145,431 research outputs found
Histone modifications influence the action of Snf2 family remodelling enzymes by different mechanisms
AbstractAlteration of chromatin structure by chromatin modifying and remodelling activities is a key stage in the regulation of many nuclear processes. These activities are frequently interlinked, and many chromatin remodelling enzymes contain motifs that recognise modified histones. Here we adopt a peptide ligation strategy to generate specifically modified chromatin templates and used these to study the interaction of the Chd1, Isw2 and RSC remodelling complexes with differentially acetylated nucleosomes. Specific patterns of histone acetylation are found to alter the rate of chromatin remodelling in different ways. For example, histone H3 lysine 14 acetylation acts to increase recruitment of the RSC complex to nucleosomes. However, histone H4 tetra-acetylation alters the spectrum of remodelled products generated by increasing octamer transfer in trans. In contrast, histone H4 tetra-acetylation was also found to reduce the activity of the Chd1 and Isw2 remodelling enzymes by reducing catalytic turnover without affecting recruitment. These observations illustrate a range of different means by which modifications to histones can influence the action of remodelling enzymes
Impaired decidual natural killer cell regulation of vascular remodelling in early human pregnancies with high uterine artery resistance
During human pregnancy, natural killer (NK) cells accumulate in the maternal decidua, but their specific roles remain to be determined. Decidual NK (dNK) cells are present during trophoblast invasion and uterine spiral artery remodelling. These events are crucial for successful placentation and the provision of an adequate blood supply to the developing fetus. Remodelling of spiral arteries is impaired in the dangerous pregnancy complication pre-eclampsia. We studied dNK cells isolated from pregnancies at 9-14 weeks' gestation, screened by uterine artery Doppler ultrasound to determine resistance indices which relate to the extent of spiral artery remodelling. dNK cells were able to promote the invasive behaviour of fetal trophoblast cells, partly through HGF. Cells isolated from pregnancies with higher resistance indices were less able to do this and secreted fewer pro-invasive factors. dNK cells from pregnancies with normal resistance indices could induce apoptotic changes in vascular smooth muscle and endothelial cells in vitro, events of importance in vessel remodelling, partly through Fas signalling. dNK cells isolated from high resistance index pregnancies failed to induce vascular apoptosis and secreted fewer pro-apoptotic factors. We have modelled the cellular interactions at the maternal-fetal interface and provide the first demonstration of a functional role for dNK cells in influencing vascular cells. A potential mechanism contributing to impaired vessel remodelling in pregnancies with a higher uterine artery resistance is presented. These findings may be informative in determining the cellular interactions contributing to the pathology of pregnancy disorders where remodelling is impaired, such as pre-eclampsia. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
Determinants of a transcriptionally competent environment at the GM-CSF promoter
Granulocyte macrophage-colony stimulating factor
(GM-CSF) is produced by T cells, but not B cells,
in response to immune signals. GM-CSF gene
activation in response to T-cell stimulation requires
remodelling of chromatin associated with the
gene promoter, and these changes do not occur in
B cells. While the CpG methylation status of the
murine GM-CSF promoter shows no correlation with
the ability of the gene to respond to activation, we
find that the basal chromatin environment of the
gene promoter influences its ability to respond to
immune signals. In unstimulated T cells but not B
cells, the GM-CSF promoter is selectively marked
by enrichment of histone acetylation, and association
of the chromatin-remodelling protein BRG1.
BRG1 is removed from the promoter upon activation
concomitant with histone depletion and BRG1
is required for efficient chromatin remodelling and
transcription. Increasing histone acetylation at
the promoter in T cells is paralleled by increased
BRG1 recruitment, resulting in more rapid chromatin
remodelling, and an associated increase in GM-CSF
mRNA levels. Furthermore, increasing histone
acetylation in B cells removes the block in chromatin
remodelling and transcriptional activation
of the GM-CSF gene. These data are consistent
with a model in which histone hyperacetylation
and BRG1 enrichment at the GM-CSF promoter,
generate a chromatin environment competent
to respond to immune signals resulting in gene
activation
Dynamic chromatin: concerted nucleosome remodelling and acetylation
The flexibility of chromatin that enables translation of environmental cues into changes in genome utilisation, relies on a battery of enzymes able to modulate chromatin structure in a highly targeted and regulated manner. The most dynamic structural changes are brought about by two kinds of enzymes with different functional principles. Changes in the acetylation status of histones modulate the folding of the nucleosomal fibre. The histone-DNA interactions that define the nucleosome itself can be disrupted by ATP-dependent remodelling factors. This review focuses on recent developments that illustrate various strategies for integrating these disparate activities into complex regulatory schemes. Synergies may be brought about by consecutive or parallel action during the stepwise process of chromatin opening or closing. Tight co-ordination may be achieved by direct interaction of (de-)acetylation enzymes and remodelling ATPases or even permanent residence within the same multi-enzyme complex. The fact that remodelling ATPases can be acetylated by histone acetyltransferases themselves suggests exciting possibilities for the coordinate modulation of chromatin structure and remodelling enzymes
Control of bone remodelling by applied dynamic loads
The data showing the relationship between bone mass and peak strain magnitude prepared and submitted for publication. The data from experiments relating remodelling activity with static or dynamic loads were prepared and submitted for publication. Development of programs to relate the location of remodelling activity with he natural and artificial dynamic strain distributions continued. Experiments on the effect of different strain rates on the remodelling response continued
Control of human adenovirus type 5 gene expression by cellular Daxx/ATRX chromatin-associated complexes
Death domain–associated protein (Daxx) cooperates with X-linked α-thalassaemia retardation syndrome protein (ATRX), a putative member of the sucrose non-fermentable 2 family of ATP-dependent chromatin-remodelling proteins, acting as the core ATPase subunit in this complex, whereas Daxx is the targeting factor, leading to histone deacetylase recruitment, H3.3 deposition and transcriptional repression of cellular promoters. Despite recent findings on the fundamental importance of chromatin modification in host-cell gene regulation, it remains unclear whether adenovirus type 5 (Ad5) transcription is regulated by cellular chromatin remodelling to allow efficient virus gene expression. Here, we focus on the repressive role of the Daxx/ATRX complex during Ad5 replication, which depends on intact protein–protein interaction, as negative regulation could be relieved with a Daxx mutant that is unable to interact with ATRX. To ensure efficient viral replication, Ad5 E1B-55K protein inhibits Daxx and targets ATRX for proteasomal degradation in cooperation with early region 4 open reading frame protein 6 and cellular components of a cullin-dependent E3-ubiquitin ligase. Our studies illustrate the importance and diversity of viral factors antagonizing Daxx/ATRX-mediated repression of viral gene expression and shed new light on the modulation of cellular chromatin remodelling factors by Ad5. We show for the first time that cellular Daxx/ATRX chromatin remodelling complexes play essential roles in Ad gene expression and illustrate the importance of early viral proteins to counteract cellular chromatin remodelling
Role of noncoding RNA in vascular remodelling
Purpose of review: Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are becoming fundamentally important in the pathophysiology relating to injury-induced vascular remodelling. We highlight recent studies that demonstrate the involvement of ncRNAs in vein graft disease, in in-stent restenosis and in pulmonary arterial hypertension, with a particular focus on endothelial cell and vascular smooth muscle cell function. We also briefly discuss the emerging role of exosomal-derived ncRNAs and how this mechanism impacts on vascular function.
Recent findings: ncRNAs have been described as novel regulators in the pathophysiology of vascular injury, inflammation, and vessel wall remodelling. In particular, several studies have demonstrated that manipulation of miRNAs can reduce the burden of pathological vascular remodelling. Such studies have also shown that exosomal miRNA-mediated, cell-to-cell communication between endothelial cells and vascular smooth muscle cells is critical in the disease process. In addition to miRNAs, lncRNAs are emerging as regulators of vascular function in health and disease. Although lncRNAs are complex in both their sheer numbers and mechanisms of action, identifying their contribution to vascular disease is essential.
Summary: Given the important roles of ncRNAs in vascular injury and remodelling together will their capacity for cell-to-cell communication, manipulating ncRNA might provide novel therapeutic interventions
Governing equations of tissue modelling and remodelling: A unified generalised description of surface and bulk balance
Several biological tissues undergo changes in their geometry and in their
bulk material properties by modelling and remodelling processes. Modelling
synthesises tissue in some regions and removes tissue in others. Remodelling
overwrites old tissue material properties with newly formed, immature tissue
properties. As a result, tissues are made up of different "patches", i.e.,
adjacent tissue regions of different ages and different material properties,
within evolving boundaries. In this paper, generalised equations governing the
spatio-temporal evolution of such tissues are developed within the continuum
model. These equations take into account nonconservative, discontinuous surface
mass balance due to creation and destruction of material at moving interfaces,
and bulk balance due to tissue maturation. These equations make it possible to
model patchy tissue states and their evolution without explicitly maintaining a
record of when/where resorption and formation processes occurred. The time
evolution of spatially averaged tissue properties is derived systematically by
integration. These spatially-averaged equations cannot be written in closed
form as they retain traces that tissue destruction is localised at tissue
boundaries.
The formalism developed in this paper is applied to bone tissues, which
exhibit strong material heterogeneities due to their slow mineralisation and
remodelling processes. Evolution equations are proposed in particular for
osteocyte density and bone mineral density. Effective average equations for
bone mineral density (BMD) and tissue mineral density (TMD) are derived using a
mean-field approximation. The error made by this approximation when remodelling
patchy tissue is investigated. The specific time signatures of BMD or TMD
during remodelling events may provide a way to detect these events occurring at
lower, unseen spatial resolutions from microCT scans.Comment: 14 pages, 8 figures. V2: minor stylistic changes, more detailed
derivation of Eqs (30)-(31), additional comments on implication of BMD and
TMD signatures for microCT scan
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