Genetic variants in RBFOX3 are associated with sleep latency

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10-08, 6.59 × 10- 08 and 9.17 × 10- 08). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10- 02, 7.0 × 10- 03 and 2.5 × 10- 03; combined meta-analysis P-values=5.5 × 10-07, 5.4 × 10-07 and 1.0 × 10-07). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10-316) and the central nervous system (P-value=7.5 × 10- 321). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitte

A combined bioinformatics and proteomics approach identifies DNA repair factors regulated by the APC/C

Abstract Our genome is constantly challenged by endogenous and exogenous factors that induce a variety of DNA lesions. DNA double strand breaks are considered to most toxic type of DNA damage, and cells have evolved powerful mechanisms that can detect and repair such lesions. Two main mechanisms responsible for repair of DNA double strand breaks are Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). The choice between these two types of DNA double strand break repair is strongly influenced by the cell cycle. Only cells in late S and G2 phase of the cell cycle can employ HR and this differential activity is underscored by a strict requirement for Cdk activity for HR. Mechanisms that enable HR during S-phase have been previously identified, but how exactly HR DNA repair is inactivated during the mitosis-to-G1 transition is poorly understood. Based on the observed strict cell-cycle regulation of HR repair, a role for the mitotic E3 ligase APC/C was suggested. Here we present a combined proteomics and bioinformatics approach to identify APC/C targets and reveal components of DNA double strand break repair that are potential targets of the APC/C. Firstly, proteins were identified that contain evolutionary conserved and sterically accessibly APC/C targeting domains (KEN and D-boxes) using bioinformatics. Within this group of proteins with a known role in DNA repair were highlighted. Subsequently, a quantitative mass-spec approach was used to identify those proteins, whose abundance was readily lost upon mitotic exit. Reassuringly, we could identify many previously identified APC/C targets, that all showed loss of abundance during mitotic exit. We subsequently searched for DNA repair-associated factors that were down-regulated during mitotic exit and among those, we identified multiple topoisomerase subunits as likely APC/C substrates. We could subsequently confirm a role for the APC/C in regulating protein levels of these novel substrates using RNAi-mediated depletion of Cdh1 and live cell microscopy. In conclusion, we here present a novel method to identify APC/C targets and used this approach to uncover novel regulatory aspects of cell cycle-regulated DNA repair. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2960. doi:10.1158/1538-7445.AM2011-2960</jats:p

Quantitative proteomics analysis identifies MUC1 as an effect sensor of EGFR inhibition

Volume 14, Issue 12, Supplement

Unraveling the regulatory mechanisms underlying tissue-dependent genetic variation of gene expression.

It is known that genetic variants can affect gene expression, but it is not yet completely clear through what mechanisms genetic variation mediate this expression. We therefore compared the cis-effect of single nucleotide polymorphisms (SNPs) on gene expression between blood samples from 1,240 human subjects and four primary non-blood tissues (liver, subcutaneous, and visceral adipose tissue and skeletal muscle) from 85 subjects. We characterized four different mechanisms for 2,072 probes that show tissue-dependent genetic regulation between blood and non-blood tissues: on average 33.2% only showed cis-regulation in non-blood tissues; 14.5% of the eQTL probes were regulated by different, independent SNPs depending on the tissue of investigation. 47.9% showed a different effect size although they were regulated by the same SNPs. Surprisingly, we observed that 4.4% were regulated by the same SNP but with opposite allelic direction. We show here that SNPs that are located in transcriptional regulatory elements are enriched for tissue-dependent regulation, including SNPs at 3' and 5' untranslated regions (P = 1.84×10(-5) and 4.7×10(-4), respectively) and SNPs that are synonymous-coding (P = 9.9×10(-4)). SNPs that are associated with complex traits more often exert a tissue-dependent effect on gene expression (P = 2.6×10(-10)). Our study yields new insights into the genetic basis of tissue-dependent expression and suggests that complex trait associated genetic variants have even more complex regulatory effects than previously anticipated

Total serum N-glycans associate with response to immune checkpoint inhibition therapy and survival in patients with advanced melanoma

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma and other cancers. However, no reliable biomarker of survival or response has entered the clinic to identify those patients with melanoma who are most likely to benefit from ICIs. Glycosylation affects proteins and lipids' structure and functions. Tumours are characterized by aberrant glycosylation which may contribute to their progression and hinder an effective antitumour immune response.MethodsWe aim at identifying novel glyco-markers of response and survival by leveraging the N-glycome of total serum proteins collected in 88 ICI-naive patients with advanced melanoma from two European countries. Samples were collected before and during ICI treatment.ResultsWe observe that responders to ICIs present with a pre-treatment N-glycome profile significantly shifted towards higher abundancy of low-branched structures containing lower abundances of antennary fucose, and that this profile is positively associated with survival and a better predictor of response than clinical variables alone.ConclusionWhile changes in serum protein glycosylation have been previously implicated in a pro-metastatic melanoma behaviour, we show here that they are also associated with response to ICI, opening new avenues for the stratification of patients and the design of adjunct therapies aiming at improving immune response