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PubMed2003

Computational discovery of gene modules and regulatory networks.

We describe an algorithm for discovering regulatory networks of gene modules, GRAM (Genetic Regulatory Modules), that combines information from genome-wide location and expression data sets. A gene module is defined as a set of coexpressed genes to which the same set of transcription factors binds. Unlike previous approaches that relied primarily on functional information from expression data, the GRAM algorithm explicitly links genes to the factors that regulate them by incorporating DNA binding data, which provide direct physical evidence of regulatory interactions. We use the GRAM algorithm to describe a genome-wide regulatory network in Saccharomyces cerevisiae using binding information for 106 transcription factors profiled in rich medium conditions data from over 500 expression experiments. We also present a genome-wide location analysis data set for regulators in yeast cells treated with rapamycin, and use the GRAM algorithm to provide biological insights into this regulatory network

Algorithms↗

PubMed2001

The smooth muscle myosin heavy chain gene exhibits smooth muscle subtype-selective modular regulation in vivo.

Previous studies in our laboratory demonstrated that the transgene consisting of the -4.2 to +11.6 kilobase (kb) region of the smooth muscle (SM) myosin heavy chain (MHC) gene was expressed in virtually all SM tissue types in vivo in transgenic mice and that the multiple CArG elements within this region were differentially required in SMC subtypes, implying that the SM-MHC gene was controlled by multiple transcriptional regulatory modules. To investigate this hypothesis, we analyzed specific regulatory regions within the SM-MHC -4.2 to +11.6 kb region by a combination of deletion analyses of various SM-MHC transgenes as well as by DNaseI hypersensitivity assays and in vivo footprinting in intact SMC tissues. The results showed that SM-MHC transgene expression depended on a large number of required regulatory modules that were widely spread over the -4.2 to +11.6 region. Moreover, the results revealed several unexpected novel features of regulation of the SM-MHC gene including: 1) unique combinations of regulatory modules were required for SM-MHC expression in different SMC-subtypes; 2) repressor modules as well as activator modules were both critical for SMC specificity of the gene; 3) certain modules were required in certain contexts but were dispensable in others within a given SMC-subtype (i.e. the net activity of the module was determined by interaction between modules not simply by the sum of module activities); and 4) we identified a highly conserved 200-base pair transcriptional regulatory module at +8 kb that was required in the large arteries but dispensable in the coronary arteries and airways in transgenic mice and contained multiple potential cis-elements that were occupied by nuclear proteins in the intact aorta based on in vivo footprinting. Taken together, the results suggest a model of complex modular control of expression of the SM-MHC gene that varies between SMC subtypes. Moreover, the studies establish the possibility of designing derivatives of the SM-MHC promoter that might be used for targeting gene expression to specific SMC subtypes in vivo.

Animals↗

PubMed2006

CoMoDis: composite motif discovery in mammalian genomes.

Specificity of mammalian gene regulatory regions is achieved to a large extent through the combinatorial binding of sets of transcription factors to distinct binding sites, discrete combinations of which are often referred to as regulatory modules. Identification and subsequent characterization of gene regulatory modules will be a key step in assembling transcriptional regulatory networks from gene expression profiling data, with the ultimate goal of unravelling the regulatory codes that govern gene expression in various cell types. Here we describe the new bioinformatics tool, Composite Motif Discovery (CoMoDis), which streamlines computational identification of novel regulatory modules starting from a single seed motif. Seed motifs represent binding sites conserved across mammalian species. CoMoDis facilitates novel motif discovery by automating the extraction of DNA sequences flanking seed motifs and streamlining downstream motif discovery using a variety of tools, including several that utilize phylogenetic conservation criteria. CoMoDis is available at http://hscl.cimr.cam.ac.uk/CoMoDis_portal.html.

Animals↗

PubMed1999

Crry, a complement regulatory protein, modulates renal interstitial disease induced by proteinuria.

UNLABELLED: Crry, a complement regulatory protein, modulates renal interstitial disease induced by proteinuria. BACKGROUND: Recent studies have suggested a role for urinary complement components in mediating tubulointerstitial damage, which is known to have a good correlation with progression of chronic renal diseases. Although accumulating evidence suggests that complement regulatory proteins play an important protective role in glomeruli, their role in renal tubules remains unclear. In order to establish the role of a complement regulatory protein, Crry, in renal tubular injury, we employed a molecular biological approach to block the expression of Crry in tubules of animals with proteinuria induced with puromycin aminonucleoside nephritis (PAN). Methods and Results. Two different antisense oligodeoxynucleotides (ODNs) against Crry were designed and applied to cultured rat mesangial cells in vitro in order to establish their efficacy. Antisense ODN treatment resulted in decreased expression of Crry protein associated with increased sensitivity to complement attack in cell lysis assays compared with control ODN treatment or no treatment (44.7, 1.50, and 1.34%, respectively). Antisense ODNs did not affect the expression of Thy1 as a control, confirming the specificity of our ODNs. In vivo, we performed selective right renal artery perfusion to administer antisense ODNs to the kidney and showed prominent uptake of ODNs by proximal tubular cells. Reduced expression of Crry protein was demonstrated in proximal tubular cells in antisense ODNs-treated kidneys. Normal rats treated with the antisense ODNs did not show any pathological changes. However, in PAN, rats with massive proteinuria showed increased deposition of C3 and C5b-9 in tubules in antisense-treated kidneys, and histological assessment revealed more severe tubulointerstitial injury in antisense-treated animals compared with controls. CONCLUSION: These results establish a pathogenic role for complement in leading to tubulointerstitial injury during proteinuria and, to our knowledge for the first time, show a protective role of a complement regulatory protein, Crry, in renal interstitial disease.

Animals↗

PubMed2006

DNA motifs in human and mouse proximal promoters predict tissue-specific expression.

Comprehensive identification of cis-regulatory elements is necessary for accurately reconstructing gene regulatory networks. We studied proximal promoters of human and mouse genes with differential expression across 56 terminally differentiated tissues. Using in silico techniques to discover, evaluate, and model interactions among sequence elements, we systematically identified regulatory modules that distinguish elevated from inhibited expression in the corresponding transcripts. We used these putative regulatory modules to construct a single predictive model for each of the 56 tissues. These predictors distinguish tissue-specific elevated from inhibited expression with statistical significance in 80% of the tissues (45 of 56). The predictors also reveal synergy between cis-regulatory modules and explain large-scale tissue-specific differential expression. For testis and liver, the predictors include computationally predicted motifs. For most other tissues, the predictors reveal synergy between experimentally verified motifs and indicate genes that are regulated by similar tissue-specific machinery. The identification in proximal promoters of cis-regulatory modules with tissue-specific activity lays the groundwork for complete characterization and deciphering of cis-regulatory DNA code in mammalian genomes.

Animals↗

PubMed2006

CardioSignal: a database of transcriptional regulation in cardiac development and hypertrophy.

BACKGROUND: Although extensive research has characterized intricate genetic programs in heart system, the information generated is highly fragmented. Here we have developed a new database called CardioSignal, which was designed for integration of regulatory information on the transcriptional regulation involved in heart development and cardiac hypertrophy. METHODS: Data about sequences, positions and functional annotation of transcription binding sites, cis-regulatory modules as well as promoters were collected from scientific literature. Genes involved in both processes were also manually gathered, particularly those preferentially expressed in the heart. Data was stored in MySQL database and Perl was used as the server-side programming language. RESULTS: Currently, CardioSignal contains 677 cardiac genes from twenty species. Among them are 128 cardiac transcription factors. Of the approximately 179 individual promoters from six species, the database also documented 247 experimentally verified binding sites and 64 cis-regulatory modules. CardioSignal may be searched for the promoter of a specific gene by specifying a gene name, Entrez geneID, swissProt accession number and so on. Downstream targets of transcriptional factors and cardiac regulatory modules can also be retrieved through a user-friendly web interface. Also available is experimental supporting evidence. Computational analysis tools were implemented for on-the-fly motif finding and comparative genomic analysis respectively. CONCLUSIONS: CardioSignal offers a unique resource as it contains simultaneously the promoter collected while correlating the information of transcription factor binding sites and cis-regulatory modules from heart system. We are hopeful that its implementation will contribute toward the elucidation of the complex processes in cardiac development and hypertrophy.

Animals↗

PubMed2002

P-gp-induced modulation of regulatory volume increase occurs via PKC in mouse proximal tubule.

The present study examined the role of protein kinase C (PKC) in the P-glycoprotein (P-gp)-induced modulation of regulatory volume increase (RVI) in the isolated nonperfused proximal tubule S2 segments from mice lacking both mdr1a and mdr1b genes (KO) and wild-type (WT) mice. The hyperosmotic solution (500 mosmol/kgH(2)O) involving 200 mM mannitol activated PKC and elicited RVI in the tubules from KO mice but not from WT mice. The addition of the hyperosmotic solution including the PKC activator phorbol 12-myristate 13-acetate (PMA) to the tubules of the WT mice activated PKC and elicited RVI. The hyperosmotic solution in the presence of the P-gp inhibitors (verapamil or cyclosporin A) elicited RVI in the tubules from the WT mice but not from the KO mice. The PMA- and the P-gp inhibitors-induced RVI was abolished by cotreatment with the PKC inhibitors (staurosporine or calphostin C). In the tubules of the KO mice, the PKC inhibitors abolished RVI, but PMA did not. In the tubules of the WT mice, the microtubule disruptor (colchicine), the microfilament disruptor (cytochalasin B), the phosphatidylinositol 3-kinase (PI 3-kinase) blocker (wortmannin), but not another PI 3-kinase blocker (LY-294002), inhibited the PMA-induced RVI. In the tubules of the KO mice, colchicine, cytochalsin B, and wortmannin abolished RVI, but LY-294002 did not. We conclude that 1) in the mouse proximal tubule, P-gp-induced modulation of RVI occurs via PKC; and 2) the microtubule, microfilament, and wortmannin-sensitive, LY-294002-insensitive PI 3-kinase contribute to the PKC-induced RVI.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2004

[Search for new regulatory elements of the Bithorax complex in Drosophila melanogaster].

The Ultrabithorax (Ubx), Abdominal-A (Abd-A), and Abdominal-B (Abd-B) homeotic genes of the Bithorax complex are responsible for the development of body segments in Drosophila melanogaster. Their regulatory region of approximately 300 kb harbors a series of specific enhancers, each regulating expression in a single parasegment. Molecular genetic analysis of the Abd-B gene revealed the regulatory modules MCP, Fab-7, and Fab-8, which contain insulators with adjacent silencers. The present work was aimed at searching for similar regulatory elements in the promoter regions of the Abd-A and Abd-B genes and new regulatory modules in the Abd-B gene region. Four DNA fragments, each containing numerous specific sequences characteristic of regulatory modules, were tested for the ability to suppress transcription of the yellow and white genes and for the interaction with MCP. The DNA fragment of the Abd-A promoter region proved to act as an effective silencer. The fragment of the iab4 domain showed insulator properties. The fragment of the Abd-B promoter region interacted with MCP in providing for communication between the enhancer and promoter of the white gene.

Animals↗

PubMed2000

Transcriptional regulation of the MHC class Ib genes HLA-E, HLA-F, and HLA-G.

The restricted tissue expression of the MHC class Ib molecules HLA-E, HLA-F, and HLA-G has suggested specialized functions and tight transcriptional control of their genes. Transactivation of classical MHC class I genes is mediated by two groups of juxtaposed cis-acting elements, which can be viewed as regulatory modules. The most upstream module consists of the enhancer A and ISRE, and mediates constitutive and cytokine induced expression, whereas the SXY module is important for the constitutive and CIITA-mediated transactivation of MHC class I genes. Nucleotide sequence divergence in these regulatory elements in the promoters of HLA-E, HLA-F, or HLA-G determines their differential responsiveness to NF-kappaB, IRF1, and CIITA-mediated induction. HLA-E is not inducible by NF-kappaB or IRF1, but is responsive to IFN-gamma through an upstream STAT1 binding site. Furthermore, HLA-E is inducible by CIITA through the SXY regulatory module. HLA-F is inducible by NF-kappaB through the kappaB1 site of enhancer A, is responsive to IFN-gamma through the ISRE, and is inducible by CIITA. Both regulatory modules are divergent in HLA-G rendering this gene unresponsive to NF-kappaB, IRF1, and CIITA-mediated induction. This implies a unique regulation of HLA-G transcription amongst the MHC class Ib genes.

Base Sequence↗

PubMed2004

Learning module networks from genome-wide location and expression data.

We develop a systematic algorithm for discovering network of regulatory modules, which identifies regulatory modules and their regulation program by integrating genome-wide location and expression data. Unlike previous approaches [Eisen, M.B., Spellman, P.T., Brown, P.O. and Botstein, D. (1998) Proc. Natl. Acad. Sci. USA 95, 14863-14868; Tavazoie, S., Hughes, J.D., Campbell, M.J., Cho, R.J. and Church, G.M. (1999) Nat. Genet. 22, 281-285; Ihmels, J., Friedlander, G., Bergmann, S., Sarig, O., Ziv, Y. and Barkai, N. (2002) Nat. Genet. 31, 370-377; Segal, E., Shapira, M., Regev, A., Pe'er, D., Botstein, D., Koller, D. and Friedman, N. (2003) Nat. Genet. 34, 166-176] that relied primarily on gene expression data, our algorithm regards the regulator binding data as prior knowledge that provide direct evidence of physical regulatory interactions. We applied the method to a Saccharomyces cerevisiae genome-wide location data [Lee, T.I., Rinaldi, N.J., Robert, F., Odom, D.T., Bar-Joseph, Z., Gerber, G.K., Hannett, N.M., Harbison, C.T., Thompson, C.M., Simon, I., Zeitlinger, J., Jennings, E.G., Murray, H.L. Gordon, D.B., Ren, B., Wyrick, J.J., Tagne, J.B., Volkert, T.L., Fraenkel, E., Gifford, D.K. and Young, R.A. (2002) Science 298, 799-804] for 106 DNA-binding transcription factors and 250 gene expression experiments under the conditions from the cell cycle to responses to various stress conditions. The results show that our method is able to identify functionally coherent modules and their proper regulators. Supplementary materials are available at http://compbio.sibnet.org/projects/module-network/.

Algorithms↗

PubMed2005

Functional genomics identifies a mechanism for estrogen activation of the retinoic acid receptor alpha1 gene in breast cancer cells.

The identification of estrogen receptor (ERalpha) target genes is crucial to our understanding of its predominant role in breast cancer. In this study, we used a chromatin immunoprecipitation (ChIP)-cloning strategy to identify ERalpha-regulatory modules and associated target genes in the human breast cancer cell line MCF-7. We isolated 12 transcriptionally active genomic modules that recruit ERalpha and the coactivator steroid receptor coactivator (SRC)-3 to different intensities in vivo. One of the ERalpha-regulatory modules identified is located 3.7 kb downstream of the first transcriptional start site of the RARA locus, which encodes retinoic acid receptor alpha1 (RARalpha1). This module, which includes an estrogen response element (ERE), is conserved between the human and mouse genomes. Direct binding of ERalpha to the ERE was shown using EMSAs, and transient transfections in MCF-7 cells demonstrated that endogenous ERalpha can induce estrogen-dependent transcriptional activation from the module or the ERE linked to a heterologous promoter. Furthermore, ChIP assays showed that the coregulators SRC-1, SRC-3, and receptor-interacting protein 140 are recruited to this intronic module in an estrogen-dependent manner. As expected from previous studies, the transcription factor Sp1 can be detected at the RARA alpha1 promoter by ChIP. However, treatment with estradiol did not influence Sp1 recruitment nor help recruit ERalpha to the promoter. Finally, ablation of the intronic ERE was sufficient to abrogate the up-regulation of RARA alpha1 promoter activity by estradiol. Thus, this study uncovered a mechanism by which ERalpha significantly activates RARalpha1 expression in breast cancer cells and exemplifies the utility of functional genomics strategies in identifying long-distance regulatory modules for nuclear receptors.

Acetyltransferases↗

PubMed1976

Modulation of regulatory mechanisms operative in the cyclical production of antibody.

Modulation of the cyclical response in rabbits to aggregated human gamma globulin (AHuIgG) was investigated in order to study some of the parameters involved in self-regulation of the immune response. Several mitogens (lipopolysaccharide [LPS], phytohemagglutinin [PHA], and concanavalin A [Con A]), when injected simultaneously with antigen, have been shown to modulate the normal splenic plaque-forming cell (PFC) response in rabbits to a single intravenous injection of AHuIgG. This response to AHuIgG has previously been characterized by the initial appearance of PFC in the spleen 3 days later, with a peak of PFC at 5 days after injection. The number of PFC in the spleen then decreases and remains at a low level until a second increase begins on day 10, peaking on day 13. The 8-day cycle between peak PFC repeats, with a third peak appearing on day 21. In the present studies, injection of LPS with AHuIgG was shown to affect the PFC response by enhancing only the initial peak of PFC, PHA was shown to enhance both the initial and secondary peaks of PFC, while injection of Con A with AHuIgG resulted in a prolonged increase in PFC with no apparent cycling. Irradiation 24 h after injection of antigen resulted in PFC kinetics similar to those observed with PHA, although the increase in PFC was more marked with irradiation. Thus, although LPS, PHA, Con A, and irradiation markedly affected the immune response to AHuIgG, Con A was the only substance which altered the cyclical appearance of PFC to HuIgG. The cyclical nature of the PFC kinetics was shown to occur with either intravenous or intraperitoneal injection of antigen and in both primary and secondary responses, provided that the rabbits were primed with a low dose of antigen. Data were obtained that suggest that the response in distal lymph nodes may be regulated by immunological events occurring in the spleen. Cycling of PFC was not observed in the draining node after subcutaneous injection of AHuIgG in the hind foot. However, if the antigen was also injected intravenously at the same time as the subcutaneous injection, the response in the node became cyclical.

Animals↗

PubMed1999

Domain identification of hormone-sensitive lipase by circular dichroism and fluorescence spectroscopy, limited proteolysis, and mass spectrometry.

Structure-function relationship analyses of hormone-sensitive lipase (HSL) have suggested that this metabolically important enzyme consists of several functional and at least two structural domains (Osterlund, T., Danielsson, B., Degerman, E., Contreras, J. A., Edgren, G., Davis, R. C., Schotz, M. C., and Holm, C. (1996) Biochem. J. 319, 411-420; Contreras, J. A., Karlsson, M., Osterlund, T., Laurell, H., Svensson, A., and Holm, C. (1996) J. Biol. Chem. 271, 31426-31430). To analyze the structural domain composition of HSL in more detail, we applied biophysical methods. Denaturation of HSL was followed by circular dichroism measurements and fluorescence spectroscopy, revealing that the unfolding of HSL is a two-step event. Using limited proteolysis in combination with mass spectrometry, several proteolytic fragments of HSL were identified, including one corresponding exactly to the proposed N-terminal domain. Major cleavage sites were found in the predicted hinge region between the two domains and in the regulatory module of the C-terminal, catalytic domain. Analyses of a hinge region cleavage mutant and calculations of the hydropathic pattern of HSL further suggest that the hinge region and regulatory module are exposed parts of HSL. Together, these data support our previous hypothesis that HSL consists of two major structural domains, encoded by exons 1-4 and 5-9, respectively, of which the latter contains an exposed regulatory module outside the catalytic alpha/beta-hydrolase fold core.

Animals↗

PubMed2006

Causal inference of regulator-target pairs by gene mapping of expression phenotypes.

BACKGROUND: Correlations between polymorphic markers and observed phenotypes provide the basis for mapping traits in quantitative genetics. When the phenotype is gene expression, then loci involved in regulatory control can theoretically be implicated. Recent efforts to construct gene regulatory networks from genotype and gene expression data have shown that biologically relevant networks can be achieved from an integrative approach. In this paper, we consider the problem of identifying individual pairs of genes in a direct or indirect, causal, trans-acting relationship. RESULTS: Inspired by epistatic models of multi-locus quantitative trait (QTL) mapping, we propose a unified model of expression and genotype to identify quantitative trait genes (QTG) by extending the conventional linear model to include both genotype and expression of regulator genes and their interactions. The model provides mapping of specific genes in contrast to standard linkage approaches that implicate large QTL intervals typically containing tens of genes. In simulations, we found that the method can often detect weak trans-acting regulators amid the background noise of thousands of traits and is robust to transcription models containing multiple regulator genes. We reanalyze several pleiotropic loci derived from a large set of yeast matings and identify a likely alternative regulator not previously published. However, we also found that many regulators can not be so easily mapped due to the presence of cis-acting QTLs on the regulators, which induce close linkage among small neighborhoods of genes. QTG mapped regulator-target pairs linked to ARN1 were combined to form a regulatory module, which we observed to be highly enriched in iron homeostasis related genes and contained several causally directed links that had not been identified in other automatic reconstructions of that regulatory module. Finally, we also confirm the surprising, previously published results that regulators controlling gene expression are not enriched for transcription factors, but we do show that our more precise mapping model reveals functional enrichment for several other biological processes related to the regulation of the cell. CONCLUSION: By incorporating interacting expression and genotype, our QTG mapping method can identify specific regulator genes in contrast to standard QTL interval mapping. We have shown that the method can recover biologically significant regulator-target pairs and the approach leads to a general framework for inducing a regulatory module network topology of directed and undirected edges that can be used to identify leads in pathway analysis.

Algorithms↗

PubMed2003

Regulatory peptides modulate ICAM-1 gene expression and NF-kappaB activity in bronchial epithelial cells.

Intercellular adhesion molecule-1 (ICAM-1) is an important adhesion molecule leading to adhesion between cells; NF-kappaB, being universally distributed in the organism, is an important nuclear transcription factor leading to a rapid response to the stimuli. Line of evidence have shown that ICAM-1 transcription and NF-kappaB activation is an important step of inflammatory reaction. To testify that intrapulmonary regulatory peptides modulate inflammatory lesion of bronchial epithelial cells (BECs) through their effect on ICAM-1 expression and nuclear factor kappaB (NF-kappaB) activation, we used immunocytochemistry, RT-PCR, and electrophoretic mobility-shift assay (EMSA) to determine the ICAM-1 expression and NF-kappaB activity in BECs. The effects of NF-kappaB inhibitor MG-132 on ICAM-1 expression were also observed. The results showed that vasoactive intestinal peptide (VIP) and epidermal growth factor (EGF) decreased ICAM-1 expression in O(3)-stressed BECs, while endothelin-1 (ET-1) and calcitonin gene-related peptides (CGRP) increased ICAM-1 expression in resting BECs. MG-132 blocked ICAM-1 expression induced by O(3), ET-1 and CGRP. The results obtained by using EMSA confirmed that VIP and EGF restrained the activation of NF-kappaB in O(3)-stressed BECs; CGRP and ET-1 promoted activation of NF-kappaB. These observations indicate that VIP and EGF abated the injury by means of down-regulatory effects on ICAM-1 transcription and NF-kappaB activation, while ET-1 and CGRP enhanced the inflammation reaction by an up-regulatory effect. It is suggested that a developing and intensive airway inflammation correlates closely with a persistent expression of ICAM-1 and repeated activation of NF-kappaB.

Animals↗

PubMed2025

Multi-omics reveals an ecdysone-activated Eip75B-FABP signaling axis coordinating nutrient metabolism for development in Hermetia illucens.

INTRODUCTION: Efficient nutrient storage is essential for insect development and energy homeostasis; however, the mechanisms coordinating nutrient allocation during ontogeny are not well understood. Elucidating these systems may yield valuable insights to insect metabolic adaptation. OBJECTIVES: This study aimed to identify regulatory modules governing nutrient metabolism in insects, focusing on hormonal and metabolic interplay. METHODS: Multi-omics profiling (proteomics, phosphoproteomics, and transcriptomics) was conducted throughout the life cycle, from egg to adult, to identify metabolic regulators. RNAi was utilized for gene knockdown, followed by qRT-PCR and mitochondrial DNA quantification to evaluate knockdown efficiency and its metabolic implications. Assessments of nutrient metabolism were performed using assays for triglycerides, crude protein, and fatty acid synthase. EMSA and BODIPY staining examined transcriptional regulation and lipid droplet dynamics. RESULTS: Utilizing an integrative multi-omics approach, this study elucidates the temporal metabolic regulators in insects. A conserved regulatory module was identified in which the PPAR homolog, ecdysone-induced protein 75B (Eip75B), functions as a transcriptional activator of fatty acid binding protein (FABP), sustaining lipid metabolic homeostasis during the larval stage. PPARγ modulators (rosiglitazone and GW9662) alter lipid accumulation, along with the expression of Eip75B and FABP, which was measured by qRT-PCR. Furthermore, the deficiency of FABP may reprogram metabolic pathways by inhibiting lipid storage and promoting mitochondrial β-oxidation, as supported by increased mitochondrial DNA copy number, as well as enhancing protein synthesis. This metabolic change could be modulated by ecdysone signaling, as hormonal supplementation effectively rescued the lipid loss phenotype. Our results establish the ecdysone-Eip75B-FABP signaling axis as a central regulatory module that integrates hormonal and nutrient-sensing signals to control insect nutritional metabolism. CONCLUSION: The ecdysone-Eip75B-FABP axis integrates hormonal and nutrient signals to regulate metabolic plasticity, underscoring a universal strategy for developmental energy allocation. The data also offer potential implications for research on metabolic disorders and bioenergy applications.

Animals↗

PubMed2006

At the crossroads: diverse roles of early thymocyte transcriptional regulators.

Transcriptional regulation of T-cell development involves successive interactions between complexes of transcriptional regulators and their binding sites within the regulatory regions of each gene. The regulatory modules that control expression of T-lineage genes frequently include binding sites for a core set of regulators that set the T-cell-specific background for signal-dependent control, including GATA-3, Notch/CSL, c-myb, TCF-1, Ikaros, HEB/E2A, Ets, and Runx factors. Additional regulators in early thymocytes include PU.1, Id-2, SCL, Spi-B, Erg, Gfi-1, and Gli. Many of these factors are involved in simultaneous regulation of non-T-lineage genes, T-lineage genes, and genes involved in cell cycle control, apoptosis, or survival. Potential and known interactions between early thymic transcription factors such as GATA-3, SCL, PU.1, Erg, and Spi-B are explored. Regulatory modules involved in the expression of several critical T-lineage genes are described, and models are presented for shifting occupancy of the DNA-binding sites in the regulatory modules of pre-Talpha, T-cell receptor beta (TCRbeta), recombinase activating genes 1 and 2 (Rag-1/2), and CD4 during T-cell development. Finally, evidence is presented that c-kit, Erg, Hes-1, and HEBAlt are expressed differently in Rag-2(-/-) thymocytes versus normal early thymocytes, which provide insight into potential regulatory interactions that occur during normal T-cell development.

Animals↗

PubMed2005

Single-minded, Dmef2, Pointed, and Su(H) act on identified regulatory sequences of the roughest gene in Drosophila melanogaster.

Roughest (Rst) is a cell adhesion molecule of the immunoglobulin superfamily that has multiple and diverse functions during the development of Drosophila melanogaster. The pleiotropic action of Rst is reflected by its complex and dynamic expression during the development of Drosophila. By an enhancer detection screen, we previously identified several cis-regulatory modules that mediate specific expression of the roughest gene in Drosophila developmental processes. To identify trans-regulators of rst expression, we used the Gal4/UAS system to screen for factors that were sufficient to activate Rst expression when ectopically expressed. By this method we identified the transcription factors Single-minded, Pointed.P1, and Su(H)-VP16. Furthermore, we showed that these factors and, in addition, Dmef2 are able to ectopically activate rst expression via the previously described rst cis-regulatory modules. This fact and the use of mutant analysis allocates the action of the transcription factors to specific developmental contexts. In the case of Sim, we could show that it regulates rst expression in the embryonic midline, but not in the optic lobes. Mutagenesis of Sim consensus binding sites in the regulatory module required for rst expression in the embryonic midline, abolished rst expression; indicating that the regulation of rst by Sim is direct.

Animals↗