Determining the impact of alternative splicing events on transcriptome dynamics

<p>Abstract</p> <p>Background</p> <p>The complete sequencing of the human genome and its subsequent analysis revealed a predominant role for alternative splicing in the generation of proteome diversity. Splice switching oligonucleotides (SSOs) are a powerful and specific tool to experimentally control alternative splicing of endogenous messenger RNAs in living cells. SSOs also have therapeutic potential to treat diseases that are caused by aberrant splicing. The assignment of biological roles to alternative splicing events of currently unknown function promises to provide a largely untapped source of potential new therapeutic targets. Here we have developed a protocol that combines high sensitivity microarrays with the transfection of SSOs to monitor global changes in gene expression downstream of alternate, endogenous splice events.</p> <p>Results</p> <p>When applied to a well-characterized splicing event in the Bcl-x gene, the application of high sensitivity microarrays revealed a link between the induction of the Bcl-xS isoform and the repression of genes involved in protein synthesis.</p> <p>Conclusion</p> <p>The strategy introduced herein provides a useful approach to define the biological impact of any given alternative splicing event on global gene expression patterns. Furthermore, our data provide the first link between Bcl-xS expression and the repression of ribosomal protein gene expression.</p

TAF6δ Controls Apoptosis and Gene Expression in the Absence of p53

BACKGROUND: Life and death decisions of metazoan cells hinge on the balance between the expression of pro- versus anti-apoptotic gene products. The general RNA polymerase II transcription factor, TFIID, plays a central role in the regulation of gene expression through its core promoter recognition and co-activator functions. The core TFIID subunit TAF6 acts in vitro as an essential co-activator of transcription for the p53 tumor suppressor protein. We previously identified a splice variant of TAF6, termed TAF6delta that can be induced during apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the impact of TAF6delta on cell death and gene expression, we have employed modified antisense oligonucleotides to enforce expression of endogenous TAF6delta. The induction of endogenous TAF6delta triggered apoptosis in tumor cell lines, including cells devoid of p53. Microarray experiments revealed that TAF6delta activates gene expression independently of cellular p53 status. CONCLUSIONS: Our data define TAF6delta as a pivotal node in a signaling pathway that controls gene expression programs and apoptosis in the absence of p53

Women in economics: Europe and the world

Based on a data set that we collected from the top research institutions in economics around the globe (including universities, business schools and other or- ganizations such as central banks), we document the underrepresentation of women in economics. For the 238 universities and business schools in the sample, women hold 25% of senior level positions (full professor, associate professor) and 37% of junior level positions. In the 82 U.S. universities and business schools, the figures are 20% on the senior level and 32% on the entry level, while in the 122 European institutions, the numbers are 27% and 38%, respectively, with some heterogeneity across countries. The numbers also show that the highest-ranking institutions (in terms of research output) have fewer women in senior positions. Moreover, in the U.S., this effect is even present on the junior level. The “leaky pipeline” may hence begin earlier than oftentimes assumed, and is even more of an issue in the highly integrated market of the U.S. In Europe, an institution ranked 100 places higher has three percentage points fewer women in senior positions, but in the U.S. it is almost five percentage points

Women in economics: Europe and the world

Based on a data set that we collected from the top research institutions in economics around the globe (including universities, business schools and other or- ganizations such as central banks), we document the underrepresentation of women in economics. For the 238 universities and business schools in the sample, women hold 25% of senior level positions (full professor, associate professor) and 37% of junior level positions. In the 82 U.S. universities and business schools, the figures are 20% on the senior level and 32% on the entry level, while in the 122 European institutions, the numbers are 27% and 38%, respectively, with some heterogeneity across countries. The numbers also show that the highest-ranking institutions (in terms of research output) have fewer women in senior positions. Moreover, in the U.S., this effect is even present on the junior level. The “leaky pipeline” may hence begin earlier than oftentimes assumed, and is even more of an issue in the highly integrated market of the U.S. In Europe, an institution ranked 100 places higher has three percentage points fewer women in senior positions, but in the U.S. it is almost five percentage points

TAF6δ orchestrates an apoptotic transcriptome profile and interacts functionally with p53

<p>Abstract</p> <p>Background</p> <p>TFIID is a multiprotein complex that plays a pivotal role in the regulation of RNA polymerase II (Pol II) transcription owing to its core promoter recognition and co-activator functions. TAF6 is a core TFIID subunit whose splice variants include the major TAF6α isoform that is ubiquitously expressed, and the inducible TAF6δ. In contrast to TAF6α, TAF6δ is a pro-apoptotic isoform with a 10 amino acid deletion in its histone fold domain that abolishes its interaction with TAF9. TAF6δ expression can dictate life versus death decisions of human cells.</p> <p>Results</p> <p>Here we define the impact of endogenous TAF6δ expression on the global transcriptome landscape. TAF6δ was found to orchestrate a transcription profile that included statistically significant enrichment of genes of apoptotic function. Interestingly, gene expression patterns controlled by TAF6δ share similarities with, but are not equivalent to, those reported to change following TAF9 and/or TAF9b depletion. Finally, because TAF6δ regulates certain p53 target genes, we tested and demonstrated a physical and functional interaction between TAF6δ and p53.</p> <p>Conclusion</p> <p>Together our data define a TAF6δ-driven apoptotic gene expression program and show crosstalk between the p53 and TAF6δ pathways.</p

An Assessment of GUCA1C Variants in Primary Congenital Glaucoma

Note: In lieu of an abstract, this is an excerpt from the first page. In the special issue “Molecular Genetics of Retinal Dystrophies”, Morales–Cámara and colleagues reported the association of a new candidate gene with primary congenital glaucoma (PCG) [...

Comparison of stereotactic radiotherapy and protons for uveal melanoma patients

Background and purpose: Uveal melanoma (UM) is the most common primary ocular malignancy. We compared fractionated stereotactic radiotherapy (SRT) with proton therapy, including toxicity risks for UM patients. Materials and methods: For a total of 66 UM patients from a single center, SRT dose distributions were compared to protons using the same planning CT. Fourteen dose-volume parameters were compared in 2-Gy equivalent dose per fraction (EQD2). Four toxicity profiles were evaluated: maculopathy, optic-neuropathy, visual acuity impairment (Profile I); neovascular glaucoma (Profile II); radiation-induced retinopathy (Profile III); and dry-eye syndrome (Profile IV). For Profile III, retina Mercator maps were generated to visualize the geographical location of dose differences. Results: In 9/66 cases, (14 %) proton plans were superior for all dose-volume parameters. Higher T stages benefited more from protons in Profile I, especially tumors located within 3 mm or less from the optic nerve. In Profile II, only 9/66 cases resulted in a better proton plan. In Profile III, better retina volume sparing was always achievable with protons, with a larger gain for T3 tumors. In Profile IV, protons always reduced the risk of toxicity with a median RBE-weighted EQD2 reduction of 15.3 Gy. Conclusions: This study reports the first side-by-side imaging-based planning comparison between protons and SRT for UM patients. Globally, while protons appear almost always better regarding the risk of optic-neuropathy, retinopathy and dry-eye syndrome, for other toxicity like neovascular glaucoma, a plan comparison is warranted. Choice would depend on the prioritization of risks.</p

Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis

Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix® HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotyp

PTX3 Polymorphisms and Invasive Mold Infections After Solid Organ Transplant

Donor PTX3 polymorphisms were shown to influence the risk of invasive aspergillosis among hematopoietic stem cell transplant recipients. Here, we show that PTX3 polymorphisms are independent risk factors for invasive mold infections among 1101 solid organ transplant recipients, thereby strengthening their role in mold infection pathogenesis and patients' risk stratificatio