The nucleosomal kinase VRK1 regulates and coordinates histone epigenetic modifications associated with gene transcription and DNA damage

Trabajo presentado en el EpIC - EpiGene3Sys meets INC-Spain to ChromDesign the Genome International Nucleome Consortium, celebrado en Granada (España) del 17 al 20 de octubre de 2022.Epigenetic alterations are one of the main mechanisms driving different human diseases, including many cancer types and neurological diseases. The coordination of histone PTMs requires the coordination of several epigenetic enzymes. H3K4me3 and H3K27ac characterize transcriptionally active chromatin, whereas repressive states are enriched in H3K9me3 and H3K27me3 among others. We need to understand the regulatory mechanisms that coordinate these epigenetic enzymes. VRK1 (Vaccinia-related kinase 1) is a nuclear kinase implicated in gene transcription or DNA damage response. We studied the role of VRK1 depletion on various epigenetic enzymes and the levels of different PTMs (H3K4me3, H3K9ac/me3, H3K27ac/me3, and H4K16ac), in two different human cancer cell lines, A549 and U2OS. We studied the interaction of VRK1 with the histone-modifying enzymes (KAT, HDAC, KMT and KDM). VRK1 directly interacts, phosphorylates and activates Tip60/KAT5 in response to DNA damage. VRK1 depletion promotes a decrease of chromatin active marks (H3K4me3, H3K9ac, H3K27ac, and H4K16ac), and an increase of H3K9me3 and H3K27me3. Treatments with drugs targeting histone-modifying enzymes also remodel the acetylation and methylation pattern. HAT (C646 and MG149) and KDM (JMJD2i and ORY-1001) inhibitors mimic the effect of VRK1 depletion. HDAC (Vorinostat, Entinostat, Panobinostat, Selisistat, Thiomyristoil, AGK2, and AK7) and KMT (Chaetocin and Tazemetostat) inhibitors mimic the effect of VRK1 depletion on histone marks. VRK1 forms a stable protein complex with KDM1a, KDM3a, KDM4a, HDAC1, Sirt1/2, and SETDB1. We conclude that VRK1 dynamically coordinate epigenetic marks on chromatin and can be suitable target for synthetic lethality strategies in cancer