Luca Pellegrini (University of Cambridge, UK) Author paper [17]

Tel: +44 1223 333 662; E-mail: [email protected]

Other papers from Nature Structural & Molecular Biology to be published online at the same time and with the same embargo:

[18] Structural basis for the transforming activity of human cancer-related signaling adaptor protein CRK

DOI: 10.1038/nsmb1241

[19] The antibiotic viomycin traps the ribosome in an intermediate state of translocation

DOI: 10.1038/nsmb1243

[20] The redox-switch domain of Hsp33 functions as dual stress sensor

DOI: 10.1038/nsmb1244

**********************NATURE METHODS******************************************

[21] Deciphering the histone code

DOI: 10.1038/nmeth1052

A method to identify all modifications on histones, the proteins around which DNA is packed, is presented online this week in Nature Methods. This study should allow researchers a better understanding of how genes are regulated by alterations to these proteins.

DNA holds all the information for the building blocks of life, but how a cell reads this genetic information depends on histones, and in particular on modifications to these histones. For example, the attachment of methyl groups to histones usually signals that a gene is silent, whereas the attachment of acetyl groups corresponds to gene activation. Scientists have dubbed the combinatorial use of histone modifications the ‘histone code’, but the extent to which different modifications are combined in the histone code is still unknown.

To help crack the code, Neil Kelleher and colleagues devised a method to identify all the possible modifications that occur on histones in a cell. First they separated different histone variants, depending on their degree of acetylation and methylation, by hydrophilic interaction chromatography, then they applied high-resolution tandem mass spectroscopy to identify all modifications on each variant and the exact residues carrying them. By using a mass spectrometry technique known as ‘top down,’ in which intact proteins are fragmented inside the mass spectrometer, they observed better preservation of modifications than traditional mass spectrometry methods looking at pre-digested proteins. For one particular histone alone, they found over 150 different patterns of modification.

This method helps to decipher the elements that make up the histone code and will allow researchers to relate the pattern of these modifications to the regulation of gene activity.

Author contact:

Neil Kelleher (University of Illinois at Urbana-Champaign, IL, USA)

Tel: +1 217 333 5071; E-mail: [email protected]


Items from other Nature journals to be published online at the same time and with the same embargo:


[22] Hierarchical architectures by synergy between dynamical template self-assembly and biomineralization

DOI: 10.1038/nmat1912

[23] Origin and control of high-temperature ferromagnetism in semiconductors

DOI: 10.1038/nmat1910

[24] Nanoscale heterogeneity promotes energy dissipation in bone

DOI: 10.1038/nmat1911

[25] Modulus–density scaling behaviour and framework architecture of nanoporous, self-assembled silicas

DOI: 10.1038/nmat1913

[26] Enhanced ethanol production inside carbon-nanotube reactors containing catalytic particles

DOI: 10.1038/nmat1916


[27] Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia

DOI: 10.1038/nm1579

[28] Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia

DOI: 10.1038/nm1588

[29] Restoration of cone vision in a mouse model of achromatopsia

DOI: 10.1038/nm1596

[30] Neutralization of staphylococcal enterotoxin B by soluble, high-affinity receptor antagonists

DOI: 10.1038/nm1584


[31] Decoding global gene expression programs in liver cancer by noninvasive imaging

DOI: 10.1038/nbt1306

[32] A universal RNAi-based logic evaluator that operates in mammalian cells

DOI: 10.1038/nbt1307

[33] Engineering synthetic signaling proteins with ultrasensitive input/output control

DOI: 10.1038/nbt1308



The following list of places refers to the whereabouts of authors on the papers numbered in this release. The listing may be for an author's main affiliation, or for a place where they are working temporarily. Please see the PDF of the paper for full details.

Brussels: 13

Ghent: 13

Leuven: 13

Dalian: 26
Hong Kong: 31


Gif-sur-Yvette: 22

Grenoble: 22

Lille: 6

Orsay: 28

Paris: 6, 10, 28

Rennes: 22

Toulouse: 4, 22


Berlin: 12

Garching: 20

Halle: 20

Martinsried: 11

Haifa: 1

Jerusalem: 12

Rehovot: 31


Ibaraki: 23

Kobe: 14

Saitama: 14

Sapporo: 18

Tokyo: 14


Amsterdam: 8

Eindhoven: 12


Warsaw: 23


Cape Town: 2

Pretoria: 23


Barcelona: 4, 22


Zurich: 5


Birmingham: 6

Brighton: 15

Cambridge: 7, 17

London: 1, 6

Newcastle: 6

South Mimms: 16



Berkeley: 33

Davis: 24

La Jolla: 11

Los Angeles: 31

Palo Alto: 1

San Diego: 31

San Francisco: 3, 31, 33

Santa Barbara: 5

Santa Cruz: 19

Stanford: 2, 15, 31


Gainesville: 29


Urbana: 19, 21, 30


Bar Harbor: 29


Baltimore: 14

Bethesda: 19

Gaithersburg: 30

Silver Spring: 20


Boston: 1, 9, 12

Cambridge: 7, 9, 24, 32

Watertown: 30


Ann Arbor: 20


Minneapolis: 30


St Louis: 27

New Jersey

Princeton: 25, 32

New Mexico

Albuquerque: 25

New York

New York: 1, 2, 3

Stony Brook: 3

Syracuse: 29


Cleveland: 25


Fort Worth: 29

Houston: 27


Charlottesville: 16


Seattle: 13


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Katherine Anderson (Nature London)

Tel: +44 20 7843 4502; E-mail: [email protected]

Ruth Francis (Senior Press Officer, Nature, London)

Tel: +44 20 7843 4562; E-mail: [email protected]

For media inquiries relating to editorial content/policy for the Nature Research Journals, please contact the journals individually:

Nature Biotechnology (New York)

Peter Hare

Tel: +1 212 726 9284; E-mail: [email protected]

Nature Cell Biology (London)

Bernd Pulverer

Tel: +44 20 7843 4892; E-mail: [email protected]

Nature Genetics (New York)

Orli Bahcall

Tel: +1 212 726 9311; E-mail: [email protected]

Nature Materials (London)

Maria Bellantone

Tel: +44 20 7843 4556; E-mail: [email protected]

Nature Medicine (New York)

Juan Carlos Lopez

Tel: +1 212 726 9325; E-mail: [email protected]

Nature Methods (New York)

Allison Doerr

Tel: +1 212 726 9393; E-mail: [email protected]

Nature Neuroscience (New York)

Sandra Aamodt (based in California)

Tel: +1 530 795 3256; E-mail: [email protected]

Nature Physics (London)

Alison Wright

Tel: +44 20 7843 4555; E-mail: [email protected]

Nature Structural & Molecular Biology (New York)

Michelle Montoya

Tel: +1 212 726 9326; E-mail: [email protected]

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Published: 21 May 2007

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Cancer Research