UCSF

The Histone lysine demethylase 5 (KDM5) is recognized as a potential therapeutic target due to its involvement in several diseases, including cancer. While recent studies have advanced our understanding of its catalytic functions, KDM5’s scaffolding functions to recruit other factors to chromatin remain underexplored. This dissertation serves to investigate the non-catalytic roles of KDM5 in chromatin regulation, particularly in modulating immune responses. Using a multiomics approach, we have characterized KDM5A and KDM5B as regulators of the KRAB-ZNF (Krüppel-associated box domain zinc finger) genes. The loss of KDM5A and KDM5B are associated with increased expression of ERV genes and upregulation of immune response markers. Additionally, inhibition of KDM5 catalytic activity did not phenocopy genetic ablation. In contrast, acute degradation of KDM5A resulted in increased ERVs expression. Additionally, this dissertation details efforts to develop targeted protein degradation strategies that address both the catalytic and scaffolding functions of KDM5.Chapter 1 provides an introduction to KDM5 demethylases and their roles in disease, discussing recent advancements in catalysis and therapeutic efforts for KDM5 and other JMJC KDM demethylases. Chapter 2 employs a mult-iomics approach to characterize KDM5 role in regulating the chromatin landscape, highlighting the significant roles of KDM5A and KDM5B in modulating immune responses. Chapter 3 outlines the development of small molecule degraders targeting KDM5