Graded gene expression changes determine phenotype severity in mouse models of CRX-associated retinopathies

Ruzycki, Philip A.; Tran, Nicholas M.; Kefalov, Vladimir J.; Kolesnikov, Alexander V.; Chen, Shiming

doi:10.1186/s13059-015-0732-z

Cited by 43 publications

(72 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This led us to hypothesize that upregulation of ARSB may represent an important pathological mechanism associated with symptoms of cerebral embolization, consistent with previous findings that even small changes in gene expression can induce major phenotypic differences 17 . The ARSB enzyme catalyses de-sulphation of ubiquitous glycosaminoglycans such as chondroitin sulphate 23 .…”

Section: Discussionsupporting

confidence: 89%

Upregulation of arylsulfatase B in carotid atherosclerosis is associated with symptoms of cerebral embolization

Biroš

Moran

Maguire

et al. 2017

Sci Rep

View full text Add to dashboard Cite

The aim of this study was to identify genes for which the expression within carotid atherosclerosis was reproducibly associated with the symptoms of cerebral embolization. Two publically available microarray datasets E-MEXP-2257 and GSE21545 were analysed using GeneSpring 11.5. The two datasets utilized a total of 22 and 126 carotid atherosclerosis samples, obtained from patients with and without symptoms of cerebral embolization, respectively. To assess whether the findings were reproducible we analysed carotid atherosclerosis samples from another 8 patients with and 7 patients without symptoms of cerebral embolization using real-time PCR. In vitro studies using VSMC were performed to assess the functional relevance of one of the validated genes. We identified 1624 and 135 differentially expressed genes within carotid atherosclerosis samples of symptomatic compared to asymptomatic patients using the E-MEXP-2257 and GSE21545 datasets, respectively (≥1.15-absolute fold-change, P < 0.05). Only 7 differentially expressed genes or 0.4% (7/1,752) were consistent between the datasets. We validated the differential expression of ARSB which was upregulated 1.15-fold (P = 0.029) in atherosclerosis from symptomatic patients. In vitro incubation of VSMCs with the ARSB inhibitor L-ascorbic acid resulted in marked upregulation of SIRT1 and AMPK. This study suggests that ARSB may represent a novel target to limit carotid embolization.

show abstract

Section: Discussionsupporting

confidence: 89%

Upregulation of arylsulfatase B in carotid atherosclerosis is associated with symptoms of cerebral embolization

Biroš

Moran

Maguire

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Raw RNAseq data were obtained from previously published studies [GEO: GSE52006, GSE65506] [52, 53]. Reads were aligned to the mouse genome (version mm9) with TopHat2 (v.2.0.5) [54] using the following parameters: –a 5 -m 1 -i 10 -I 500000 -r 100 – p 4 –microexon-search –no-coverage-search -x 20 –segment-length 25.…”

Section: Star Methodsmentioning

confidence: 99%

Multiple Isoforms of Nesprin1 Are Integral Components of Ciliary Rootlets

et al. 2017

Self Cite

View full text Add to dashboard Cite

SUMMARY SYNE1 (Synaptic nuclear envelope 1) encodes multiple isoforms of Nesprin1 (Nuclear Envelope Spectrin 1) that associate with the nuclear envelope (NE) through a C-terminal KASH (Klarsicht/Anc1/Syne homology) domain (Figure 1A) [1–4]. This domain interacts directly with the SUN (Sad1/Unc84) domain of Sun proteins [5–7], a family of transmembrane proteins of the inner nuclear membrane (INM) [8, 9], to form the so-called LINC complexes (Linkers of the Nucleoskeleton and the Cytoskeleton) that span the whole NE and mediate nuclear positioning [10–12]. In a stark departure from this classical depiction of Nesprin1 in the context of the NE, we report that rootletin recruits Nesprin1α at the ciliary rootlets of photoreceptors and identified asymmetric NE aggregates of Nesprin1α and Sun2 that dock filaments of rootletin at the nuclear surface. In NIH3t3 cells, we show that recombinant rootletin filaments also dock to the NE through the specific recruitment of a ~600 kDa endogenous isoform of Nesprin1 (Nes1600kDa) and of Sun2. In agreement with the association of Nesprin1α with photoreceptor ciliary rootlets and the functional interaction between rootletin and Nesprin1 in fibroblasts, we demonstrate that multiple isoforms of Nesprin1 are integral components of ciliary rootlets of multiciliated ependymal and tracheal cells. Together, these data provide a novel functional paradigm for Nesprin1 at ciliary rootlets and suggest that the wide spectrum of human pathologies linked to truncating mutations of SYNE1 [13–15] may in part originate from ciliary defects.

show abstract

“…Genetically encoded variation in the transcript levels of normal or mutant CRX alleles may contribute to such variable expressivity. Indeed, mouse models of CRX-associated retinopathies provide evidence for a threshold effect in which small changes in expression cause large differences in phenotype 70 . Mutations in MRFP cause extreme hyperopia (farsightedness).…”

Section: Discussionmentioning

confidence: 99%

Ocular disease mechanisms elucidated by genetics of human fetal retinal pigment epithelium gene expression

Liu

Calton

Benchorin

et al. 2018

Preprint

View full text Add to dashboard Cite

The eye is an intricate organ with limited representation in large-scale functional genomics datasets. The retinal pigment epithelium (RPE) serves vital roles in ocular development and retinal homeostasis. We interrogated the genetics of gene expression of cultured human fetal RPE (fRPE) cells under two metabolic conditions. Genes with disproportionately high fRPE expression are enriched for genes related to inherited ocular diseases. Variants near these fRPE-selective genes explain a larger fraction of risk for both age-related macular degeneration (AMD) and myopia than variants near genes enriched in 53 other human tissues.Increased mitochondrial oxidation of glutamine by fRPE promoted expression of lipid synthesis genes implicated in AMD. Expression and splice quantitative trait loci (e/sQTL) analysis revealed shared and metabolic condition-specific loci of each type and several eQTL not previously described in any tissue. Fine mapping of fRPE e/sQTL across AMD and myopia genome-wide association data suggests new candidate genes, and mechanisms by which the same common variant of RDH5 contributes to both increased AMD risk and decreased myopia risk. Our study highlights the unique transcriptomic characteristics of fRPE and provides a resource to connect e/sQTL in a critical ocular cell type to monogenic and complex eye disorders.3The importance of vision to humans and the accessibility of the eye to examination have motivated the characterization of more than one thousand genetic conditions involving ocular phenotypes 1 . Among these, numerous monogenic diseases exhibit significant inter-and intra-familial phenotypic variability 2-7 . Imbalance in allelic expression of a handful of causative genes has been documented 8 , but common genetic variants responsible for such effects remain to be discovered.Complementing our knowledge of numerous monogenic ocular disorders, recent genome-wide association studies (GWAS) 9 have identified hundreds of independent loci associated with polygenic ocular phenotypes such as age-related macular degeneration (AMD), the leading cause of blindness in elderly individuals in developed countries 10,11 , and myopia, the most common type of refractive error worldwide and an increasingly common cause of blindness 12-14 . Despite the rapid success of GWAS in mapping novel ocular disease susceptibility loci, the functional mechanisms underlying these associations are often obscure.Connecting changes in molecular functions such as gene expression and splicing with specific GWAS genomic variants has aided the elucidation of functional mechanisms. Non-coding variants account for a preponderance of the most significant GWAS loci 15,16 , and most expression quantitative trait loci (eQTL) map to non-coding variants 17 . Thousands of eQTL have been found in a variety of human tissues 18 , but ocular celltypes are underrepresented among eQTL maps across diverse tissues, and no systematic search for eQTL has so far been described for any cell type in the human eye.The retinal pigment epithelium ...

show abstract

Graded gene expression changes determine phenotype severity in mouse models of CRX-associated retinopathies

Cited by 43 publications

References 49 publications

Upregulation of arylsulfatase B in carotid atherosclerosis is associated with symptoms of cerebral embolization

Upregulation of arylsulfatase B in carotid atherosclerosis is associated with symptoms of cerebral embolization

Multiple Isoforms of Nesprin1 Are Integral Components of Ciliary Rootlets

Ocular disease mechanisms elucidated by genetics of human fetal retinal pigment epithelium gene expression

Contact Info

Product

Resources

About