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Multi-tissue coexpression networks reveal unexpected subnetworks associated with disease.

ABSTRACT: BACKGROUND: Obesity is a particularly complex disease that at least partially involves genetic and environmental perturbations to gene-networks connecting the hypothalamus and several metabolic tissues, resulting in an energy imbalance at the systems level. RESULTS: To provide an inter-tissue view of obesity with respect to molecular states that are associated with physiological states, we developed a framework for constructing tissue-to-tissue coexpression networks between genes in the hypothalamus, liver or adipose tissue. These networks have a scale-free architecture and are strikingly independent of gene-gene coexpression networks that are constructed from more standard analyses of single tissues. This is the first systematic effort to study inter-tissue relationships and highlights genes in the hypothalamus that act as information relays in the control of peripheral tissues in obese mice. The subnetworks identified as specific to tissue-to-tissue interactions are enriched in genes that have obesity-relevant biological functions such as circadian rhythm, energy balance, stress response, or immune response. CONCLUSIONS: Tissue-to-tissue networks enable the identification of disease-specific genes that respond to changes induced by different tissues and they also provide unique details regarding candidate genes for obesity that are identified in genome-wide association studies. Identifying such genes from single tissue analyses would be difficult or impossible.

SUBMITTER: Dobrin R

PROVIDER: S-EPMC2718521 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Multi-tissue coexpression networks reveal unexpected subnetworks associated with disease.

Dobrin Radu R Zhu Jun J Molony Cliona C Argman Carmen C Parrish Mark L ML Carlson Sonia S Allan Mark F MF Pomp Daniel D Schadt Eric E EE

Genome biology 20090522 5

<h4>Background</h4>Obesity is a particularly complex disease that at least partially involves genetic and environmental perturbations to gene-networks connecting the hypothalamus and several metabolic tissues, resulting in an energy imbalance at the systems level.<h4>Results</h4>To provide an inter-tissue view of obesity with respect to molecular states that are associated with physiological states, we developed a framework for constructing tissue-to-tissue coexpression networks between genes in ...[more]

PMID: 19463160

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Project description:BackgroundThe oral and pharyngeal jaw of cichlid fishes are a classic example of evolutionary modularity as their functional decoupling boosted trophic diversification and contributed to the success of cichlid adaptive radiations. Most studies until now have focused on the functional, morphological, or genetic aspects of cichlid jaw modularity. Here we extend this concept to include transcriptional modularity by sequencing whole transcriptomes of the two jaws and comparing their gene coexpression networks.ResultsWe show that transcriptional decoupling of gene expression underlies the functional decoupling of cichlid oral and pharyngeal jaw apparatus and the two units are evolving independently in recently diverged cichlid species from Lake Tanganyika. Oral and pharyngeal jaw coexpression networks reflect the common origin of the jaw regulatory program as there is high preservation of gene coexpression modules between the two sets of jaws. However, there is substantial rewiring of genetic architecture within those modules. We define a global jaw coexpression network and highlight jaw-specific and species-specific modules within it. Furthermore, we annotate a comprehensive in silico gene regulatory network linking the Wnt and AHR signalling pathways to jaw morphogenesis and response to environmental cues, respectively. Components of these pathways are significantly differentially expressed between the oral and pharyngeal jaw apparatus.ConclusionThis study describes the concerted expression of many genes in cichlid oral and pharyngeal jaw apparatus at the onset of the independent life of cichlid fishes. Our findings suggest that - on the basis of an ancestral gill arch network-transcriptional rewiring may have driven the modular evolution of the oral and pharyngeal jaws, highlighting the evolutionary significance of gene network reuse. The gene coexpression and in silico regulatory networks presented here are intended as resource for future studies on the genetics of vertebrate jaw morphogenesis and trophic adaptation.

Project description:Puberty is a complex physiological event by which animals mature into an adult capable of sexual reproduction. In order to enhance our understanding of the genes and regulatory pathways and networks involved in puberty, we characterized the transcriptome of five reproductive tissues (i.e. hypothalamus, pituitary gland, ovary, uterus, and endometrium) as well as tissues known to be relevant to growth and metabolism needed to achieve puberty (i.e., longissimus dorsi muscle, adipose, and liver). These tissues were collected from pre- and post-pubertal Brangus heifers (3/8 Brahman; Bos indicus x 5/8 Angus; Bos taurus) derived from a population of cattle used to identify quantitative trait loci associated with fertility traits (i.e., age of first observed corpus luteum (ACL), first service conception (FSC), and heifer pregnancy (HPG)). In order to exploit the power of complementary omics analyses, pre- and post-puberty co-expression gene networks were constructed by combining the results from genome-wide association studies (GWAS), RNA-Seq, and bovine transcription factors. Eight tissues among pre-pubertal and post-pubertal Brangus heifers revealed 1,515 differentially expressed and 943 tissue-specific genes within the 17,832 genes confirmed by RNA-Seq analysis. The hypothalamus experienced the most notable up-regulation of genes via puberty (i.e., 204 out of 275 genes). Combining the results of GWAS and RNA-Seq, we identified 25 loci containing a single nucleotide polymorphism (SNP) associated with ACL, FSC, and (or) HPG. Seventeen of these SNP were within a gene and 13 of the genes were expressed in uterus or endometrium. Multi-tissue omics analyses revealed 2,450 co-expressed genes relative to puberty. The pre-pubertal network had 372,861 connections whereas the post-pubertal network had 328,357 connections. A sub-network from this process revealed key transcriptional regulators (i.e., PITX2, FOXA1, DACH2, PROP1, SIX6, etc.). Results from these multi-tissue omics analyses improve understanding of the number of genes and their complex interactions for puberty in cattle.

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Multi-tissue coexpression networks reveal unexpected subnetworks associated with disease.

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Multi-tissue coexpression networks reveal unexpected subnetworks associated with disease.

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