Chromatin readers of the WD-repeat containing protein family

Tryptophan-aspartate 40 repeat-containing (WD40 repeat, WD repeat, or WDR) proteins are a large and broadly distributed protein family. The WD40 domain has multiple copies of WD40 repeats that fold into highly conserved anti-parallel β-sheet, propeller tertiary structure. Approximately 600 human WDR proteins are widely expressed across tissue types and cellular organelles. They participate in many cellular processes, including nuclear and chromatin functions, such as RNA splicing, gene expression, DNA replication and repair, and higher order genome organization. In this chapter, we examine these genome- and chromatin-templated processes, focusing on WDR “reader” interactions with histones and chromatin, and the resulting downstream effects on the epigenome. We specifically explore those involved in histone chaperone-mediated chromatin assembly (CAF1, Chaf1b, HIRA) and their roles in human cancer and in congenital heart disease. We also focus on WDR proteins in histone-modifying complexes, such as RBBP4/7, EED, and WDR5, and how they are regulated by interactions with histone post-translational modifications. Overall, we highlight how intrinsically disordered regions (IDRs) and folded domains of both histone and nonhistone proteins associate with WDR proteins by engaging three potential interaction interfaces: (1) at either of the central pores, (2) at accessory domains outside of the β-propeller, or (3) by wrapping around the lateral surface of the WDR protein.