Search

Hypoxia-inducible transcription factors (HIFs) directly dictate the expression of multiple RNA species including novel and as yet uncharacterized long noncoding transcripts with unknown function. We used pan-genomic HIF-binding and transcriptomic data to identify a novel long noncoding RNA Noncoding Intergenic Co-Induced transcript (NICI) on chromosome 12p13.31 which is regulated by hypoxia via HIF-1 promoter-binding in multiple cell types. CRISPR/Cas9-mediated deletion of the hypoxia-response element revealed co-regulation of NICI and the neighboring protein-coding gene, solute carrier family 2 member 3 (SLC2A3) which encodes the high-affinity glucose transporter 3 (GLUT3). Knockdown or knockout of NICI attenuated hypoxic induction of SLC2A3, indicating a direct regulatory role of NICI in SLC2A3 expression, which was further evidenced by CRISPR/Cas9-VPR-mediated activation of NICI expression. We also demonstrate that regulation of SLC2A3 is mediated through transcriptional activation rather than posttranscriptional mechanisms because knockout of NICI leads to reduced recruitment of RNA polymerase 2 to the SLC2A3 promoter. Consistent with this we observe NICI-dependent regulation of glucose consumption and cell proliferation. Furthermore, NICI expression is regulated by the von Hippel-Lindau (VHL) tumor suppressor and is highly expressed in clear cell renal cell carcinoma (ccRCC), where SLC2A3 expression is associated with patient prognosis, implying an important role for the HIF/NICI/SLC2A3 axis in this malignancy.

Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel–Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins. Moreover, we demonstrate that the risk-associated polymorphisms increase chromatin accessibility and activity as well as HIF binding to the enhancer. These findings provide further evidence that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL–HIF axis and provide a functional explanation for the disease-associated effects of SNPs in ccRCC., Genome-wide association studies have identified multiple loci associated with the risk of developing renal cancer. Here, the authors show that one of these loci generates open chromatin, which enhances the binding of HIF and HIF-mediated transactivation of MYC.

Parametric surfaces are an essential modeling tool in computer aided design and movie production. Even though their use is well established in industry, generating ray-traced images adds significant cost in time and memory consumption. Ray tracing such surfaces is usually accomplished by subdividing the surfaces on the fly, or by conversion to a polygonal representation. However, on-the-fly subdivision is computationally very expensive, whereas polygonal meshes require large amounts of memory. This is a particular problem for parametric surfaces with displacement, where very fine tessellation is required to faithfully represent the shape. Hence, memory restrictions are the major challenge in production rendering. In this article, we present a novel solution to this problem. We propose a compression scheme for a priori Bounding Volume Hierarchies (BVHs) on parametric patches, that reduces the data required for the hierarchy by a factor of up to 48. We further propose an approximate evaluation method that does not require leaf geometry, yielding an overall reduction of memory consumption by a factor of 60 over regular BVHs on indexed face sets and by a factor of 16 over established state-of-the-art compression schemes. Alternatively, our compression can simply be applied to a standard BVH while keeping the leaf geometry, resulting in a compression rate of up to 2:1 over current methods. Although decompression generates additional costs during traversal, we can manage very complex scenes even on the memory restrictive GPU at competitive render times.