A Chemical Probe For Tudor Domain Protein Spin1 to Investigate Chromatin Functions

<div>Lysine and arginine methylation are amongst the most frequent modifications on unstructured histone tails and in</div><div>combination with other modifications provide the basis for a combinatorial 'chromatin or histone code'. Recognition of modified</div><div>histone residues is accomplished in a specific manner by 'reader' domains that recognize chromatin modifications, allowing for</div><div>association with specific effector complexes that mediate chromatin functions. The methyl-lysine and methyl-arginine reader domain</div><div>protein SPINDLIN1 (SPIN1) belongs to a family of 5 human genes, and has been identified as a putative oncogene and transcriptional</div><div>co-activator. It contains three Tudor domains that are able to mediate chromatin binding. Here we report on the discovery</div><div>of a potent and selective bidentate Tudor domain inhibitor, which simultaneously engages Tudor domains 1 and 2 and effectively</div><div>competes with chromatin binding in cells. Inhibitor, chemoproteomic and knockdown studies in squamous cell carcinoma indicate</div><div>complex SPIN-mediated chromatin interactions leading to transcriptional changes in cellular differentiation processes.</div>