Articles in 2009

Editing and class switch recombination, two processes in the development of B cells, are thought to be separated in the bone marrow and spleen, respectively. Errors in either of these processes can initiate chromosomal translocations, including those of B cell lymphomas, but collaboration between them may also initiate translocations. Here it is shown that both editing and class switch recombination can occur in peripheral B cells, offering insights into the origin of the translocations observed in certain B cell lymphomas.

A hallmark of stem cells is an open chromatin largely devoid of heterochromatin, but which molecules are required to maintain it is unknown, as well as whether an open chromatin is necessary for the differentiation potential of stem cells. Here, the chromatin remodelling factor Chd1 is shown to be required to maintain the open chromatin state of pluripotent mouse embryonic stem cells and to be essential for the pluripotency of these cells.

Evidence for a single microRNA (miRNA) that can efficiently differentiate multipotent stem cells into a specific lineage or regulate direct reprogramming of cells into an alternative cell fate has been elusive. Two miRNAs, miR-145 and miR-143, are now shown to be co-transcribed in multipotent cardiac progenitors before becoming localized to smooth muscle cells. miR-145 was found to be necessary for myocardin-induced reprogramming of adult fibroblasts and sufficient to induce differentiation of multipotent neural crest stem cells.

By using an integrated GFP transgene to track the major limb tissues during limb regeneration in the salamander Ambystoma mexicanum (the axolotl), it has been possible to demonstrate that each limb tissue produces a different set of progenitors with restricted potential. Thus, the blastema—the collection of cells that regenerates the diverse tissues of the limb—is composed of a heterogeneous collection of restricted progenitor cells instead of dedifferentiated pluripotent cells, as previously thought.

The genetic pathways controlling stem cells are frequently dysregulated during tumorigenesis, with either stimulation of Wnt/β-catenin signalling or overexpression of telomerase sufficient to activate epidermal stem cells in vivo. Here, the telomerase protein component TERT (telomerase reverse transcriptase) is shown to have a role as a transcriptional modulator of the Wnt/β-catenin pathway, revealing a significant level of integration between the two pathways.

A genome-wide screen has identified a frequent region of amplification on chromosome 5p13 in a number of cancer types. Functional studies now identify a protein localized to the Golgi apparatus, GOLPH3, as a novel oncogene affected by this amplification which can transform cells in vitro and lead to tumour formation in vivo. GOLPH3 overexpression activates the mTOR signalling pathway and renders cancer cells sensitive to the drug rapamycin.

The bird hand is thought to derive from the second, third and fourth digits of an ancestral five-digit hand. However, the three-fingered hand of theropod dinosaurs, which are the closest extinct relatives of birds, are thought to derive from the first, second and third digits. The discovery of a small, primitive herbivorous theropod from the Jurassic period of China with a stub of the first digit alongside more developed second, third and fourth digits, sheds light on this problem.

Malaria parasites reside in vacuoles during intracellular infection of erythrocytes and export many proteins into the host cell, a process that is essential for the virulence and viability of Plasmodium. Whereas transport across the parasite membrane is known to rely on the secretory pathway, the transporter responsible for the translocation of proteins across the vacuole membrane is now identified.

MicroRNAs (miRNAs) are short RNAs that are ubiquitous, potent regulators of gene expression; however, as miRNA activity requires base pairing with only 6–8 nucleotides of messenger RNA, predicting target mRNAs is a major challenge. By using a method known as HITS-CLIP, combined with bioinformatic analysis, it has now been possible to demonstrate how the in vivo interactions between miRNAs and the mRNA targets can be validated.

Habitats where environmental change occurs in a reliable order offer microorganisms the opportunity to prepare in advance. Here, in both the bacterium Escherichia coli and the yeast Saccharomyces cerevisiae, stimuli that typically appear early in the ecology of the organism are shown to induce genes that are useful for coping with conditions that normally occur later, a process that is also shown to improve fitness.

During spermiogenesis, canonical histones are largely exchanged for protamines, and whether the rarely retained nucleosomes have any function has been unclear. Here, high-resolution genomic approaches are used to localize the nucleosomes retained in mature human sperm; they are found to be significantly enriched at developmentally important genes and to have distinctive patterns of histone modifications.

Age-related macular degeneration (AMD) is a major cause of blindness. Now, the eosinophil/mast cell chemokine receptor CCR3 is shown to be specifically expressed in choroidal neovascular endothelial cells in humans with AMD, and targeting CCR3 or its ligands in mice inhibits the choroidal neovascularization that underlies AMD. In the mouse model, CCR3 blockade was more effective and less toxic than VEGF-A neutralization, which is currently in clinical use.

Yeast Sir2 deacetylates histone H4 lysine 16 and is known to have a role in ageing, but the exact mechanism is not known. Here, an age-associated decrease in Sir2 abundance is shown to be accompanied by an increase in H4 lysine 16 acetylation and loss of histones in replicatively old yeast cells, resulting in compromised transcriptional silencing.

A class of enzymes known as alkyltransferase-like proteins (ATLs) can protect against alkylation damage to DNA. To gain insight into how this occurs, the structure of a yeast ATL has been solved in the presence and absence of damaged DNA, revealing that ATL flips the alkylated base out of the DNA helix, leaving the lesion to be acted on by proteins of the nucleotide excision repair pathway.

Although the soma ages during life, the germ line of multicellular organisms does not. Here it is shown that Caenorhabditis elegans mutants with increased longevity turn on gene expression programs in somatic tissue that are normally limited to the germ line; this may be the secret behind the increased health and lifespan of these mutant worms.

Amino acid mutations that alter a protein's function can affect the stability of the protein, but these mutations are believed to be 'buffered' by chaperones, or heat-shock proteins-potentially facilitating the acquisition of genetic diversity and the rate of adaptation. Here, the overexpression of bacterial GroEL/GroES chaperonins is found to double the number of accumulating mutations in four different enzymes in vitro.

The generation of patient-specific induced pluripotent stem cells (iPS cells) is thought to hold great therapeutic potential. Here, somatic cells from Fanconi anaemia patients are reprogrammed to pluripotency after correction of the genetic defect, generating patient-specific iPS cells.

The common marmoset is an attractive candidate for transgenic modification, and has potential as a non-human primate animal model in biomedical research. Here, for the first time in non-human primates, an integrated transgene is transmitted through the germ line to the offspring, in which it continues to be expressed.

Variable lymphocyte receptors (VLRs) are used for antigen recognition in jawless vertebrates. Distinctive gene expression profiles for VLRA⁺ and VLRB⁺ lymphocytes in lampreys are now shown to resemble those of mammalian T and B cells, offering insight into the evolution of adaptive immunity.

Candida species are the most common cause of opportunistic fungal infection worldwide. Here, the genomes of six Candida species are sequenced and compared with each other and with related pathogens and non-pathogens; providing insight into the genetic features that underlie the diversity of Candida biology, including pathogenesis and the architecture of mating and meiotic processes.