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PubMed2001

Catabolite repression mediated by the CcpA protein in Bacillus subtilis: novel modes of regulation revealed by whole-genome analyses.

Previous studies have shown that the CcpA protein of Bacillus subtilis is a major transcription factor mediating catabolite repression. We report here whole-transcriptome analyses that characterize CcpA-dependent, glucose-dependent gene expression and correlate the results with full-genome computer analyses of DNA binding (CRE) sites for CcpA. The data obtained using traditional approaches show good agreement with those obtained using the transcriptome approach. About 10% of all genes in B. subtilis are regulated > 3x by glucose, with repressed genes outnumbering activated genes three to one. Eighty per cent of these genes depend on CcpA for regulation. Classical approaches have provided only evidence for CcpA-mediated, glucose-dependent activation or repression. We show here that CcpA also mediates glucose-independent activation or repression, and that glucose may alter either the direction or the intensity of either effect. Computer analyses revealed the presence of CRE sites in most operons subject to CcpA-mediated glucose repression, but not in those subject to glucose activation, suggesting that either secondary transcription factors regulate the latter genes or activation by CcpA involves a dissimilar binding site. Operons encoding the constituents of ABC-type transporters that are subject to CcpA-mediated glucose regulation show two distinct patterns: either all genes in the operon are regulated in parallel (the minor class) or the gene encoding the extracytoplasmic solute-binding receptor is preferentially regulated (the major class). Genes subject to CcpA-independent catabolite repression are primarily concerned with sporulation. Several transcription factors were identified that are themselves regulated by CcpA at the transcriptional level. Representative data with functionally characterized genes are presented to illustrate the novel findings. The comprehensive transcriptome data are available on our website: www.biology.uesd.edu/~MSAIER/regulation/ and also on http://www.blackwell-science.com/ products/journals/suppmat/MMI/MMI2328/MMI2328sm.htm

ATP-Binding Cassette Transporters↗

PubMed2006

Mechanisms of genomic rearrangements and gene expression changes in plant polyploids.

Polyploidy is produced by multiplication of a single genome (autopolyploid) or combination of two or more divergent genomes (allopolyploid). The available data obtained from the study of synthetic (newly created or human-made) plant allopolyploids have documented dynamic and stochastic changes in genomic organization and gene expression, including sequence elimination, inter-chromosomal exchanges, cytosine methylation, gene repression, novel activation, genetic dominance, subfunctionalization and transposon activation. The underlying mechanisms for these alterations are poorly understood. To promote a better understanding of genomic and gene expression changes in polyploidy, we briefly review origins and forms of polyploidy and summarize what has been learned from genome-wide gene expression analyses in newly synthesized auto-and allopolyploids. We show transcriptome divergence between the progenitors and in the newly formed allopolyploids. We propose models for transcriptional regulation, chromatin modification and RNA-mediated pathways in establishing locus-specific expression of orthologous and homoeologous genes during allopolyploid formation and evolution.

Chromosomes, Plant↗

PubMed2004

Pioglitazone prevents alcohol-induced fatty liver in rats through up-regulation of c-Met.

BACKGROUND & AIMS: Treatment of steatosis is important in preventing development of fibrosis in alcoholic liver diseases. This study aimed to examine if pioglitazone, an antidiabetic reagent serving as a ligand of peroxisome proliferator-activated receptor gamma (PPAR gamma), could prevent alcoholic fatty liver. METHODS: Rats fed with an ethanol-containing liquid diet were given the reagent at 10 mg/kg per day intragastrically for 6 weeks. Hepatic genes involved in actions of the reagent were mined by transcriptome analyses, and their changes were confirmed by real-time polymerase chain reaction and Western blotting analyses. The direct effects of pioglitazone on primary-cultured hepatocytes were also assessed in vitro. RESULTS: Pioglitazone significantly attenuated steatosis and lipid peroxidation elicited by chronic ethanol exposure without altering insulin resistance. Mechanisms for improving effects of the reagent appeared to involve restoration of the ethanol-induced down-regulation of c-Met and up-regulation of stearoyl-CoA desaturase (SCD). Such effects of pioglitazone on the c-Met signaling pathway resulted from its tyrosine phosphorylation and resultant up-regulation of the apolipoprotein B (apoB)-mediated lipid mobilization from hepatocytes through very low-density lipoprotein (VLDL) as well as down-regulation of sterol regulatory element binding protein (SREBP) -1c and SCD levels and a decrease in triglyceride synthesis in the liver. CONCLUSIONS: Pioglitazone activates c-Met and VLDL-dependent lipid retrieval and suppresses triglyceride synthesis and thereby serves as a potentially useful stratagem to attenuate ethanol-induced hepatic steatosis.

Alcohol Drinking↗

PubMed2025

Defining the networks that connect RNase III and RNase J-mediated regulation of primary and specialized metabolism in Streptomyces venezuelae.

UNLABELLED: RNA metabolism involves coordinating RNA synthesis with RNA processing and degradation. Ribonucleases play fundamental roles within the cell, contributing to the cleavage, modification, and degradation of RNA molecules, with these actions ensuring appropriate gene regulation and cellular homeostasis. Here, we employed RNA sequencing to explore the impact of RNase III and RNase J on the transcriptome of Streptomyces venezuelae. Differential expression analysis comparing wild-type and RNase mutant strains at distinct developmental stages revealed significant changes in transcript abundance, particularly in pathways related to multicellular development, nutrient acquisition, and specialized metabolism. Both RNase mutants exhibited dysregulation of the BldD regulon, including altered expression of many cyclic-di-GMP-associated enzymes. We also observed precocious chloramphenicol production in these RNase mutants and found that in the RNase III mutant, this was associated with PhoP-mediated regulation. We further found that RNase III directly targeted members of the PhoP regulon, suggesting a link between RNA metabolism and a regulator that bridges primary and specialized metabolism. We connected RNase J function with translation through the observation that RNase J directly targets multiple ribosomal protein transcripts for degradation. These findings establish distinct but complementary roles for RNase III and RNase J in coordinating the gene expression dynamics critical for S. venezuelae development and specialized metabolism. IMPORTANCE: RNA processing and metabolism are mediated by ribonucleases and are fundamental processes in all cells. In the morphologically complex and metabolically sophisticated Streptomyces bacteria, RNase III and RNase J influence both development and metabolism through poorly understood mechanisms. Here, we show that both ribonucleases are required for the proper expression of the BldD developmental pathway and contribute to the control of chloramphenicol production, with an interesting connection to phosphate regulation for RNase III. Additionally, we show that both RNases have the potential to impact translation through distinct mechanisms and can function cooperatively in degrading specific transcripts. This study advances our understanding of RNases in Streptomyces biology by providing insight into distinct contributions made by these enzymes and the intriguing interplay between them.

Streptomyces↗

PubMed2006

Transcriptome analysis of a cnidarian-dinoflagellate mutualism reveals complex modulation of host gene expression.

BACKGROUND: Cnidarian-dinoflagellate intracellular symbioses are one of the most important mutualisms in the marine environment. They form the trophic and structural foundation of coral reef ecosystems, and have played a key role in the evolutionary radiation and biodiversity of cnidarian species. Despite the prevalence of these symbioses, we still know very little about the molecular modulators that initiate, regulate, and maintain the interaction between these two different biological entities. In this study, we conducted a comparative host anemone transcriptome analysis using a cDNA microarray platform to identify genes involved in cnidarian-algal symbiosis. RESULTS: We detected statistically significant differences in host gene expression profiles between sea anemones (Anthopleura elegantissima) in a symbiotic and non-symbiotic state. The group of genes, whose expression is altered, is diverse, suggesting that the molecular regulation of the symbiosis is governed by changes in multiple cellular processes. In the context of cnidarian-dinoflagellate symbioses, we discuss pivotal host gene expression changes involved in lipid metabolism, cell adhesion, cell proliferation, apoptosis, and oxidative stress. CONCLUSION: Our data do not support the existence of symbiosis-specific genes involved in controlling and regulating the symbiosis. Instead, it appears that the symbiosis is maintained by altering expression of existing genes involved in vital cellular processes. Specifically, the finding of key genes involved in cell cycle progression and apoptosis have led us to hypothesize that a suppression of apoptosis, together with a deregulation of the host cell cycle, create a platform that might be necessary for symbiont and/or symbiont-containing host cell survival. This first comprehensive molecular examination of the cnidarian-dinoflagellate associations provides critical insights into the maintenance and regulation of the symbiosis.

Animals↗

PubMed2026

Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type, and sex specificity of gene expression with novel genetic risk for MERTK in female.

BackgroundAlzheimer's disease (AD), the most common age-related neurodegenerative disease, is closely associated with both amyloid-β plaque and neuroinflammation. Two thirds of AD patients are female, and they have a higher disease risk; women with AD have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration.ObjectiveThis study aimed to determine how sex difference induces structural brain changes and molecular cell vulnerabilities in AD, with a focus on identifying sex-specific transcriptional alterations and genetic risk factors.MethodsWe performed single nucleus RNA sequencing on postmortem brains from individuals with AD and age- and sex-matched controls, focusing on the middle temporal gyrus, a cortical brain region strongly affected by the disease, and integrated single nucleus RNA sequencing results with genome-wide association study (GWAS) data using cell type-specific enrichment and generalized gene-set analysis approaches. The analysis pipeline is provided with threshold information.ResultsWe identified a selectively vulnerable subpopulation of layer 2/3 excitatory neurons that were RORB-negative and CDH9-expressing in both males and females. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of AD brains differed between males and females. Integrating single cell transcriptomic data with results from GWAS, we identified MERTK genetic variation as a candidate novel risk factor for AD selectively in females.ConclusionsTaken together, our single cell atlas of middle temporal gyrus revealed a unique cellular-level view of sex-specific transcriptional changes in AD, illuminating GWAS identification of sex-specific AD genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of AD.

Alzheimer's disease↗

PubMed2006

Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways.

Monitoring genome-wide, cell-specific responses to human disease, although challenging, holds great promise for the future of medicine. Patients with injuries severe enough to develop multiple organ dysfunction syndrome have multiple immune derangements, including T cell apoptosis and anergy combined with depressed monocyte antigen presentation. Genome-wide expression analysis of highly enriched circulating leukocyte subpopulations, combined with cell-specific pathway analyses, offers an opportunity to discover leukocyte regulatory networks in critically injured patients. Severe injury induced significant changes in T cell (5,693 genes), monocyte (2,801 genes), and total leukocyte (3,437 genes) transcriptomes, with only 911 of these genes common to all three cell populations (12%). T cell-specific pathway analyses identified increased gene expression of several inhibitory receptors (PD-1, CD152, NRP-1, and Lag3) and concomitant decreases in stimulatory receptors (CD28, CD4, and IL-2Ralpha). Functional analysis of T cells and monocytes confirmed reduced T cell proliferation and increased cell surface expression of negative signaling receptors paired with decreased monocyte costimulation ligands. Thus, genome-wide expression from highly enriched cell populations combined with knowledge-based pathway analyses leads to the identification of regulatory networks differentially expressed in injured patients. Importantly, application of cell separation, genome-wide expression, and cell-specific pathway analyses can be used to discover pathway alterations in human disease.

Gene Expression Profiling↗

PubMed2025

PARTAGE: Parallel analysis of replication timing and gene expression.

The human genome is partitioned into functional compartments that replicate at specific times during the S-phase. This temporal program, referred to as replication timing (RT), is co-regulated with the 3D genome organization, is cell type-specific, and changes during development in coordination with gene expression. Moreover, RT alterations are linked to abnormal gene expression, genome instability, and structural variation in multiple diseases, including cancer. However, mechanistic links between RT, large-scale 3D genome architecture, and transcriptional regulation remain poorly understood. A major limitation is that current approaches require the separate profiling of RT and transcriptomes from independent batches of samples, obscuring the complex co-regulation between the epigenome and transcriptome. Here, we developed PARTAGE, a multiomics approach that enables joint profiling of copy number variation (CNV), RT, and gene expression from the same sample, providing a more accurate integrative view of the complex relationships between RT and gene regulation.

Journal Article↗

PubMed2006

The identification of human tumour antigens: Current status and future developments.

The biggest challenge facing us today in cancer control and prevention is the identification of novel biomarkers for detection and improved therapeutic interventions to reduce mortality and morbidity rates. Biomarkers are important indicators to inform us of the physiological state of the cell at a specific time. It is now clear that malignant transformation occurs by changes in cellular DNA and protein expression with subsequent clonal proliferation of the altered cells. The affected genes and their expressed protein products or biomarkers are those involved in the normal growth and maintenance of the cancerous cells. These biomarkers could prove pivotal for the identification of early cancer and people at risk of developing cancer. Altered proteins or changes in gene expression in malignant cells may lead to the expression of tumour antigens recognised by host immune system. In this review we discuss current research into the molecular technologies making possible the global genomic-wide analysis of changes in DNA (genotyping), RNA expression (transcriptomics) and protein expression (proteomics) that have accelerated the rate of new biomarker/tumour antigen discovery. To gain a comprehensive understanding of the physiology and pathophysiology of cancer an approach that harmoniously integrates the various 'omic' platforms are key to unraveling the complexity 'needle-in-a-haystack' quality of biomarker/tumour antigen discovery.

Antigens, Neoplasm↗

PubMed2026

Impaired leptin A signaling disrupts hepatic lipid metabolism and growth in female medaka (Oryzias latipes).

Leptin is a central regulator of appetite and energy metabolism in vertebrates, and its deficiency in mammals typically results in hyperphagia and severe obesity. In fish, however, the physiological roles of leptin remain less clearly defined, partly due to the whole genome duplication (WGD) and divergent expression patterns. In this study, we generated a leptin A (lepa) loss-of-function mutant in medaka (Oryzias latipes) using CRISPR/Cas9 to investigate the function of leptin signaling. Phenotypic analysis revealed that female homozygous mutants exhibited significantly reduced body length and body weight compared with wild-type females, indicating growth impairment. Unexpectedly, despite their lean phenotype, the female mutants developed pronounced hepatic steatosis accompanied by the formation of spongiosis hepatis structures, while no obvious fibrosis was detected. To explore the molecular mechanisms underlying these abnormalities, transcriptomic profiling of mutant livers was performed. Differentially expressed genes were significantly enriched in pathways related to lipid metabolism, including Fatty acid metabolism and PPAR signaling pathway, suggesting a potential reduction in hepatic fatty acid β-oxidation capacity. In addition, genes involved in endoplasmic reticulum stress, autophagy, and apoptosis were altered, indicating transcriptional changes in cellular stress-response pathways under leptin A deficiency. Together, these findings suggest that leptin A may play an important role in coordinating growth and hepatic lipid metabolism in medaka and highlight potential differences in leptin-mediated metabolic regulation between fish and mammals.

Animals↗

PubMed2006

LmrCD is a major multidrug resistance transporter in Lactococcus lactis.

When Lactococcus lactis is challenged with drugs it displays a multidrug resistance (MDR) phenotype. In silico analysis of the genome of L. lactis indicates the presence of at least 40 putative MDR transporters, of which only four, i.e. the ABC transporters LmrA, LmrC and LmrD, and the major facilitator LmrP, have been experimentally associated with the MDR. To understand the molecular basis of the MDR phenotype in L. lactis, we have performed a global transcriptome analysis comparing four independently isolated drug-resistant strains of L. lactis with the wild-type strain. The results show a strong and consistent upregulation of the lmrC and lmrD genes in all four strains, while the mRNA levels of other putative MDR transporters were not significantly altered. Deletion of lmrCD renders L. lactis sensitive to several toxic compounds, and this phenotype is associated with a reduced ability to secrete these compounds. Another gene, which is strongly upregulated in all mutant strains, specifies LmrR (YdaF), a local transcriptional repressor of lmrCD that belongs to the PadR family of transcriptional regulators and that binds to the promoter region of lmrCD. These results demonstrate that the heterodimeric MDR ABC transporter LmrCD is a major determinant of both acquired and intrinsic drug resistance of L. lactis.

ATP-Binding Cassette Transporters↗

PubMed2005

Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart.

BACKGROUND: Down syndrome, caused by trisomic chromosome 21, is the leading genetic cause of mental retardation. Recent studies demonstrated that dosage-dependent increases in chromosome 21 gene expression occur in trisomy 21. However, it is unclear whether the entire transcriptome is disrupted, or whether there is a more restricted increase in the expression of those genes assigned to chromosome 21. Also, the statistical significance of differentially expressed genes in human Down syndrome tissues has not been reported. RESULTS: We measured levels of transcripts in human fetal cerebellum and heart tissues using DNA microarrays and demonstrated a dosage-dependent increase in transcription across different tissue/cell types as a result of trisomy 21. Moreover, by having a larger sample size, combining the data from four different tissue and cell types, and using an ANOVA approach, we identified individual genes with significantly altered expression in trisomy 21, some of which showed this dysregulation in a tissue-specific manner. We validated our microarray data by over 5,600 quantitative real-time PCRs on 28 genes assigned to chromosome 21 and other chromosomes. Gene expression values from chromosome 21, but not from other chromosomes, accurately classified trisomy 21 from euploid samples. Our data also indicated functional groups that might be perturbed in trisomy 21. CONCLUSIONS: In Down syndrome, there is a primary transcriptional effect of disruption of chromosome 21 gene expression, without a pervasive secondary effect on the remaining transcriptome. The identification of dysregulated genes and pathways suggests molecular changes that may underlie the Down syndrome phenotypes.

Astrocytes↗

PubMed2026

An oxidative stress - and immunotherapy-related six-gene signature defines immune subtypes and predicts prognosis and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: Oxidative stress and the tumor immune microenvironment jointly shape hepatocellular carcinoma (HCC) progression and response to immunotherapy, yet integrated biomarkers linking these processes are lacking. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to identify oxidative stress- and immunotherapyrelated differentially expressed genes (OSIRDEGs). Functional enrichment, weighted gene co-expression network analysis (WGCNA) and LASSO-Cox regression were used to construct a prognostic signature. Consensus clustering, TIDE, CIBERSORT and ssGSEA characterized immune phenotypes. Somatic mutation, copy-number and drug-response data were integrated to assess genomic alterations and drug sensitivity. Expression of model genes was validated by qRT-PCR and western blotting in HCC cell lines. RESULTS: We identified 24 OSIRDEGs enriched in cell-cycle and mitotic pathways. WGCNA intersection yielded 18 module genes, from which a six-gene signature (BUB1B, CDKN2A, CENPE, HMMR, PTTG1, SPP1) was derived. The signature robustly stratified patients into high- and low-risk groups with significantly different progression-free and disease-free survival in both TCGA-LIHC and GSE14520. Based on signature expression, two molecular subtypes were defined, exhibiting distinct survival, immune landscapes and predicted immunotherapy responsiveness. Model genes harbored recurrent alterations and showed significant correlations with anticancer agents. All six genes were upregulated at mRNA and protein levels in metastatic HCC cell lines versus normal hepatocytes. CONCLUSIONS: We systematically explored the landscape of OSIRDEGs in HCC, and proposed a validated six-gene signature that refines prognostic stratification, delineates immunerelevant HCC subtypes and highlights candidate biomarkers for therapeutic selection and mechanistic investigation.

Humans↗

PubMed2026

Integrated transcriptomic analysis of mRNA and miRNA in Brown adipose tissue of the greater horseshoe bats during hibernation.

Hibernation enables animals survive harsh environments by conserving energy through reduced metabolism and body temperature. Brown adipose tissue (BAT) plays a critical role in non-shivering thermogenesis, crucial for warming up during arousal phase. The greater horseshoe bats (Rhinolophus nippon) are typical hibernators and non-shivering thermogenesis in BAT tissue may persist throughout the arousal process in bats. This study examines gene expression and regulatory changes in BAT of these bats across active, hibernation, and arousal phases using transcriptome and miRNA sequencing. A total of 2721 differentially expressed mRNAs and 268 differentially expressed miRNAs were identified. The results reveal that the BAT transcriptome undergoes state-dependent remodeling throughout the hibernation process. The most pronounced divergence occurs between the active phase and torpor, involving cell cycle arrest, immunosuppression, thermogenic signal desensitization, and upregulation of lipid metabolism and autophagy pathways, reflecting the coordinated adaptation of energy conservation and thermogenic reserve. In contrast, transcriptional alterations between torpor and arousal are extremely limited, indicating that torpid BAT is already pre-primed for thermogenesis and requires only modest transcriptional adjustments to activate heat production. Notably, although body temperature recovers to active-phase levels during arousal, the molecular signature of BAT remains highly similar to that of the torpid state. Furthermore, the core thermogenic gene UCP1 showed no significant expression differences across the three groups. In conclusion, this study systematically delineates the miRNA-mRNA regulatory landscape of bat BAT across the hibernation process, and deepens our understanding of the thermoregulatory mechanisms underlying mammalian hibernation.

BAT↗

PubMed2006

Defining the Mga regulon: Comparative transcriptome analysis reveals both direct and indirect regulation by Mga in the group A streptococcus.

The regulator Mga in the group A streptococcus (GAS) is known to directly activate several virulence genes important for colonization and immune evasion. Transcriptome analysis comparing two mga-1 serotypes (M1 SF370, M6 JRS4) and one mga-2 serotype (M4 GA40634) against their isogenic mga-inactivated strains uncovered a broader Mga regulon profile containing both activated and repressed genes with predicted functions primarily related to sugar metabolism. This was reflected in the altered abilities of M1 and M4 Mga mutants to grow in chemically defined media with a single sugar source compared with their wild-type counterparts. Although the M1 and M4 Mga profiles were similar, the M6 JRS4 was clearly distinct, even from other M6 strains. Real-time RT-PCR and Northern blots confirmed that established core Mga regulon genes directly activated by Mga (emm, scpA, sof, fba) exhibited the highest activation levels across all strains tested. Spy2036 encoding a cytosolic hypothetical protein was highly activated in all three serotypes and was called gene regulated by Mga (grm). Mga bound directly to Pgrm, which overlaps the Mga-regulated Psof in OF+ strains, suggesting that grm is part of the core Mga regulon and Mga is able to activate divergently transcribed genes from a single site. Furthermore, Mga activated speB when detectable in the wild-type strain, although direct binding of Mga to PspeB could not be demonstrated. Thus, Mga is able to both directly and indirectly regulate genes shown to be important for virulence and the metabolic homeostasis of GAS.

Bacterial Proteins↗

PubMed2026

Bridging the gap: multi-omic insights into exercise responses in postmenopausal women.

Postmenopausal women represent the fastest-growing demographic at risk of sarcopenia and cardiometabolic disease, yet exercise biology research remains disproportionately derived from male or hormone-replete phenotypes. Menopause constitutes a chronic endocrine perturbation characterized by sustained reductions in estrogen and progesterone, and altered androgen balance, superimposed on the acute and chronic perturbations induced by exercise. This hormonal shift modifies substrate metabolism, inflammation, redox balance, and recovery capacity, factors that shape molecular responses to exercise across tissues and time. Here, we synthesize current evidence on exercise responses in postmenopausal females across genomics, epigenomics, transcriptomics, proteomics, and metabolomics/lipidomics. Across omics layers, direct data in postmenopausal cohorts remain limited, with frequent underreporting of menopausal status, hormone therapy exposure, circulating hormone concentrations, medication use, and biosampling timing relative to exercise and hormone dosing. We outline a menopause-aware framework for exercise-omics that prioritizes endocrine stratification, repeated sampling across exercise and recovery, and integrative multi-omics approaches linking molecular responses to functional outcomes. We also outline minimum reporting standards to improve reproducibility, inclusivity, and translational relevance. Advancing menopause-aware exercise-omics will be essential for developing precision exercise strategies that improve health span and functional independence in later life.

Humans↗

PubMed2003

Cancer target discovery using SAGE.

Cancer is a genetic disease. Genetic events including mutations, chromosomal gains, losses and rearrangements, along with epigenetic alterations, lead to significant transcriptional changes in cancer cells. Changes in the expression of many genes associated with the onset and progression of cancer likely contribute to the cancerous phenotype. SAGE (Serial Analysis of Gene Expression) is an expression profiling method that allows for global, unbiased and quantitative characterisation of transcriptomes. The expression of thousands of genes can be analysed simultaneously without prior knowledge of their sequence, thus leading to the discovery of novel transcripts. In addition to characterising normal and malignant gene expression patterns, SAGE can be used to identify downstream targets of tumour suppressors and oncogenes and further annotate genomes. Comprehensive analyses of expression profiles using SAGE will yield many new diagnostic and prognostic markers as well as therapeutic targets in cancer.

Antineoplastic Agents↗

PubMed2004

Suppression of tumorigenesis and activation of Wnt signaling by bone morphogenetic protein 4 in human cancer cells.

Aberrations in BMP signaling have recently been implicated as a cause of human cancer. Here we demonstrate and define the tumor suppressive properties of BMP4. Consistent with its potential role in a tumor suppressor pathway, BMP4 treatment eliminated the tumorigenic potential of an undifferentiated human cancer cell line. This loss of tumorigenicity was accompanied by an increase in apoptosis, alterations in cell cycle profile, and an increase in cell size. Interestingly, human colon cancer cells were resistant to the growth-suppressive properties of BMP4. To identify putative downstream mediators of BMP4-mediated tumor suppression, Affymetrix Genechips were employed to identify BMP4-regulated genes. The human BMP4 transcriptome was characterized by the modulation of many genes well known to play important roles in differentiation and development, including the induction of numerous genes involved in Wnt signaling. Modulation of Wnt gene expression by BMP4 had several functional consequences--BMP4 treatment led to activation of TCF reporters; complete activation of at least one BMP4-responsive gene required TCF sites; and treatment with a Wnt ligand was sufficient to mimic several of the phenotypic effects of BMP4 treatment. These data demonstrate the tumor suppressive properties of BMP4 signaling, show that colon cancer cells are resistant to BMP4-induced differentiation and growth suppression, further define the BMP4 transcriptome, and raise the intriguing possibility that interactions between the Wnt and BMP signaling pathways may play an important role in differentiation and tumor suppression.

Animals↗