1,720,979 research outputs found
Regulation of HIV1 gene expression by histone acetylation and factor recruitment at the LTR promoter.
No full textAcetylation of conserved lysines in the catalytic core of cyclin-dependent kinase 9 inhibits kinase activity and regulates transcription
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Negative regulation of HIV-1 transcription by a heterodimeric NF-κB1/p50 and C-terminally truncated STAT5 complex.
No full textSignal transducers and activator of transcription (STAT) proteins are often constitutively activated in leukocytes of HIV-1(+) individuals, which frequently show a dominant expression of a C-terminally truncated isoform of STAT5 (STAT5Δ). STAT5Δ can act as a negative regulator of human immunodeficiency virus type 1 (HIV-1) expression in both CD8-depleted primary leukocytes and chronically infected promonocytic U1 cells stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF). Activated STAT5Δ can directly bind to two consensus sequences in the HIV-1 long terminal repeat (LTR) promoter; binding impairs recruitment of RNA polymerase II (Crotti, A., Lusic, M., Lupo, R., Lievens, P. M., Liboi, E., Della Chiara, G., et al. (2007). Naturally occurring C-terminally truncated STAT5 is a negative regulator of HIV-1 expression. Blood, 109, 5380-5389). One of the STAT consensus sequences overlaps with one nuclear factor κB (NF-κB) binding site; interestingly, NF-κB1/p50 homodimers, frequently detected in monocytic cells, are negative regulators of HIV transcription. Here, we show that GM-CSF stimulation of U1 cells, while not inducing NF-κB activation, leads to STAT5Δ phosphorylation and binding to the NF-κB/STAT target sequence in the HIV LTR promoter, which already associates with p50 under unstimulated conditions. STAT5Δ was found to associate with p50, but not with RelA/p65, in both U1 cells expressing endogenous proteins and 293T cells overexpressing these factors. Furthermore, GM-CSF stimulation promoted concurrent binding of STAT5Δ and p50 at the HIV LTR promoter in U1 cells. Immunoprecipitation of chromatin from GM-CSF-stimulated U1 cells confirmed in vivo binding of p50 to the viral promoter together with STAT5Δ. Thus, cytokine-activated STAT5Δ/p50 complexes can contribute to the maintenance of HIV-1 latency in monocytic cells
Transcription-dependent gene looping of the HIV-1 provirus is dictated by recognition of pre-mRNA processing signals.
No full textHIV-1 provirus, either as a chromosomal integrant or as an episomal plasmid in HeLa cells, forms a transcription-dependent gene loop structure between the 5'LTR promoter and 3'LTR poly(A) signal. Flavopiridol-mediated inhibition of RNA polymerase II elongation blocks 5' to 3'LTR juxtaposition, indicating that this structure is maintained during transcription. Analysis of mutant or hybrid HIV-1 plasmids demonstrates that replacement of the 5'LTR promoter with CMV or the 3'LTR poly(A) signal with a synthetic element (SPA) permits gene loop formation, suggesting that these interactions are not retroviral specific. In addition, activation of the 5'LTR poly(A) signal or inactivation of the 3'LTR poly(A) signal abolishes gene loop formation. Overall, we demonstrate that both ongoing transcription and pre-mRNA processing are essential for gene loop formation, and predict that these structures represent a defining feature of active gene transcription
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Physical Principles of Retroviral Integration in the Human Genome
Full text linkCertain retroviruses, including HIV, insert their DNA in a non-random fraction of the host genome via poorly understood selection mechanisms. Here, we develop a biophysical model for retroviral integrations as stochastic and quasi-equilibrium topological reconnections between polymers. We discover that physical effects, such as DNA accessibility and elasticity, play important and universal roles in this process. Our simulations predict that integration is favoured within nucleosomal and flexible DNA, in line with experiments, and that these biases arise due to competing energy barriers associated with DNA deformations. By considering a long chromosomal region in human T-cells during interphase, we discover that at these larger scales integration sites are predominantly determined by chromatin accessibility. Finally, we propose and solve a reaction-diffusion problem that recapitulates the distribution of HIV hot-spots within T-cells. With few generic assumptions, our model can rationalise experimental observations and identifies previously unappreciated physical contributions to retroviral integration site selection.</jats:p
Epigenetic modification at notch responsive promoters blunts efficacy of inducing notch pathway reactivation after myocardial infarction.
No full textRATIONALE:
The Notch pathway plays a key role in stimulating mammalian cardiomyocyte proliferation during development and in the early postnatal life; in adult zebrafish, reactivation of this pathway is also essential to drive cardiac regeneration after injury.
OBJECTIVE:
We wanted to assess efficacy of Notch pathway stimulation in neonatal and adult hearts as a means to induce cardiac regeneration after myocardial infarction in mice.
METHODS AND RESULTS:
In early postnatal life, cardiomyocyte exit from the cell cycle was paralleled by decreased Notch signaling and the establishment of a repressive chromatin environment at Notch-responsive genes, characterized by recruitment of the polycomb group enhancer of zeste homolog 2 methyltransferase and the acquisition of the histone 3 Lysine 27 trimethylation histone mark, as detected by chromatin immunoprecipitation. Forced Notch pathway activation by adenoassociated virus gene transfer of activated Notch1 or its ligand Jagged1 expanded the proliferative capacity of neonatal cardiomyocytes; this correlated with increased transcription of Notch target genes and maintenance of an open chromatin conformation at their promoters. The same adenoassociated virus vectors, however, were largely ineffective in stimulating cardiac repair after myocardial infarction in adult mice, despite optimal and long-lasting transgene expression. Analysis of Notch-responsive promoters in adult cardiomyocytes showed marks of repressed chromatin and irreversible CpG DNA methylation. Induction of adult cardiomyocyte re-entry into the cell cycle with microRNAs was independent from Notch pathway reactivation.
CONCLUSIONS:
Notch pathway activation is crucial in regulating cardiomyocyte proliferation during the early postnatal life, but it is largely ineffective in driving cardiac regeneration in adults, because of permanent epigenetic modification at Notch-responsive promoters
Recruitment of human cyclin T1 to nuclear bodies through direct interaction with the PML protein
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