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  • 1
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    Setd1a and NURF mediate chromatin dynamics and gene regulation during erythroid lineage commitment and differentiation (2016)
    Oxford University Press
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    Publication Date: 2016-09-03
    Description: 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
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Methylated Cytosines Mutate to Transcription Factor Binding Sites that Drive Tetrapod Evolution (2015)
    Oxford University Press
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    Publication Date: 2015-11-30
    Description: 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.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Mutant activated FGFR3 impairs endochondral bone growth by preventing SOX9 downregulation in differentiating chondrocytes (2015)
    Oxford University Press
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    Publication Date: 2015-02-26
    Description: 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
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 4
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    New archaeomagnetic direction results from China and their constraints on palaeosecular variation of the geomagnetic field in Eastern Asia (2016)
    Oxford University Press
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    Publication Date: 2016-10-09
    Description: 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.
    Keywords: Geomagnetism, Rock Magnetism and Palaeomagnetism
    Print ISSN: 0956-540X
    Electronic ISSN: 1365-246X
    Topics: Geosciences
    Published by Oxford University Press on behalf of The Deutsche Geophysikalische Gesellschaft (DGG) and the Royal Astronomical Society (RAS).
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  • 5
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    Hi absorption in nearby compact radio galaxies (2017)
    Oxford University Press
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    Publication Date: 2017-01-25
    Description: 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
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press on behalf of The Royal Astronomical Society.
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