Many low-penetrance breast cancer susceptibility loci are found to be located in non-protein-coding regions, suggesting their involvement in gene expression regulation. We identified the human/rat-conserved breast cancer susceptibility locus MCS5A/Mcs5a. This locus has been shown to act in a non-mammary cell-autonomous fashion through the immune system. The resistant Mcs5a allele from the Wistar–Kyoto (WKy) rat strain consists of two non-protein-coding genetic elements that must be located on the same chromosome to elicit the phenotype. In this study, we show the presence of a conserved higher order chromatin structure in MCS5A/Mcs5a located in between the synthetically interacting genetic elements. The looped elements are shown to be bound by CTCF and cohesin. We identify the downregulation of Fbxo10 expression in T cells as a strong candidate mechanism through which the interacting genetic elements of the resistant Mcs5a allele modulate mammary carcinoma susceptibility. Finally, we show that the human MCS5A polymorphisms associated with breast cancer risk are located at both sides of the looped structure and functionally interact to downregulate transcriptional activity, similar to rat Mcs5a. We propose a mechanistic model for MCS5a/Mcs5a in which a CTCF-mediated insulator loop encompassing the TOMM5/Tomm5 gene, resides in between and brings into closer physical proximity the synthetically and functionally interacting resistant genetic variants.
Smits, Bart M. G.; Traun, Benjamin D.; Devries, Thomas L.; Tran, Ann; Samuelson, David; Haag, Jill D.; Gould, Michael
Bacterial heat-labile (LT) enterotoxins signal through tightly regulated interactions with host cell gangliosides. LT-IIa and LT-IIb of Escherichia coli bind preferentially to gangliosides with a NeuAcα2-3Galβ1-3GalNAc terminus, with key distinctions in specificity. LT-IIc, a newly discove ... more
Phosphate deficiency is characteristic for many natural habitats, resulting in different physiological responses in plants and bacteria including the replacement of phospholipids by glycolipids and other phosphorous-free lipids. The plant pathogenic bacterium Agrobacterium tumefaciens, whi ... more
A tryptophan side chain was introduced into subsite +1 of family GH-18 (class V) chitinases from Nicotiana tabacum and Arabidopsis thaliana (NtChiV and AtChiC, respectively) by the mutation of a glycine residue to tryptophan (G74W-NtChiV and G75W-AtChiC). The specific activity toward glyco ... more