The pattern of histone H3 epigenetic posttranslational modifications is regulated by the VRK1 chromatin kinase

by Selleckchem | Jun 29 2023

Background: Dynamic chromatin remodeling is associated with changes in the epigenetic pattern of histone acetylations and methylations required for processes based on dynamic chromatin remodeling and implicated in different nuclear functions. These histone epigenetic modifications need to be coordinated, a role that may be mediated by chromatin kinases such as VRK1, which phosphorylates histones H3 and H2A.

Methods: The effect of VRK1 depletion and VRK1 inhibitor, VRK-IN-1, on the acetylation and methylation of histone H3 in K4, K9 and K27 was determined under different conditions, arrested or proliferating cells, in A549 lung adenocarcinoma and U2OS osteosarcoma cells.

Results: Chromatin organization is determined by the phosphorylation pattern of histones mediated by different types of enzymes. We have studied how the VRK1 chromatin kinase can alter the epigenetic posttranslational modifications of histones by using siRNA, a specific inhibitor of this kinase (VRK-IN-1), and of histone acetyl and methyl transferases, as well as histone deacetylase and demethylase. Loss of VRK1 implicated a switch in the state of H3K9 posttranslational modifications. VRK1 depletion/inhibition causes a loss of H3K9 acetylation and facilitates its methylation. This effect is similar to that of the KAT inhibitor C646, and to KDM inhibitors as iadademstat (ORY-1001) or JMJD2 inhibitor. Alternatively, HDAC inhibitors (selisistat, panobinostat, vorinostat) and KMT inhibitors (tazemetostat, chaetocin) have the opposite effect of VRK1 depletion or inhibition, and cause increase of H3K9ac and a decrease of H3K9me3. VRK1 stably interacts with members of these four enzyme families. However, VRK1 can only play a role on these epigenetic modifications by indirect mechanisms in which these epigenetic enzymes are likely targets to be regulated and coordinated by VRK1.

Conclusions: The chromatin kinase VRK1 regulates the epigenetic patterns of histone H3 acetylation and methylation in lysines 4, 9 and 27. VRK1 is a master regulator of chromatin organization associated with its specific functions, such as transcription or DNA repair.

Comments:

Summary: The study investigated the role of the chromatin kinase VRK1 in regulating the epigenetic modifications of histone H3, specifically acetylation and methylation at lysines 4, 9, and 27. The researchers used siRNA to deplete VRK1 and a specific VRK1 inhibitor (VRK-IN-1) to inhibit its activity. They also studied the effects of inhibitors targeting histone acetyltransferases (HATs), histone methyltransferases (HMTs), histone deacetylases (HDACs), and histone demethylases (HDMs).

The results showed that loss of VRK1 led to a switch in the state of H3K9 modifications. Depletion or inhibition of VRK1 resulted in a loss of H3K9 acetylation and facilitated its methylation. This effect was similar to the inhibition of KATs and KDMs. On the other hand, inhibition of HDACs and HMTs had the opposite effect, increasing H3K9 acetylation and decreasing H3K9 methylation.

VRK1 was found to interact with members of the four enzyme families involved in histone modifications. However, VRK1's role in these modifications was indirect, likely involving the regulation and coordination of these epigenetic enzymes.

In conclusion, VRK1 acts as a master regulator of chromatin organization and is associated with specific nuclear functions such as transcription or DNA repair. It plays a crucial role in coordinating the epigenetic patterns of histone H3 acetylation and methylation at lysines 4, 9, and 27.