Transcriptome correlation analysis identifies two unique craniosynostosis subtypes associated with IRS1 activation

Stamper, Brendan D.; Mecham, Brig; Park, S. S.; Wilkerson, H.; Farin, Frederico M.; Beyer, Richard P.; Bammler, Theo K.; Mangravite, Lara M.; Cunningham, Michael L.

doi:10.1152/physiolgenomics.00085.2012

Cited by 17 publications

(16 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, MSX2 and IGF1 were upregulated in sagOB-Fs with low BrdU incorporation and both MSX2 and IGF1 have well established roles in osteoblast differentiation. [55-57] Previous studies in our laboratory identified an IGF1 subtype within our craniosynostosis population [58] suggesting an important role of IGF1 in the development of craniosynostosis. Our correlation analysis also identified genes that while not found in the GO search, contribute to osteoblast biology.…”

Section: Discussionmentioning

confidence: 94%

Osteoblast differentiation profiles define sex specific gene expression patterns in craniosynostosis

Park¹,

Beyer

Smyth

et al. 2015

Bone

View full text Add to dashboard Cite

Single suture craniosynostosis (SSC) is the premature fusion of one calvarial suture and occurs in 1-1,700-2,500 live births. Congenital fusion of either the sagittal, metopic, or coronal sutures represents 95% of all cases of SSC. Sagittal and metopic synostosis have a male preponderance (3:1) while premature fusion of the coronal suture has a female preponderance (2:1). Although environmental and genetic factors contribute to SSC, the etiology of the majority of SSC cases remains unclear. In this study, 227 primary calvarial osteoblast cell lines from patients with coronal, metopic, or sagittal synostosis and unaffected controls were established and assayed for ALP activity and BrdU incorporation (n=226) as respective measures of early stage osteoblast differentiation and proliferation. Primary osteoblast cell lines from individuals with sagittal synostosis demonstrated higher levels of ALP activity and reduced proliferation when compared to control lines. In order to address the sex differences in SSC types, the data was further stratified by sex. Osteoblasts from males and females with sagittal synostosis as well as males with metopic synostosis demonstrated higher levels of ALP activity when compared to sex matched controls, and males with sagittal or metopic synostosis demonstrated reduced levels of proliferation. In order to elucidate genes and pathways involved in these observed phenotypes, correlation analyses comparing ALP activity and proliferation to global gene expression was performed. Transcripts related to osteoblast differentiation were identified both differentially up and down regulated, correlated with ALP activity when compared to controls, and demonstrated a striking sex specific gene expression pattern. These data support that the dysregulation of osteoblast differentiation plays a role in the development of SSC and that genetic factors contribute to the observed sex related differences.

show abstract

Section: Discussionmentioning

confidence: 94%

Osteoblast differentiation profiles define sex specific gene expression patterns in craniosynostosis

Park¹,

Beyer

Smyth

et al. 2015

Bone

View full text Add to dashboard Cite

show abstract

“…In addition, gain-of-function mutations in IGF1R have been identified in some non-syndromic craniosynastosis where the mechanism seems to be through activation of IRS1. 56 IGF-1 is likely to regulate both local and systemic energy metabolism. For example, it has been shown that during osteoblast differentiation the cells that are in a predifferentiation stage have lower number of active mitochondria and are more glycolytic in their energy consumption.…”

Section: Resultsmentioning

confidence: 99%

IGF-1 regulation of key signaling pathways in bone

2013

View full text Add to dashboard Cite

Insulin-like growth factor 1 (IGF-1) is an unique peptide that functions in an endocrine/paracrine and autocrine manner in most tissues. Although it was postulated initially that liver-derived IGF-1 was the major source of IGF-1 (that is, the somatomedin hypothesis), it is also produced in a wide variety of tissues and can function in numerous ways as both a proliferative and differentiative factor. One such tissue is bone and all cell lineages in the skeleton have been shown to not only require IGF-1 for normal development and function but also to respond to IGF-1 via the IGF-1 receptor. Ligandreceptor activation leads to several distinct downstream signaling cascades, which have significant implications for cell survival, protein synthesis and energy utilization. The novel role of IGF-1 in regulating metabolic demands of the bone remodeling unit is currently under investigation. More studies are likely to shed new light on various aspects of skeletal physiology and potentially may lead to new therapeutics.

show abstract

“…Various strategies have been employed to overcome these obstacles, ranging from protocol standardization across research centers to mandatory reporting standards such as MIAME (Beyer et al, 2007;Brazma et al, 2001). These strategies, coupled with public and private gene expression data repositories have greatly facilitated biomarker discovery efforts; however, a large number of these studies are required to generate the necessary statistical power and leverage to fuel these discoveries (Kodama et al, 2012;Stamper et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of reactive metabolites for elucidating toxicological mechanisms: a case study of quinoneimine-forming agents

Stamper

2014

Drug Metabolism Reviews

View full text Add to dashboard Cite

Toxicogenomics can be broadly defined as the study of how the genetic material responds to toxicant exposure. This sub-discipline of toxicology utilizes numerous genomic technologies to relate adverse toxicologic effects with their associated changes in gene expression. The scope of this review will focus on microarray technology and its use in identifying key biomarkers at both the single gene and pathway levels to elucidate toxicologic mechanisms in the liver. Microarrays have been used to study global transcriptomic changes associated with toxicants for years; however, limited emphasis has been placed on what role their reactive metabolites play in this process. Reactive metabolites, which can be generated by normal oxidative metabolism, have the potential to react with endogenous biomolecules, alter their function, and elicit a toxicogenomic response. Quinoneimines are an example of such a species, eliciting toxicity through the generation of oxidative and electrophilic stress. Five compounds with differing toxicity profiles are evaluated herein that are capable of forming quinoneimine intermediates by cytochrome P450 enzymes. They include acetaminophen (APAP), amodiaquine, atorvastatin, carvedilol, and diclofenac. Perspectives on the consistency between the hepatic gene expression profiles of these quinoneimine-forming agents as well as the untapped value of structure-based transcriptome profiling are discussed in this review.

show abstract

Transcriptome correlation analysis identifies two unique craniosynostosis subtypes associated with IRS1 activation

Cited by 17 publications

References 51 publications

Osteoblast differentiation profiles define sex specific gene expression patterns in craniosynostosis

Osteoblast differentiation profiles define sex specific gene expression patterns in craniosynostosis

IGF-1 regulation of key signaling pathways in bone

Transcriptional profiling of reactive metabolites for elucidating toxicological mechanisms: a case study of quinoneimine-forming agents

Contact Info

Product

Resources

About