217 research outputs found
Optimizing information flow in small genetic networks. II: Feed forward interactions
Central to the functioning of a living cell is its ability to control the
readout or expression of information encoded in the genome. In many cases, a
single transcription factor protein activates or represses the expression of
many genes. As the concentration of the transcription factor varies, the target
genes thus undergo correlated changes, and this redundancy limits the ability
of the cell to transmit information about input signals. We explore how
interactions among the target genes can reduce this redundancy and optimize
information transmission. Our discussion builds on recent work [Tkacik et al,
Phys Rev E 80, 031920 (2009)], and there are connections to much earlier work
on the role of lateral inhibition in enhancing the efficiency of information
transmission in neural circuits; for simplicity we consider here the case where
the interactions have a feed forward structure, with no loops. Even with this
limitation, the networks that optimize information transmission have a
structure reminiscent of the networks found in real biological systems
Information transmission in genetic regulatory networks: a review
Genetic regulatory networks enable cells to respond to the changes in
internal and external conditions by dynamically coordinating their gene
expression profiles. Our ability to make quantitative measurements in these
biochemical circuits has deepened our understanding of what kinds of
computations genetic regulatory networks can perform and with what reliability.
These advances have motivated researchers to look for connections between the
architecture and function of genetic regulatory networks. Transmitting
information between network's inputs and its outputs has been proposed as one
such possible measure of function, relevant in certain biological contexts.
Here we summarize recent developments in the application of information theory
to gene regulatory networks. We first review basic concepts in information
theory necessary to understand recent work. We then discuss the functional
complexity of gene regulation which arrises from the molecular nature of the
regulatory interactions. We end by reviewing some experiments supporting the
view that genetic networks responsible for early development of multicellular
organisms might be maximizing transmitted 'positional' information.Comment: Submitted to J Phys: Condens Matter, 31 page
The role of the segmentation gene hairy in Tribolium
Hairy stripes in Tribolium are generated during blastoderm and germ band extension, but a direct role for Tc-h in trunk segmentation was not found. We have studied here several aspects of hairy function and expression in Tribolium, to further elucidate its role. First, we show that there is no functional redundancy with other hairy paralogues in Tribolium. Second, we cloned the hairy orthologue from Tribolium confusum and show that its expression mimics that of Tribolium castaneum, implying that stripe expression should be functional in some way. Third, we show that the dynamics of stripe formation in the growth zone is not compatible with an oscillatory mechanism comparable to the one driving the expression of hairy homologues in vertebrates. Fourth, we use parental RNAi experiments to study Tc-h function and we find that mandible and labium are particularly sensitive to loss of Tc-h, reminiscent of a pair-rule function in the head region. In addition, lack of Tc-h leads to cell death in the gnathal region at later embryonic stages, resulting in a detachment of the head. Cell death patterns are also altered in the midline. Finally, we have analysed the effect of Tc-h knockdown on two of the target genes of hairy in Drosophila, namely fushi tarazu and paired. We find that the trunk expression of Tc-h is required to regulate Tc-ftz, although Tc-ftz is itself also not required for trunk segmentation in Tribolium. Our results imply that there is considerable divergence in hairy function between Tribolium and Drosophila
Network Evolution of Body Plans
Segmentation in arthropod embryogenesis represents a well-known example of
body plan diversity. Striped patterns of gene expression that lead to the
future body segments appear simultaneously or sequentially in long and short
germ-band development, respectively. Regulatory genes relevant for stripe
formation are evolutionarily conserved among arthropods, therefore the
differences in the observed traits are thought to have originated from how the
genes are wired. To reveal the basic differences in the network structure, we
have numerically evolved hundreds of gene regulatory networks that produce
striped patterns of gene expression. By analyzing the topologies of the
generated networks, we show that the characteristics of stripe formation in
long and short germ-band development are determined by Feed-Forward Loops
(FFLs) and negative Feed-Back Loops (FBLs) respectively. Network architectures,
gene expression patterns and knockout responses exhibited by the artificially
evolved networks agree with those reported in the fly Drosophila melanogaster
and the beetle Tribolium castaneum. For other arthropod species, principal
network architectures that remain largely unknown are predicted.Comment: 35 pages, 4 figures and 1 tabl
A Software Tool to Model Genetic Regulatory Networks. Applications to the Modeling of Threshold Phenomena and of Spatial Patterning in Drosophila
We present a general methodology in order to build mathematical models of genetic regulatory networks. This approach is based on the mass action law and on the Jacob and Monod operon model. The mathematical models are built symbolically by the Mathematica software package GeneticNetworks. This package accepts as input the interaction graphs of the transcriptional activators and repressors of a biological process and, as output, gives the mathematical model in the form of a system of ordinary differential equations. All the relevant biological parameters are chosen automatically by the software. Within this framework, we show that concentration dependent threshold effects in biology emerge from the catalytic properties of genes and its associated conservation laws. We apply this methodology to the segment patterning in Drosophila early development and we calibrate the genetic transcriptional network responsible for the patterning of the gap gene proteins Hunchback and Knirps, along the antero-posterior axis of the Drosophila embryo. In this approach, the zygotically produced proteins Hunchback and Knirps do not diffuse along the antero-posterior axis of the embryo of Drosophila, developing a spatial pattern due to concentration dependent thresholds. This shows that patterning at the gap genes stage can be explained by the concentration gradients along the embryo of the transcriptional regulators
Functional Conservation of the Drosophila gooseberry Gene and Its Evolutionary Alleles
The Drosophila Pax gene gooseberry (gsb) is required for development of the larval cuticle and CNS, survival to adulthood, and male fertility. These functions can be rescued in gsb mutants by two gsb evolutionary alleles, gsb-Prd and gsb-Pax3, which express the Drosophila Paired and mouse Pax3 proteins under the control of gooseberry cis-regulatory region. Therefore, both Paired and Pax3 proteins have conserved all the Gsb functions that are required for survival of embryos to fertile adults, despite the divergent primary sequences in their C-terminal halves. As gsb-Prd and gsb-Pax3 uncover a gsb function involved in male fertility, construction of evolutionary alleles may provide a powerful strategy to dissect hitherto unknown gene functions. Our results provide further evidence for the essential role of cis-regulatory regions in the functional diversification of duplicated genes during evolution
Canalization of Gene Expression and Domain Shifts in the Drosophila Blastoderm by Dynamical Attractors
The variation in the expression patterns of the gap genes in the blastoderm of
the fruit fly Drosophila melanogaster reduces over time as a
result of cross regulation between these genes, a fact that we have demonstrated
in an accompanying article in PLoS Biology (see Manu et al.,
doi:10.1371/journal.pbio.1000049). This biologically essential process is an
example of the phenomenon known as canalization. It has been suggested that the
developmental trajectory of a wild-type organism is inherently stable, and that
canalization is a manifestation of this property. Although the role of gap genes
in the canalization process was established by correctly predicting the response
of the system to particular perturbations, the stability of the developmental
trajectory remains to be investigated. For many years, it has been speculated
that stability against perturbations during development can be described by
dynamical systems having attracting sets that drive reductions of volume in
phase space. In this paper, we show that both the reduction in variability of
gap gene expression as well as shifts in the position of posterior gap gene
domains are the result of the actions of attractors in the gap gene dynamical
system. Two biologically distinct dynamical regions exist in the early embryo,
separated by a bifurcation at 53% egg length. In the anterior region,
reduction in variation occurs because of stability induced by point attractors,
while in the posterior, the stability of the developmental trajectory arises
from a one-dimensional attracting manifold. This manifold also controls a
previously characterized anterior shift of posterior region gap domains. Our
analysis shows that the complex phenomena of canalization and pattern formation
in the Drosophila blastoderm can be understood in terms of the
qualitative features of the dynamical system. The result confirms the idea that
attractors are important for developmental stability and shows a richer variety
of dynamical attractors in developmental systems than has been previously
recognized
Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids.
Altered daily patterns of hormone action are suspected to contribute to metabolic disease. It is poorly understood how the adrenal glucocorticoid hormones contribute to the coordination of daily global patterns of transcription and metabolism. Here, we examined diurnal metabolite and transcriptome patterns in a zebrafish glucocorticoid deficiency model by RNA-Seq, NMR spectroscopy and liquid chromatography-based methods. We observed dysregulation of metabolic pathways including glutaminolysis, the citrate and urea cycles and glyoxylate detoxification. Constant, non-rhythmic glucocorticoid treatment rescued many of these changes, with some notable exceptions among the amino acid related pathways. Surprisingly, the non-rhythmic glucocorticoid treatment rescued almost half of the entire dysregulated diurnal transcriptome patterns. A combination of E-box and glucocorticoid response elements is enriched in the rescued genes. This simple enhancer element combination is sufficient to drive rhythmic circadian reporter gene expression under non-rhythmic glucocorticoid exposure, revealing a permissive function for the hormones in glucocorticoid-dependent circadian transcription. Our work highlights metabolic pathways potentially contributing to morbidity in patients with glucocorticoid deficiency, even under glucocorticoid replacement therapy. Moreover, we provide mechanistic insight into the interaction between the circadian clock and glucocorticoids in the transcriptional regulation of metabolism
Identification of RegIV as a Novel GLI1 Target Gene in Human Pancreatic Cancer
GLI1 is the key transcriptional factor in the Hedgehog signaling pathway in pancreatic cancer. RegIV is associated with regeneration, and cell growth, survival, adhesion and resistance to apoptosis. We aimed to study RegIV expression in pancreatic cancer and its relationship to GLI1.GLI1 and RegIV expression were evaluated in tumor tissue and adjacent normal tissues of pancreatic cancer patients and 5 pancreatic cancer cell lines by qRT-PCR, Western blot, and immunohistochemistry (IHC), and the correlation between them. The GLI1-shRNA lentiviral vector was constructed and transfected into PANC-1, and lentiviral vector containing the GLI1 expression sequence was constructed and transfected into BxPC-3. GLI1 and RegIV expression were evaluated by qRT-PCR and Western blot. Finally we demonstrated RegIV to be the target of GLI1 by chromatin immunoprecipitation (CHIP) and electrophoretic mobility shift assays (EMSA).The results of IHC and qRT-PCR showed that RegIV and GLI1 expression was higher in pancreatic cancer tissues versus adjacent normal tissues (p<0.001). RegIV expression correlated with GLI1 expression in these tissues (R = 0.795, p<0.0001). These results were verified for protein (R = 0.939, p = 0.018) and mRNA expression (R = 0.959, p = 0.011) in 5 pancreatic cancer cell lines. RegIV mRNA and protein expression was decreased (94.7±0.3%, 84.1±0.5%; respectively) when GLI1 was knocked down (82.1±3.2%, 76.7±2.2%; respectively) by the RNAi technique. GLI1 overexpression in mRNA and protein level (924.5±5.3%, 362.1±3.5%; respectively) induced RegIV overexpression (729.1±4.3%, 339.0±3.7%; respectively). Moreover, CHIP and EMSA assays showed GLI1 protein bound to RegIV promotor regions (GATCATCCA) in pancreatic cancer cells.GLI1 promotes RegIV transcription by binding to the RegIV gene promoter in pancreatic cancer
Expression of osterix Is Regulated by FGF and Wnt/β-Catenin Signalling during Osteoblast Differentiation
Osteoblast differentiation from mesenchymal cells is regulated by multiple signalling pathways.
Here we have analysed the roles of Fibroblast Growth Factor (FGF) and canonical
Wingless-type MMTV integration site (Wnt/β-Catenin) signalling pathways on zebrafish
osteogenesis. We have used transgenic and chemical interference approaches to manipulate
these pathways and have found that both pathways are required for osteoblast differentiation
in vivo. Our analysis of bone markers suggests that these pathways act at the same
stage of differentiation to initiate expression of the osteoblast master regulatory gene osterix
(osx). We use two independent approaches that suggest that osx is a direct target of these
pathways. Firstly, we manipulate signalling and show that osx gene expression responds
with similar kinetics to that of known transcriptional targets of the FGF and Wnt pathways.
Secondly, we have performed ChIP with transcription factors for both pathways and our
data suggest that a genomic region in the first intron of osx mediates transcriptional activation.
Based upon these data, we propose that FGF and Wnt/β-Catenin pathways act in part
by directing transcription of osx to promote osteoblast differentiation at sites of bone
formation
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