Chemical Probe For Tudor Domain Protein Spin1 to Investigate Chromatin Functions
Fagan V., Johansson C., Gileadi C., Monteiro O., Dunford JAMES., Nibhani R., Philpott M., Malzahn J., Wells G., Farham R., Cribbs A., Halidi N., Li F., Chau I., Greschik H., Velupillai S., Hassani AA., Bennett J., Christott T., Giroud C., Lewis A., Huber K., Athanasou N., Bountra C., Jung M., Schüle R., Vedadi M., Arrowsmith C., Xiong Y., Jin J., Fedorov O., Farnie G., Brennan P., Oppermann UDO.
Lysine and arginine methylation are amongst the most frequent modifications on unstructured histone tails and incombination with other modifications provide the basis for a combinatorial 'chromatin or histone code'. Recognition of modifiedhistone residues is accomplished in a specific manner by 'reader' domains that recognize chromatin modifications, allowing forassociation with specific effector complexes that mediate chromatin functions. The methyl-lysine and methyl-arginine reader domainprotein SPINDLIN1 (SPIN1) belongs to a family of 5 human genes, and has been identified as a putative oncogene and transcriptionalco-activator. It contains three Tudor domains that are able to mediate chromatin binding. Here we report on the discoveryof a potent and selective bidentate Tudor domain inhibitor, which simultaneously engages Tudor domains 1 and 2 and effectivelycompetes with chromatin binding in cells. Inhibitor, chemoproteomic and knockdown studies in squamous cell carcinoma indicatecomplex SPIN-mediated chromatin interactions leading to transcriptional changes in cellular differentiation processes.