Using Transcription Modules to Identify Expression Clusters Perturbed in Williams-Beuren Syndrome

Henrichsen, Charlotte N.; Csárdi, Gábor; Zabot, Marie Thérèse; Fusco, Carmela; Bergmann, Sven; Merla, Giuseppe; Reymond, Alexandre

doi:10.1371/journal.pcbi.1001054

Cited by 37 publications

(38 citation statements)

References 73 publications

(60 reference statements)

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“…Abnormal expression of FBN1 and its interactors have been reported before in heart diseases (Mohamed et al, 2009) and in connective tissue diseases (Henrichsen et al, 2011), providing an idea of their importance in those systems.…”

Section: Resultsmentioning

confidence: 78%

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An integrative computational analysis provides evidence for FBN1-associated network deregulation in trisomy 21

2013

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SummaryAlthough approximately 50% of Down Syndrome (DS) patients have heart abnormalities, they exhibit an overprotection against cardiac abnormalities related with the connective tissue, for example a lower risk of coronary artery disease. A recent study reported a case of a person affected by DS who carried mutations in FBN1, the gene causative for a connective tissue disorder called Marfan Syndrome (MFS). The fact that the person did not have any cardiac alterations suggested compensation effects due to DS. This observation is supported by a previous DS meta-analysis at the molecular level where we have found an overall upregulation of FBN1 (which is usually downregulated in MFS). Additionally, that result was cross-validated with independent expression data from DS heart tissue. The aim of this work is to elucidate the role of FBN1 in DS and to establish a molecular link to MFS and MFS-related syndromes using a computational approach. To reach that, we conducted different analytical approaches over two DS studies (our previous meta-analysis and independent expression data from DS heart tissue) and revealed expression alterations in the FBN1 interaction network, in FBN1 co-expressed genes and FBN1-related pathways. After merging the significant results from different datasets with a Bayesian approach, we prioritized 85 genes that were able to distinguish control from DS cases. We further found evidence for several of these genes (47%), such as FBN1, DCN, and COL1A2, being dysregulated in MFS and MFS-related diseases. Consequently, we further encourage the scientific community to take into account FBN1 and its related network for the study of DS cardiovascular characteristics.

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Section: Resultsmentioning

confidence: 78%

“…FBN1 network components are already found deregulated in other syndromes/diseases (Henrichsen et al, 2011; Mohamed et al, 2009) indicates their importance for understanding heart-related disorders and abnormalities.…”

Section: Introductionmentioning

confidence: 96%

An integrative computational analysis provides evidence for FBN1-associated network deregulation in trisomy 21

2013

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“…Like ABHD11, ABHD14A may be involved in the pathophysiology of Williams-Beuren syndrome (WBS). In contrast to the deletion of ABHD11 in WBS, ABHD14A expression is higher in skin fibroblasts from WBS patients [85]. In addition, ABHD14A is also a candidate gene associated with autism spectrum disorder, a genetically complex disorder [86].…”

Section: Introductionmentioning

confidence: 99%

Mammalian alpha beta hydrolase domain (ABHD) proteins: Lipid metabolizing enzymes at the interface of cell signaling and energy metabolism

Lord

Thomas

Brown

2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

137

145

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Dysregulation of lipid metabolism underlies many chronic diseases such as obesity, diabetes, cardiovascular disease, and cancer. Therefore, understanding enzymatic mechanisms controlling lipid synthesis and degradation is imperative for successful drug discovery for these human diseases. Genes encoding α/β hydrolase fold domain (ABHD) proteins are present in virtually all reported genomes, and conserved structural motifs shared by these proteins predict common roles in lipid synthesis and degradation. However, the physiological substrates and products for these lipid metabolizing enzymes and their broader role in metabolic pathways remain largely uncharacterized. Recently, mutations in several members of the ABHD protein family have been implicated in inherited inborn errors of lipid metabolism. Furthermore, studies in cell and animal models have revealed important roles for ABHD proteins in lipid metabolism, lipid signal transduction, and metabolic disease. The purpose of this review is to provide a comprehensive summary surrounding the current state of knowledge regarding mammalian ABHD protein family members. In particular, we will discuss how ABHD proteins are ideally suited to act at the interface of lipid metabolism and signal transduction. Although, the current state of knowledge regarding mammalian ABHD proteins is still in its infancy, this review highlights the potential for the ABHD enzymes as being attractive targets for novel therapies targeting metabolic disease.

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“…Of the 868 identified differentially expressed genes, these authors found significant overrepresentation in major histocompatibility complex genes and gene products that localize to the postsynaptic membrane (39). This study went on to identify modules specific to the transcriptional profile of WS fibroblasts and compare them to other studies analyzing the transcriptional profile of control fibroblasts.…”

Section: Williams Syndromementioning

confidence: 99%

The developmental transcriptome of the human brain

Tebbenkamp¹,

Willsey

State

et al. 2014

Current Opinion in Neurology

105

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Purpose of review Recent characterizations of the transcriptome of the developing human brain by several groups have generated comprehensive datasets on coding and noncoding RNAs that will be instrumental for illuminating the underlying biology of complex neurodevelopmental disorders. This review summarizes recent studies successfully utilizing these data to increase our understanding of the molecular mechanisms of pathogenesis. Recent findings Several approaches have successfully integrated developmental transcriptome data with gene discovery to generate testable hypotheses about when and where in the developing human brain disease-associated genes converge. Specifically, these include the projection neurons in the prefrontal and primary motor-somatosensory cortex during mid-fetal development in autism spectrum disorder and the frontal cortex during fetal development in schizophrenia. Summary Developmental transcriptome data is a key to interpreting disease-associated mutations and transcriptional changes. Novel approaches integrating the spatial and temporal dimensions of these data have increased our understanding of when and where pathology occurs. Refinement of spatial and temporal properties and expanding these findings to other neurodevelopmental disorders will provide critical insights for understanding disease biology.

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Using Transcription Modules to Identify Expression Clusters Perturbed in Williams-Beuren Syndrome

Cited by 37 publications

References 73 publications

An integrative computational analysis provides evidence for FBN1-associated network deregulation in trisomy 21

An integrative computational analysis provides evidence for FBN1-associated network deregulation in trisomy 21

Mammalian alpha beta hydrolase domain (ABHD) proteins: Lipid metabolizing enzymes at the interface of cell signaling and energy metabolism

The developmental transcriptome of the human brain

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