Promoters are DNA sequences that have an essential role in controlling gene expression. While recent whole cancer genome analyses have identified numerous hotspots of somatic point mutations within promoters, many have not yet been shown to perturb gene expression or drive cancer development. As such, positive selection alone may not adequately explain the frequency of promoter point mutations in cancer genomes. Here we show that increased mutation density at gene promoters can be linked to promoter activity and differential nucleotide excision repair (NER). By analysing 1,161 human cancer genomes across 14 cancer types, we find evidence for increased local density of somatic point mutations within the centres of DNase I-hypersensitive sites (DHSs) in gene promoters. Mutated DHSs were strongly associated with transcription initiation activity, in which active promoters but not enhancers of equal DNase I hypersensitivity were most mutated relative to their flanking regions. Notably, analysis of genome-wide maps of NER shows that NER is impaired within the DHS centre of active gene promoters, while XPC-deficient skin cancers do not show increased promoter mutation density, pinpointing differential NER as the underlying cause of these mutation hotspots. Consistent with this finding, we observe that melanomas with an ultraviolet-induced DNA damage mutation signature show greatest enrichment of promoter mutations, whereas cancers that are not highly dependent on NER, such as colon cancer, show no sign of such enrichment. Taken together, our analysis has uncovered the presence of a previously unknown mechanism linking transcription initiation and NER as a major contributor of somatic point mutation hotspots at active gene promoters in cancer genomes.

Key Points Genome-wide binding profiles of FLI1, ERG, GATA2, RUNX1, SCL, LMO2, and LYL1 in human HSPCs reveals patterns of combinatorial TF binding. Integrative analysis of transcription factor binding reveals a densely interconnected network of coding and noncoding genes in human HSPCs.

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Based on the principle of stability of geopolymer gel as refractory binder, a geopolymeric paste in the K2O-Al2O3-SiO 2 system was developed and used to produce refractory concretes by adding various amount of α-quartz sand (grain size in the range 0.1 μm to 1 mm) and fine powder alumina (grain size in the range 0.1-100 μm). The consolidated samples were characterized before and after sintering using optical dilatometer, DSC, XRD and SEM. The total shrinkage in the range of 25-900 °C was less than 3%, reduced with respect to the most diffused potassium or sodium based geopolymer systems, which generally records a >5% shrinkage. The maximum shrinkage of the basic geopolymer composition was recorded at 1000 °C with a 17% shrinkage which is reduced to 12% by alumina addition. The temperature of maximum densification was shifted from 1000 °C to 1150 or 1200 °C by adding 75 wt% α-quartz sand or fine powder alumina respectively. The sequences of sintering of geopolymer concretes could be resumed as dehydration, dehydroxylation, densification and finally plastic deformation due to the importance of liquid phase. The geopolymer formulations developed in this study appeared as promising candidates for high-temperature applications: refractory, fire resistant or insulating materials

Transmission electron microscopy of a geopolymer phase, derived from metakaolin and alkaline silicate solutions and having nominal Na/Al and Si/Al molar ratios of 1 and 2, respectively, showed it to be amorphous on the ∼1 nm scale after curing at 40°C. In samples containing 5 wt% Cs or Sr, Cs inhabited the amorphous phase, whereas Sr was incorporated only partly, being preferentially partitioned to crystalline SrCO3. Heating progressively to dewater the material had little effect on the overall structure for temperatures up to 500°C. From solid‐state nuclear magnetic resonance in material cured at near‐ambient temperatures, Cs, like Na, was found to be basically associated with pore water, but with significant linkage to the aluminosilicate framework, more so than for Na. Subsequent heating to 300°C increased the linkage of Cs and Na to the framework.

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The presence of Panx1 in the colon and changes to its distribution in disease suggests that Panx1 channels may play an important role in mediating gut function and in IBD pathophysiology.

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