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  • 1
    Publikationsdatum: 2016-09-03
    Beschreibung: The modulation of chromatin structure is a key step in transcription regulation in mammalian cells and eventually determines lineage commitment and differentiation. USF1/2, Setd1a and NURF complexes interact to regulate chromatin architecture in erythropoiesis, but the mechanistic basis for this regulation is hitherto unknown. Here we showed that Setd1a and NURF complexes bind to promoters to control chromatin structural alterations and gene activation in a cell context dependent manner. In human primary erythroid cells USF1/2, H3K4me3 and the NURF complex were significantly co-enriched at transcription start sites of erythroid genes, and their binding was associated with promoter/enhancer accessibility that resulted from nucleosome repositioning. Mice deficient for Setd1a , an H3K4 trimethylase, in the erythroid compartment exhibited reduced Ter119/CD71 positive erythroblasts, peripheral blood RBCs and hemoglobin levels. Loss of Setd1a led to a reduction of promoter-associated H3K4 methylation, inhibition of gene transcription and blockade of erythroid differentiation. This was associated with alterations in NURF complex occupancy at erythroid gene promoters and reduced chromatin accessibility. Setd1a deficiency caused decreased associations between enhancer and promoter looped interactions as well as reduced expression of erythroid genes such as the adult β-globin gene. These data indicate that Setd1a and NURF complexes are specifically targeted to and coordinately regulate erythroid promoter chromatin dynamics during erythroid lineage differentiation.
    Print ISSN: 0305-1048
    Digitale ISSN: 1362-4962
    Thema: Biologie
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 2
    Publikationsdatum: 2015-11-30
    Beschreibung: In mammals, the cytosine in CG dinucleotides is typically methylated producing 5-methylcytosine (5mC), a chemically less stable form of cytosine that can spontaneously deaminate to thymidine resulting in a T•G mismatched base pair. Unlike other eukaryotes that efficiently repair this mismatched base pair back to C•G, in mammals, 5mCG deamination is mutagenic, sometimes producing TG dinucleotides, explaining the depletion of CG dinucleotides in mammalian genomes. It was suggested that new TG dinucleotides generate genetic diversity that may be critical for evolutionary change. We tested this conjecture by examining the DNA sequence properties of regulatory sequences identified by DNase I hypersensitive sites (DHSs) in human and mouse genomes. We hypothesized that the new TG dinucleotides generate transcription factor binding sites (TFBS) that become tissue-specific DHSs (TS-DHSs). We find that 8-mers containing the CG dinucleotide are enriched in DHSs in both species. However, 8-mers containing a TG and no CG dinucleotide are preferentially enriched in TS-DHSs when compared with 8-mers with neither a TG nor a CG dinucleotide. The most enriched 8-mer with a TG and no CG dinucleotide in tissue-specific regulatory regions in both genomes is the AP-1 motif ( TG A C / G T CA N), and we find evidence that TG dinucleotides in the AP-1 motif arose from CG dinucleotides. Additional TS-DHS-enriched TFBS containing the TG/CA dinucleotide are the E-Box motif (G CA GC TG C), the NF-1 motif (GG CA—TG CC), and the GR (glucocorticoid receptor) motif (G-A CA—TG T-C). Our results support the suggestion that cytosine methylation is mutagenic in tetrapods producing TG dinucleotides that create TFBS that drive evolution.
    Digitale ISSN: 1759-6653
    Thema: Biologie
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 3
    Publikationsdatum: 2012-08-28
    Beschreibung: Achondroplasia (ACH) and thanatophoric dysplasia (TD) are caused by gain-of-function mutations of fibroblast growth factor receptor 3 ( FGFR3 ) and they are the most common forms of dwarfism and lethal dwarfism, respectively. Currently, there are few effective treatments for ACH. For the neonatal lethality of TD patients, no practical effective therapies are available. We here showed that systemic intermittent PTH (1-34) injection can rescue the lethal phenotype of TD type II (TDII) mice and significantly alleviate the retarded skeleton development of ACH mice. PTH-treated ACH mice had longer naso-anal length than ACH control mice, and the bone lengths of humeri and tibiae were rescued to be comparable with those of wild-type control mice. Our study also found that the premature fusion of cranial synchondroses in ACH mice was partially corrected after the PTH (1-34) treatment, suggesting that the PTH treatment may rescue the progressive narrowing of neurocentral synchondroses that cannot be readily corrected by surgery. In addition, we found that the PTH treatment can improve the osteopenia and bone structure of ACH mice. The increased expression of PTHrP and down-regulated FGFR3 level may be responsible for the positive effects of PTH on bone phenotype of ACH and TDII mice.
    Print ISSN: 0964-6906
    Digitale ISSN: 1460-2083
    Thema: Biologie , Medizin
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 4
    Publikationsdatum: 2015-02-26
    Beschreibung: Fibroblast growth factor receptor 3 (FGFR3) plays a critical role in the control of endochondral ossification, and bone growth and mutations that cause hyperactivation of FGFR3 are responsible for a collection of developmental disorders that feature poor endochondral bone growth. FGFR3 is expressed in proliferating chondrocytes of the cartilaginous growth plate but also in chondrocytes that have exited the cell cycle and entered the prehypertrophic phase of chondrocyte differentiation. Achondroplasia disorders feature defects in chondrocyte proliferation and differentiation, and the defects in differentiation have generally been considered to be a secondary manifestation of altered proliferation. By initiating a mutant activated knockin allele of FGFR3 (FGFR3K650E) that causes Thanatophoric Dysplasia Type II (TDII) specifically in prehypertrophic chondrocytes, we show that mutant FGFR3 induces a differentiation block at this stage independent of any changes in proliferation. The differentiation block coincided with persistent expression of SOX9, the master regulator of chondrogenesis, and reducing SOX9 dosage allowed chondrocyte differentiation to proceed and significantly improved endochondral bone growth in TDII. These findings suggest that a proliferation-independent and SOX9-dependent differentiation block is a key driving mechanism responsible for poor endochondral bone growth in achondroplasia disorders caused by mutations in FGFR3.
    Print ISSN: 0964-6906
    Digitale ISSN: 1460-2083
    Thema: Biologie , Medizin
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 5
    Publikationsdatum: 2014-05-24
    Beschreibung: A composite likelihood technique based on pairwise contributions provides a computationally simple but potentially inefficient approach for fitting spatial point process models. We propose a new estimation procedure that improves the efficiency. Our approach combines estimating functions derived from pairwise composite likelihood estimation and estimating functions that account for correlations among the pairwise contributions. Our method can be used to fit a variety of parametric spatial point process models and can yield more efficient estimators for the clustering parameters than pairwise composite likelihood estimation. We demonstrate the efficacy of our proposed method through a simulation study and an application to the longleaf pine data.
    Print ISSN: 0006-3444
    Digitale ISSN: 1464-3510
    Thema: Biologie , Mathematik , Medizin
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 6
    Publikationsdatum: 2014-06-27
    Beschreibung: Exponential convergence rates in the L 2 -tail norm and entropy are characterized for the second quantization semigroups by using the corresponding base Dirichlet form. This supplements the well-known result on the L 2 -exponential convergence rate of second quantization semigroups. As applications, birth–death-type processes on Poisson spaces and the path space of Lévy processes are investigated.
    Print ISSN: 0033-5606
    Digitale ISSN: 1464-3847
    Thema: Mathematik
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 7
    Publikationsdatum: 2012-12-07
    Beschreibung: Gain-of-function mutations in fibroblast growth factor receptor-3 (FGFR3) lead to several types of human skeletal dysplasia syndromes including achondroplasia, hypochondroplasia and thanatophoric dysplasia (TD). Currently, there are no effective treatments for these skeletal dysplasia diseases. In this study, we screened, using FGFR3 as a bait, a random 12-peptide phage library and obtained 23 positive clones that share identical amino acid sequences (VSPPLTLGQLLS), named as peptide P3. This peptide had high binding specificity to the extracellular domain of FGFR3. P3 inhibited tyrosine kinase activity of FGFR3 and its typical downstream molecules, extracellular signal-regulated kinase/mitogen-activated protein kinase. P3 also promoted proliferation and chondrogenic differentiation of cultured ATDC5 chondrogenic cells. In addition, P3 alleviated the bone growth retardation in bone rudiments from mice mimicking human thanatophoric dysplasia type II (TDII). Finally, P3 reversed the neonatal lethality of TDII mice. Thus, this study identifies a novel inhibitory peptide for FGFR3 signaling, which may serve as a potential therapeutic agent for the treatment of FGFR3-related skeletal dysplasia.
    Print ISSN: 0964-6906
    Digitale ISSN: 1460-2083
    Thema: Biologie , Medizin
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 8
    Publikationsdatum: 2016-10-09
    Beschreibung: We carried out an archaeomagnetic directional study on 38 oriented samples (bricks and baked clays) collected from four archaeological locations at three provinces in China. The ages of our samples, spanning from ~3000 BCE to ~1300 CE, were constrained using a combination of archaeological context, radiocarbon dating and stratigraphic information. Rock magnetic results demonstrate that the main magnetic minerals of the studied samples are magnetite and/or hematite in single domain and superparamagnetic states. A total of 20 new reliable archaeodirectional data from 12 independent sites are obtained after thermal demagnetization experiments. These are the first set of archaeodirectional data in China produced since the 1990s. The published data are largely from the past 2 kyr and data from older time periods are rare. Our new data, especially those from period older than 3 ka, fill many gaps of the presently published dataset and will provide strong constraints on palaeosecular variation of the geomagnetic field in Eastern Asia and on the improvement of global models. Quite a few inflection points in the direction of the geomagnetic field are recorded in Eastern Asia over the past 10 kyr and some of them synchronize with the maximums or minimums of the palaeointensity. The palaeosecular variation rates are very low (based on present data distribution) before 2000 BCE and then start to increase and fluctuate afterward, which is generally consistent with the pattern of palaeointensity variations in this area.
    Schlagwort(e): Geomagnetism, Rock Magnetism and Palaeomagnetism
    Print ISSN: 0956-540X
    Digitale ISSN: 1365-246X
    Thema: Geologie und Paläontologie
    Publiziert von Oxford University Press im Namen von The Deutsche Geophysikalische Gesellschaft (DGG) and the Royal Astronomical Society (RAS).
    Standort Signatur Erwartet Verfügbarkeit
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  • 9
    Publikationsdatum: 2017-01-25
    Beschreibung: H i absorption studies yield information on both active galactic nucleus (AGN) feeding and feedback processes. This AGN activity interacts with the neutral gas in compact radio sources, which are believed to represent the young or recently re-triggered AGN population. We present the results of a survey for H i absorption in a sample of 66 compact radio sources at 0.040 〈 z 〈 0.096 with the Australia Telescope Compact Array. In total, we obtained seven detections, five of which are new, with a large range of peak optical depths (3–87 per cent). Of the detections, 71 per cent exhibit asymmetric, broad (ΔvFWHM 〉 100 km s−1) features, indicative of disturbed gas kinematics. Such broad, shallow and offset features are also found within low-excitation radio galaxies which is attributed to disturbed circumnuclear gas, consistent with early-type galaxies typically devoid of a gas-rich disc. Comparing mid-infrared colours of our galaxies with H i detections indicates that narrow and deep absorption features are preferentially found in late-type and high-excitation radio galaxies in our sample. These features are attributed to gas in galactic discs. By combining XMM–Newton archival data with 21-cm data, we find support that absorbed X-ray sources may be good tracers of H i content within the host galaxy. This sample extends previous H i surveys in compact radio galaxies to lower radio luminosities and provides a basis for future work exploring the higher redshift universe.
    Print ISSN: 0035-8711
    Digitale ISSN: 1365-2966
    Thema: Physik
    Standort Signatur Erwartet Verfügbarkeit
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  • 10
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