Regulatory networks

BACKGROUND: Latent HIV-1 reservoirs are identified as one of the major challenges to achieve HIV-1 cure. Currently available strategies are associated with wide variability in outcomes both in patients and CD4(+) T cell models. This underlines the critical need to develop innovative strategies to predict and recognize ways that could result in better reactivation and eventual elimination of latent HIV-1 reservoirs. RESULTS AND DISCUSSION: In this study, we combined genome wide transcriptome datasets post activation with Systems Biology approach (Signaling and Dynamic Regulatory Events Miner, SDREM analyses) to reconstruct a dynamic signaling and regulatory network involved in reactivation mediated by specific activators using a latent cell line...

During mammalian pre-implantation embryo development, when the first asymmetry emerges and how it develops to direct distinct cell fates remain longstanding questions. Here, by analyzing single-blastomere transcriptome data from mouse and human pre-implantation embryos, we revealed that the initial blastomere-to-blastomere biases emerge as early as the first embryonic cleavage division, following a binomial distribution pattern. The subsequent zygotic transcriptional activation further elevated overall blastomere-to-blastomere biases during the two- to 16-cell embryo stages...

BACKGROUND: Bistability in genetic networks allows cells to remember past events and to make discrete decisions in response to graded signals. Bistable behavior can result from positive feedback, but feedback loops can have other roles in signal transduction as well. RESULTS: We introduced positive feedback into the budding-yeast pheromone response to convert it into a bistable system. In the presence of feedback, transient induction with high pheromone levels caused persistent pathway activation, whereas at lower levels a fraction of cells became persistently active but the rest inactivated completely...

As bona fide p53 transcriptional targets, miR-34 microRNAs (miRNAs) exhibit frequent alterations in many human tumor types and elicit multiple p53 downstream effects upon overexpression. Unexpectedly, miR-34 deletion alone fails to impair multiple p53-mediated tumor suppressor effects in mice, possibly due to the considerable redundancy in the p53 pathway. Here, we demonstrate that miR-34a represses HDM4, a potent negative regulator of p53, creating a positive feedback loop acting on p53. In a Kras-induced mouse lung cancer model, miR-34a deficiency alone does not exhibit a strong oncogenic effect...

Signaling pathways are reused for multiple purposes in plant and animal development. The Hippo pathway in mammals and Drosophila coordinates proliferation and apoptosis via the coactivator and oncoprotein YAP/Yorkie (Yki), which is homeostatically regulated through negative feedback. In the Drosophila eye, cross-repression between the Hippo pathway kinase LATS/Warts (Wts) and growth regulator Melted generates mutually exclusive photoreceptor subtypes. Here, we show that this all-or-nothing neuronal differentiation results from Hippo pathway positive feedback: Yki both represses its negative regulator, warts, and promotes its positive regulator, melted...

During segmentation of vertebrate embryos, somites form in accordance with a periodic pattern established by the segmentation clock. In the zebrafish (Danio rerio), the segmentation clock includes six hairy/enhancer of split-related (her/hes) genes, five of which oscillate due to negative autofeedback. The nonoscillating gene hes6 forms the hub of a network of 10 Her/Hes protein dimers, which includes 7 DNA-binding dimers and 4 weak or non-DNA-binding dimers. The balance of dimer species is critical for segmentation clock function, and loss-of-function studies suggest that the her genes have both unique and redundant functions within the clock...

INTRODUCTION: Nuclear accumulation of β-catenin is important for cancer development and it is found to overlap with p68 (DDX5) immunoreactivity in most breast cancers, as indicated by both clinical investigations and studies in cell lines. In this study, we aim to investigate the regulation of p68 gene expression through β-catenin/transcription factor 4 (TCF4) signaling in breast cancer. METHODS: Formalin-fixed paraffin-embedded sections derived from normal human breast and breast cancer samples were used for immunohistochemical analysis...

Spatial organization of different epigenomic marks was used to infer functions of the epigenome. It remains unclear what can be learned from the temporal changes of the epigenome. Here, we developed a probabilistic model to cluster genomic sequences based on the similarity of temporal changes of multiple epigenomic marks during a cellular differentiation process. We differentiated mouse embryonic stem (ES) cells into mesendoderm cells. At three time points during this differentiation process, we used high-throughput sequencing to measure seven histone modifications and variants--H3K4me1/2/3, H3K27ac, H3K27me3, H3K36me3, and H2A...

The diversity of pigmentation patterns observed in plants occurs due to the spatial distribution and accumulation of colored compounds, which may also be associated with structural changes to the tissue. Anthocyanins are flavonoids that provide red/purple/blue coloration to plants, often forming complex patterns such as spots, stripes, and vein-associated pigmentation, particularly in flowers. These patterns are determined by the activity of MYB-bHLH-WDR (MBW) transcription factor complexes, which activate the anthocyanin biosynthesis genes, resulting in anthocyanin pigment accumulation...

Activating transcription factor 3 (Atf3) is rapidly and transiently upregulated in numerous systems, and is associated with various disease states. Atf3 is required for negative feedback regulation of other genes, but is itself subject to negative feedback regulation possibly by autorepression. In cardiomyocytes, Atf3 and Egr1 mRNAs are upregulated via ERK1/2 signalling and Atf3 suppresses Egr1 expression. We previously developed a mathematical model for the Atf3-Egr1 system. Here, we adjusted and extended the model to explore mechanisms of Atf3 feedback regulation...

The intercellular communication that regulates cell fate during animal development must be precisely controlled to avoid dangerous errors. How is this achieved? Recent work has highlighted the importance of positive and negative feedback loops in the dynamic regulation of developmental signalling. These feedback interactions can impart precision, robustness and versatility to intercellular signals. Feedback failure can cause disease.

Autoregulatory feedback loops, where the protein expressed from a gene inhibits or activates its own expression are common gene network motifs within cells. In these networks, stochastic fluctuations in protein levels are attributed to two factors: intrinsic noise (i.e., the randomness associated with mRNA/protein expression and degradation) and extrinsic noise (i.e., the noise caused by fluctuations in cellular components such as enzyme levels and gene-copy numbers). We present results that predict the level of both intrinsic and extrinsic noise in protein numbers as a function of quantities that can be experimentally determined and/or manipulated, such as the response time of the protein and the level of feedback strength...

The deduction of phenotypic cellular responses from the structure and behavior of complex gene regulatory networks is one of the defining challenges of systems biology. This goal will require a quantitative understanding of the modular components that constitute such networks. We pursued an integrated approach, combining theory and experiment, to analyze and describe the dynamics of an isolated genetic module, an in vivo autoregulatory gene network. As predicted by the model, temperature-induced protein destabilization led to the existence of two expression states, thus elucidating the trademark bistability of the positive feedback-network architecture...

Feedback is a ubiquitous control mechanism of gene networks. Here, we have used positive feedback to construct a synthetic eukaryotic gene switch in Saccharomyces cerevisiae. Within this system, a continuous gradient of constitutively expressed transcriptional activator is translated into a cell phenotype switch when the activator is expressed autocatalytically. This finding is consistent with a mathematical model whose analysis shows that continuous input parameters are converted into a bimodal probability distribution by positive feedback, and that this resembles analog-digital conversion...

Mitogen-activated protein kinases (MAPKs) are ancient signal transducers well characterized as mediators of inflammation and neoplastic transformation. Recent work has expanded our understanding of their developmental functions, particularly in the regulation of bone mass via control of osteoblast differentiation. Here, we review the functions of MAPK pathways in osteoblasts, including a consideration of MAPK substrates. In particular, MAPKs function to regulate the key transcriptional mediators of osteoblast differentiation, with ERK and p38 MAPKs phosphorylating RUNX2, the master regulator of osteoblast differentiation...

To understand regulatory systems, it would be useful to uniformly determine how different components contribute to the expression of all other genes. We therefore monitored mRNA expression genome-wide, for individual deletions of one-quarter of yeast genes, focusing on (putative) regulators. The resulting genetic perturbation signatures reflect many different properties. These include the architecture of protein complexes and pathways, identification of expression changes compatible with viability, and the varying responsiveness to genetic perturbation...