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HDAC inhibition through valproic acid modulates the methylation profiles in human embryonic kidney cells

Post-translational modifications on the tails of core and linker histones dictate transcription and have vital roles in disease and development. Acetylation and deacetylation events enabled by histone acetyl transferases and histone deacetylases (HDACs) on the chromatin milieu are intricately involved in gene regulation. Inhibition of HDACs is emerging as a powerful strategy in regenerative therapy, transplantation, development and in nuclear reprogramming events. Valproic acid (VPA), belonging to the short-chain fatty acid group of HDAC inhibitors, modulates the epigenome altering gene expression profiles across cell lines. This work attempts to explore the methylation profiles triggered by VPA treatment on human embryonic kidney cells (HEK 293) through a biochemical and computational approach. VPA treatment (for 48 h) has been observed to hypermethylate lysine 4 on the core histone H3 and confers a hypomethylation status of H3 lysine 27 in HEK 293 cells leaving the nuclear area and nuclear contour unaltered. Our structural docking and Binding Free Energy (BFE) calculations establish an active role for VPA in inhibiting the demethylase JARID1A (Jumonji, AT Rich Interactive Domain 1A) and the methyl-transferase EZH2 (Enhancer of Zeste Homologue 2). This work has also proven that VPA can inhibit the activity of proteins like GSK3β and PKCβII involved in developmental disorders. This work establishes a dynamic correlation between histone methylation events and HDAC inhibition and may define newer epigenetic strategies for treating neurodevelopmental and oncological disorders.