Conserved Antagonism between JMJD2A/KDM4A and HP1γ during Cell Cycle Progression

The KDM4/JMJD2 family of histone demethylases is amplified in human cancers. However, little is known about their physiologic or tumorigenic roles. We have identified a conserved and unappreciated role for the JMJD2A/KDM4A H3K9/36 tridemethylase in cell cycle progression. We demonstrate that JMJD2A protein levels are regulated in a cell cycle-dependent manner and that JMJD2A overexpression increased chromatin accessibility, S phase progression, and altered replication timing of specific genomic loci. These phenotypes depended on JMJD2A enzymatic activity. Strikingly, depletion of the only C. elegans homolog, JMJD-2, slowed DNA replication and increased ATR/p53-dependent apoptosis. Importantly, overexpression of HP1γ antagonized JMJD2A-dependent progression through S phase, and depletion of HPL-2 rescued the DNA replication-related phenotypes in jmjd-2−/− animals. Our findings describe a highly conserved model whereby JMJD2A regulates DNA replication by antagonizing HP1γ and controlling chromatin accessibility. [Display omitted] ► Histone tridemethylase JMJD2A/KDM4A regulates S phase progression from worm to human ► JMJD2A increases chromatin accessibility and DNA replication ► JMJD2A regulates sat2 replication timing ► JMJD2A and JMJD-2 specifically antagonize HP1γ and HPL-2 during DNA Replication