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Glioblastoma multiforme is a brain malignancy characterized by high heterogeneity, invasiveness, and resistance to current therapies, attributes related to the occurrence of glioma stem cells (GSCs). Transforming growth factor β (TGFβ) promotes self-renewal and bone morphogenetic protein (BMP) induces differentiation of GSCs. BMP7 induces the transcription factor Snail to promote astrocytic differentiation in GSCs and suppress tumor growth in vivo. We demonstrate that Snail represses stemness in GSCs. Snail interacts with SMAD signaling mediators, generates a positive feedback loop of BMP signaling and transcriptionally represses the TGFB1 gene, decreasing TGFβ1 signaling activity. Exogenous TGFβ1 counteracts Snail function in vitro, and in vivo promotes proliferation and re-expression of Nestin, confirming the importance of TGFB1 gene repression by Snail. In conclusion, novel insight highlights mechanisms whereby Snail differentially regulates the activity of the opposing BMP and TGFβ pathways, thus promoting an astrocytic fate switch and repressing stemness in GSCs.

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis -eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis- eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis- eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis- eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2 . Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues. Mechanistic inference following GWAS is hampered by the lack of tissue-specific transcriptomic resources. Here the authors combine genetic variants predisposing to type 2 diabetes with human pancreatic islet RNA-seq data. They identify 7741 islet expression quantitative trait loci (eQTLs), providing a resource for functional interpretation of association signals mapping to non-coding sequence.

Background Optical coherence tomography angiography (OCTA) is a relatively new extension of Optical coherence tomography (OCT) that generates non-invasive, depth-resolved images of the retinal microvasculature which allows for the detection of various features of diabetic retinopathy. Objectives This study aimed to detect biomarkers that may predict an early anatomical response to the treatment of diabetic macular edema (DME) with intravitreal ranibizumab (IVR) by means of OCTA. Patients and methods This prospective interventional study was undertaken on 111 eyes of 102 naïve participants who had diabetic macular edema; enrolled patients were evaluated by taking a complete ophthalmologic history, examination and investigations by use of a pre-designed checklist involving Optical Coherence Tomography Angiography. Results Regarding the best corrected visual acuity (BCVA) the Mean ± SD was 0.704 ± 0.158 preoperatively and 0.305 ± 0.131 postoperatively in good responder patients; and was 0.661 ± 0.164 preoperatively and 0.54 ± 0.178 postoperatively in poor responders. The central macular thickness (CMT) was 436.22 ± 54.66 μm preoperatively and 308.12 ± 33.09 μm postoperatively in good responder patients; and was 387.74 ± 44.05 μm preoperatively and 372.09 ± 52.86 μm postoperatively in poor responders. By comparing the pre injection size of the foveal avascular zone area (FAZ-A) in both groups, it found that the mean ± SD of FAZ-A was 0.297 ± 0.038 mm in good responder patients compared to 0.407 ± 0.05 mm in non-responder patients. The preoperative superficial capillary plexus (SCP) foveal vascular density (VD) was 24.02 ± 3.01% in good responder patients versus 17.89 ± 3.19% um in poor responders. The preoperative SCP parafoveal VD was 43.06 ± 2.67% in good responder patients versus 37.96 ± 1.82% um in poor responders. The preoperative deep capillary plexus (DCP) foveal VD was 30.58 ± 2.89% in good responder patients versus 25.45 ± 3.14% in poor responders. The preoperative DCP parafoveal VD was 45.66 ± 2.21% in good responder patients versus 43.26 ± 2.35% um in poor responders, this was statistically significant. Conclusion OCTA offers an accurate measurement for VD in the macula as well as the FAZ-A which could be used to predict an early anatomical response of anti-VEGF treatment in DME.

Parent-of-origin effects (POE) and sex-specific parental effects have been reported for plasma lipid levels, and a strong relationship exists between dyslipidemia and obesity. We aim to explore whether genetic variants previously reported to have an association to lipid traits also show POE on blood lipid levels and obesity. Families from the Botnia cohort and the Hungarian Transdanubian Biobank (HTB) were genotyped for 12 SNPs, parental origin of alleles were inferred, and generalized estimating equations were modeled to assess parental-specific associations with lipid traits and obesity. POE were observed for the variants at the TMEM57, DOCK7/ANGPTL3, LPL, and APOA on lipid traits, the latter replicated in HTB. Sex-specific parental effects were also observed; variants at ANGPTL3/DOCK7 showed POE on lipid traits and obesity in daughters only, while those at LPL and TMEM57 showed POE on lipid traits in sons. Variants at LPL and DOCK7/ANGPTL3 showed POE on obesity-related traits in Botnia and HTB, and POE effects on obesity were seen to a higher degree in daughters. This highlights the need to include analysis of POEs in genetic studies of complex traits.

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs. Objective Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we aimed to identify and characterize embryonic signaling pathways that were reinitiated during tumor formation and expansion. Methods and Results Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC‐1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells. Conclusion Our findings illustrate that E2F1 and E2F8 transcription factors are expressed in pancreatic progenitor and PDAC cells, where they contribute to tumor cell expansion by regulation of cell proliferation, viability, and cell migration making these genes attractive therapeutic targets and potential prognostic markers for pancreatic cancer.

Characterization of gene expression in pancreatic islets and its alteration in type 2 diabetes (T2D) are vital in understanding islet function and T2D pathogenesis. We leveraged RNA sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. Expression data were related to islet phenotypes, diabetes status, other islet-expressed genes, islet hormone-encoding genes and for expression in insulin target tissues. The IGW web application produces output graphs for a particular gene of interest. In IGW, 284 differentially expressed genes (DEGs) were identified in T2D donor islets compared with controls. Forty percent of DEGs showed cell-type enrichment and a large proportion significantly co-expressed with islet hormone-encoding genes; glucagon ( GCG , 56%), amylin ( IAPP , 52%), insulin ( INS , 44%), and somatostatin ( SST , 24%). Inhibition of two DEGs, UNC5D and SERPINE2 , impaired glucose-stimulated insulin secretion and impacted cell survival in a human β-cell model. The exploratory use of IGW could help designing more comprehensive functional follow-up studies and serve to identify therapeutic targets in T2D.

Glioblastoma multiforme is a brain malignancy characterized by high heterogeneity, invasiveness, and resistance to current therapies, attributes related to the occurrence of glioma stem cells (GSCs). Transforming growth factor [beta] (TGF[beta]) promotes self-renewal and bone morphogenetic protein (BMP) induces differentiation of GSCs. BMP7 induces the transcription factor Snail to promote astrocytic differentiation in GSCs and suppress tumor growth in vivo. We demonstrate that Snail represses stemness in GSCs. Snail interacts with SMAD signaling mediators, generates a positive feedback loop of BMP signaling and transcriptionally represses the TGFB1 gene, decreasing TGF[beta]1 signaling activity. Exogenous TGF[beta]1 counteracts Snail function in vitro, and in vivo promotes proliferation and re-expression of Nestin, confirming the importance of TGFB1 gene repression by Snail. In conclusion, novel insight highlights mechanisms whereby Snail differentially regulates the activity of the opposing BMP and TGF[beta] pathways, thus promoting an astrocytic fate switch and repressing stemness in GSCs.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with limited treatment options, illustrating an urgent need to identify new drugable targets in PDACs. Using the similarities between tumor development and normal embryonic development, which is accompanied by rapid cell expansion, we identified embryonic signalling pathways that were reinitiated during tumor formation and expansion. Here, we report that the transcription factors E2F1 and E2F8 are potential key regulators in PDAC. E2F1 and E2F8 RNA expression is mainly localized in proliferating cells in the developing pancreas and in malignant ductal cells in PDAC. Silencing of E2F1 and E2F8 in PANC-1 pancreatic tumor cells inhibited cell proliferation and impaired cell spreading and migration. Moreover, loss of E2F1 also affected cell viability and apoptosis with E2F expression in PDAC tissues correlating with expression of apoptosis and mitosis pathway genes, suggesting that E2F factors promote cell cycle regulation and tumorigenesis in PDAC cells. In conclusion, our findings show that E2F1 and E2F8 transcription factors regulate cell proliferation, survival, and migration during pancreatic carcinogenesis.Competing Interest StatementThe authors have declared no competing interest.

Abstract Changes in the hormone-producing pancreatic islets are central culprits in type 2 diabetes (T2D) pathogenesis. Characterization of gene expression in islets how it is altered in T2D are therefore vital in understanding islet function and T2D pathogenesis. We leveraged RNA-sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. The IGW combines expression data for a given gene with phenotypical data such as T2D status, BMI, HbA1c, insulin secretion, purity of islets, etc.), regulation of gene expression by genetic variants e.g., expression quantitative trait loci (eQTLs) and relationship with expression of islet hormones. In IGW, 285 differentially expressed genes (DEGs) were identified in T2D donors islets compared to controls. Forty percent of the DEGs showed cell-type enrichment and a large proportion of them were significantly co-expressed with islet hormone-encoding genes like glucagon (GCG, 56%), amylin (IAPP, 52%), insulin (INS, 44%) and somatostatin (SST, 24%). Inhibition of two DEGs, UNC5D and SERPINE2 impaired glucose-stimulated insulin secretion and impacted cell survival in a human beta-cell model. Significance Statement We present Islet Gene View (IGW), a web resource facilitating information on gene expression in human pancreatic islets from organ donors easily accessible to the scientific community. In IGW, we explored RNA expression from 188 donor-islets and examined their relationship with islet phenotypes including insulin secretion and expression of genes encoding islet hormones. GWAS have shown 403 genetic variants associated with risk of type 2 diabetes (T2D) risk, however, the target genes and function of these variants in islets are largely unknown. By linking T2D risk variants to expression in islets from T2D and non-diabetic donors as well as islet phenotypes, use of IGW provided new insight into mechanisms by which variants in these loci may increase risk of T2D. Competing Interest Statement The authors have declared no competing interest.

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, many key tissues and cell-types required for appropriate functional inference are absent from large-scale resources such as ENCODE and GTEx. We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors. We find: (a) eQTLs have a variable replication rate across the 44 GTEx tissues (<73%), indicating that our study captured islet-specific cis-eQTL signals; (b) islet eQTL signals show marked overlap with islet epigenome annotation, though eQTL effect size is reduced in the stretch enhancers most strongly implicated in GWAS signal location; (c) selective enrichment of islet eQTL overlap with the subset of T2D variants implicated in islet dysfunction; and (d) colocalization between islet eQTLs and variants influencing T2D or related glycemic traits, delivering candidate effector transcripts at 23 loci, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in tissues of greatest disease-relevance while expanding our mechanistic insights into complex traits association loci activity with an expanded list of putative transcripts implicated in T2D development.