From biological pathways to regulatory networks

This paper presents a general theoretical framework for generating Boolean networks whose state transitions realize a set of given biological pathways or minor variations thereof. This ill-posed inverse problem, which is of crucial importance across practically all areas of biology, is solved by using Karnaugh maps which are classical tools for digital system design. It is shown that the incorporation of prior knowledge, presented in the form of biological pathways, can bring about a dramatic reduction in the cardinality of the network search space. Constraining the connectivity of the network, the number and relative importance of the attractors, and concordance with observed time-course data are additional factors that can be used to further reduce the cardinality of the search space. The networks produced by the approaches developed here should facilitate the understanding of multivariate biological phenomena and the subsequent design of intervention approaches that are more likely to be successful in practice. As an example, the results of this paper are applied to the widely studied p53 pathway and it is shown that the resulting network exhibits dynamic behavior consistent with experimental observations from the published literature.     

Intervention in a family of Boolean networks

MOTIVATION: Intervention in a gene regulatory network is used to avoid undesirable states, such as those associated with a disease. Several types of intervention have been studied in the framework of a probabilistic Boolean network (PBN), which is a collection of Boolean networks in which the gene state vector transitions according to the rules of one of the constituent networks and where network choice is governed by a selection distribution. The theory of automatic control has been applied to find optimal strategies for manipulating external control variables that affect the transition probabilities to desirably affect dynamic evolution over a finite time horizon. In this paper we treat a case in which we lack the governing probability structure for Boolean network selection, so we simply have a family of Boolean networks, but where these networks possess a common attractor structure. This corresponds to the situation in which network construction is treated as an ill-posed inverse problem in which there are many Boolean networks created from the data under the constraint that they all possess attractor structures matching the data states, which are assumed to arise from sampling the steady state of the real biological network. RESULTS: Given a family of Boolean networks possessing a common attractor structure composed of singleton attractors, a control algorithm is derived by minimizing a composite finite-horizon cost function that is a weighted average over all the individual networks, the idea being that we desire a control policy that on average suits the networks because these are viewed as equivalent relative to the data. The weighting for each network at any time point is taken to be proportional to the instantaneous estimated probability of that network being the underlying network governing the state transition. The results are applied to a family of Boolean networks derived from gene-expression data collected in a study of metastatic melanoma, the intent being to devise a control strategy that reduces the WNT5A gene's action in affecting biological regulation. AVAILABILITY: The software is available on request. SUPPLEMENTARY INFORMATION: The supplementary Information is available at http://ee.tamu.edu/~edward/tree     

A functional link between housekeeping selenoproteins and phase II enzymes

Sec (selenocysteine) is biosynthesized on its tRNA and incorporated into selenium-containing proteins (selenoproteins) as the 21st amino acid residue. Selenoprotein synthesis is dependent on Sec tRNA and the expression of this class of proteins can be modulated by altering Sec tRNA expression. The gene encoding Sec tRNA (Trsp) is a single-copy gene and its targeted removal in liver demonstrated that selenoproteins are essential for proper function wherein their absence leads to necrosis and hepatocellular degeneration. In the present study, we found that the complete loss of selenoproteins in liver was compensated for by an enhanced expression of several phase II response genes and their corresponding gene products. The replacement of selenoprotein synthesis in mice carrying mutant Trsp transgenes, wherein housekeeping, but not stress-related selenoproteins are expressed, led to normal expression of phase II response genes. Thus the present study provides evidence for a functional link between housekeeping selenoproteins and phase II enzymes.     

Loss of housekeeping selenoprotein expression in mouse liver modulates lipoprotein metabolism

Selenium is incorporated into proteins as selenocysteine (Sec), which is dependent on its specific tRNA, designated tRNA^[Ser]Sec. Targeted removal of the tRNA^[Ser]Sec gene (Trsp) in mouse hepatocytes previously demonstrated the importance of selenoproteins in liver function. Herein, analysis of plasma proteins in this Trsp knockout mouse revealed increases in apolipoprotein E (ApoE) that was accompanied by elevated plasma cholesterol levels. The expression of genes involved in cholesterol biosynthesis, metabolism and transport were also altered in knockout mice. Additionally, in two transgenic Trsp mutant mouse lines (wherein only housekeeping selenoprotein synthesis was restored), the expression of ApoE, as well as genes involved in cholesterol biosynthesis, metabolism and transport were similar to those observed in wild type mice. These data correlate with reports that selenium deficiency results in increased levels of ApoE, indicating for the first time that housekeeping selenoproteins have a role in regulating lipoprotein biosynthesis and metabolism.     

Effect of heparin and adrenocorticotropin on the hepatic and serum cholesterol in catfish, Heteropneustes fossils.

The administration of heparin with or without ACTH significantly decreased hepatic cholesterol content in catfish. In serum, heparin alone produced first hypercholesterolemia which was followed by hypocholesterolemia whereas it potentiated hypercholesterolemic action of ACTH three hours after administration. It is concluded that heparin normally caused hypercholesterolemia by releasing cholesterol from liver as lipoprotein complex. The hypocholesterolemic action of heparin might be an indirect one.     

A Route to Direct Fitness: Natural and Experimentally Induced Queen Succession in the Tropical Primitively Eusocial Wasp <Emphasis Type="Italic">Ropalidia marginata</Emphasis>

Insect societies are hallmarks of cooperation because one or a few queens monopolize reproduction and several non-reproductive workers cooperatively raise brood. However, the loss of the queen exposes a colony to potential reproductive conflict, which is resolved only after a new queen takes over. We studied queen succession in natural and experimental colonies of the primitively eusocial wasp Ropalidia marginata to understand the proximate behavioral strategies involved in the resolution of this conflict. Previous work has shown that in this species, experimental queen removal always results in only one worker becoming hyper-aggressive and taking over the colony as its next queen, without ever being challenged. Here we show that even during natural queen turnover, one and only one worker becomes hyper-aggressive and takes over as the next queen, without being challenged. During natural queen turn-over, aggression of the successor may sometimes begin before the loss of the old queen and may sometimes decline more rapidly, unlike in the case of experimental queen removal. The successor begins to lay eggs sooner after a natural queen turn-over as compared to experimental queen removal. This is expected because workers might detect the gradual decline of the queen preceding her disappearance. Because queen succession is expected to be more prevalent in tropical perennial species, we expect natural selection to have favored such an orderly queen succession so that a route to direct fitness is available without significant reduction in cooperation.