Chromatin Regulation through Ubiquitin and Ubiquitin-like Histone Modifications

Chromatin functions are influenced by the addition, removal, and recognition of histone post-translational modifications (PTMs). Ubiquitin and ubiquitin-like (UBL) PTMs on histone proteins can function as signaling molecules by mediating protein–protein interactions. Fueled by the identification of novel ubiquitin and UBL sites and the characterization of the writers, erasers, and readers, the breadth of chromatin functions associated with ubiquitin signaling is emerging. Here, we highlight recently appreciated roles for histone ubiquitination in DNA methylation control, PTM crosstalk, nucleosome structure, and phase separation. We also discuss the expanding diversity and functions associated with histone UBL modifications. We conclude with a look toward the future and pose key questions that will drive continued discovery at the interface of epigenetics and ubiquitin signaling. Histones are among the most abundant ubiquitinated proteins in cells, perhaps due to their E3-independent ubiquitination by many E2 enzymes.The histone and ubiquitin ‘codes’ function together to regulate DNA-templated cellular processes.The maintenance of DNA methylation through cell division is emerging as a ubiquitin-dependent process.Inhibitors of ubiquitin transfer are an emerging class of targeted therapeutics for cancer management.Ubiquitin and ubiquitin-like proteins may play key roles in phase separation of chromatin and other nuclear components.