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Drug resistance is a major hurdle in oncology. Responses of acute myeloid leukaemia (AML) patients to cytarabine (Ara-C)-based therapies are often short lived with a median overall survival of months [...]

Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) that is initiated when self-reactive T cells enter the brain and become locally activated after encountering their specific [...]

Hepatitis C virus (HCV) interacts extensively with host factors to not only establish productive infection but also trigger unique pathological processes. Our recent genome-wide siRNA screen demonstrated that IκB kinase-α [...]

Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration, which ultimately leads to paralysis and death. Mutation of TAR DNA binding protein 43 (TDP-43) has been linked to the development of an inherited form of ALS. Existing TDP-43 transgenic animals develop a limited loss of motor neurons and therefore do not faithfully reproduce the core phenotype of ALS. Here, we report the creation of multiple lines of transgenic rats in which expression of ALS-associated mutant human TDP-43 is restricted to either motor neurons or other types of neurons and skeletal muscle and can be switched on and off. All of these rats developed progressive paralysis reminiscent of ALS when the transgene was switched on. Rats expressing mutant TDP-43 in motor neurons alone lost more spinal motor neurons than rats expressing the disease gene in varying neurons and muscle cells, although these rats all developed remarkable denervation atrophy of skeletal muscles. Intriguingly, progression of the disease was halted after transgene expression was switched off; in rats with limited loss of motor neurons, we observed a dramatic recovery of motor function, but in rats with profound loss of motor neurons, we only observed a moderate recovery of motor function. Our finding suggests that mutant TDP-43 in motor neurons is sufficient to promote the onset and progression of ALS and that motor neuron degeneration is partially reversible, at least in mutant TDP-43 transgenic rats., Introduction Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons and denervation atrophy of skeletal muscles. The disease inexorably progresses to paralysis and to death, often within [...]

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function., The model organism Encyclopedia of DNA Elements (modENCODE) project is generating a comprehensive map of chromatin components, transcription factors, transcripts, small RNAs and origins of replication in Drosophila melanogaster and [...]

Although recurrent gene fusions involving erythroblastosis virus E26 transformation-specific (ETS) family transcription factors are common in prostate cancer, their products are considered 'undruggable' by conventional approaches. Recently, rare targetable gene fusions involving the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, have been identified in 1-5% of lung cancers (1), suggesting that similar rare gene fusions may occur in other common epithelial cancers, including prostate cancer. Here we used paired-end transcriptome sequencing to screen ETS rearrangement--negative prostate cancers for targetable gene fusions and identified the SLC45A3-BRAF (solute carrier family 45, member 3-v-raf murine sarcoma viral oncogene homolog B1) and ESRP1-RAF1 (epithelial splicing regulatory protein-1-v-raf-1 murine leukemia viral oncogene homolog-1) gene fusions. Expression of SLC45A3-BRAF or ESRP1-RAF1 in prostate cells induced a neoplastic phenotype that was sensitive to RAF and mitogen-activated protein kinase kinase (MAP2K1) inhibitors. Screening a large cohort of patients, we found that, although rare, recurrent rearrangements in the RAF pathway tend to occur in advanced prostate cancers, gastric cancers and melanoma. Taken together, our results emphasize the key role of RAF family gene rearrangements in cancer, suggest that RAF and MEK inhibitors may be useful in a subset of gene fusion--harboring solid tumors and demonstrate that sequencing of tumor transcriptomes and genomes may lead to the identification of rare targetable fusions across cancer types., Recurrent gene fusions characterized by 5' genomic regulatory elements (most commonly controlled by androgens) fused to members of the ETS family of transcription factors are present in at least half [...]

The freshwater cnidarian Hydra was first described in 1702 (1) and has been the object of study for 300 years. Experimental studies of Hydra between 1736 and 1744 culminated in the discovery of asexual reproduction of an animal by budding, the first description of regeneration in an animal, and successful transplantation of tissue between animals (2).Today, Hydra is an important model for studies of axial patterning (3), stem cell biology (4) and regeneration (5).Here were port the genome of Hydra magnipapillata and compare it to the genomes of the anthozoan Nematostella vectensiS (6) and other animals. The Hydra genome has been shaped by bursts of transposable element expansion, horizontal gene transfer, trans-splicing, and simplification of gene structure and gene content that parallel simplification of the Hydra life cycle. We also report the sequence of the genome of a novel bacterium stably associated with H. magnipapillata. Comparisons of the Hydra genome to the genomes of other animals shed light on the evolution of epithelia, contractile tissues, developmentally regulated transcription factors, the Spemann-Mangold organizer, pluripotency genes and the neuromuscular junction., The genomic basis of cnidarian evolution has so far been viewed from the perspective of an anthozoan, the sea anemone Nematostella vectensis (6). Hydra is a medusozoan that diverged from [...]

The worldwide epidemic of obesity has increased the urgency to develop a deeper understanding of physiological systems related to energy balance and energy storage, including the mechanisms controlling the development of fat cells (adipocytes). The differentiation of committed preadipocytes to adipocytes is controlled by PPARγ and several other transcription factors (1), but the molecular basis for preadipocyte determination is not understood. Using a new method for the quantitative analysis of transcriptional components, we identified the zinc-finger protein Zfp423 as a factor enriched in preadipose versus non-preadipose fibroblasts. Ectopic expression of Zfp423 in non-adipogenic NIH3T3 fibroblasts robustly activates expression of Pparg in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA (shRNA)-mediated reduction of Zfp423 expression in 3T3-L1 cells blunts preadipocyte Pparg expression and diminishes the ability of these cells to differentiate. Furthermore, both brown and white adipocyte differentiation is markedly impaired in Zfp423-deficient mouse embryos. Zfp423 regulates Pparg expression, in part, through amplification of the BMP signalling pathway, an effect dependent on the SMAD-binding capacity of Zfp423. This study identifies Zfp423 as a transcriptional regulator of preadipocyte determination., There has been great progress in unravelling the transcriptional pathways controlling adipocyte differentiation--the process by which committed preadipose fibroblasts undergo a morphological and biochemical transition into mature adipocytes in response [...]

Recent landmark experiments have shown that transient overexpression of a small number of transcription factors can reprogram differentiated cells into induced pluripotent stem (iPS) cells that resemble embryonic stem (ES) [...]

Since the initial description of induced pluripotent stem (iPS) cells created by forced expression of four transcription factors in mouse fibroblasts, the technique has been used to generate embryonic stem [...]

Tissue macrophages comprise a heterogeneous group of cell types differing in location, surface markers and function (1). Red pulp macrophages are a distinct splenic subset involved in removing senescent red blood cells (2). Transcription factors such as PU.1 (also known as Sfpil) and C/EBPa (Cebpa) have general roles in myelomonocytic development (3,4), but the transcriptional basis for producing tissue macrophage subsets remains unknown. Here we show that Spi-C (encoded by Spic), a PU.1-related transcription factor, selectively controls the development of red pulp macrophages. Spi-C is highly expressed in red pulp macrophages, but not monocytes, dendritic cells or other tissue macrophages. [Spic.sup.-/-] mice have a cell-autonomous defect in the development of red pulp macrophages that is corrected by retroviral Spi-C expression in bone marrow cells, but have normal monocyte and other macrophage subsets. Red pulp macrophages highly express genes involved in capturing circulating haemoglobin and in iron regulation. [Spic.sup.-/-] mice show normal trapping of red blood cells in the spleen, but fail to phagocytose these red blood cells efficiently, and develop an iron overload localized selectively to splenic red pulp. Thus, Spi-C controls development of red pulp macrophages required for red blood cell recycling and iron homeostasis., Spi-C belongs to the Spi subfamily of Ets transcription factors, which includes PU.1 and Spi-B (5,6), and was initially reported to be expressed in B cells (5,7). We compared expression [...]

The lymphatic system plays a key role in tissue fluid regulation and tumour metastasis, and lymphatic defects underlie many pathological states including lymphoedema, lymphangiectasia, lymphangioma and lymphatic dysplasia (1-3). However, [...]

In yeast, the transcription factor Crz1 is dephosphorylated and translocates into the nucleus in response to extracellular calcium. Here we show, using time-lapse microscopy, that Crz1 exhibits short bursts of [...]

The Sox9 transcription factor plays an essential role in promoting chondrogenesis and regulating expression of chondrocyte extracellular-matrix genes. To identify genes that interact with Sox9 in promoting chondrocyte differentiation, we screened a cDNA library generated from the murine chondrogenic ATDC5 cell line to identify activators of the collagen, type II, α 1 (Col2a1) promoter. Here we have shown that paraspeckle regulatory protein 54-kDa nuclear RNA-binding protein ([p54.sup.nrb]) is an essential link between Sox9-regulated transcription and maturation of Sox9-target gene mRNA. We found that [p54.sup.nrb] physically interacted with Sox9 and enhanced Sox9-dependent transcriptional activation of the Col2a1 promoter. In ATDC5 cells, [p54.sup.nrb] colocalized with Sox9 protein in nuclear paraspeckle bodies, and knockdown of [p54.sup.nrb] suppressed Sox9-dependent Col2a1 expression and promoter activity. We generated a [p54.sup.nrb] mutant construct lacking RNA recognition motifs, and overexpression of mutant [p54.sup.nrb] in ATDC5 cells markedly altered the appearance of paraspeckle bodies and inhibited the maturation of Col2a1 mRNA. The mutant [p54.sup.nrb] inhibited chondrocyte differentiation of mesenchymal cells and mouse metatarsal explants. Furthermore, transgenic mice expressing the mutant [p54.sup.nrb] in the chondrocyte lineage exhibited dwarfism associated with impairment of chondrogenesis. These data suggest that [p54.sup.nrb] plays an important role in the regulation of Sox9 function and the formation of paraspeckle bodies during chondrogenesis., Introduction Chondrogenesis is an important biological event in endochondral bone development, skeletogenesis, and tissue patterning (1), (2). After condensation of chondrogenic mesenchymal cells, they begin to differentiate into chondrocytes (3). [...]

Abstract: Hyperhomocysteinemia is regarded as an independent risk factor for cardiovascular disorders. Although renal dysfunction or failure is one of the important factors causing hyperhomocysteinemia, the role of homocysteine (Hcy) [...]

Blockade of just one protein is sufficient to change skin cells into neurons. Several research groups have already converted one cell type to another by adding, for example, specific genes. [...]

PLoS Biol. 6, e38 (2008) Evolution has massively rewired molecular circuits controlling gene expression in yeast, Hao Li and Alexander Johnson of the University of California, San Francisco, and their [...]

Author(s): Gerald Crabtree [1] A developmental biologist muses on the magic of the egg. Many biologists, myself included, grew up watching frogs' eggs hatch into tadpoles at the warm surfaces [...]