Small molecule modulators of histone acetylation and methylation: A disease perspective

Chromatin modifications have gained immense significance in the past few decades as key regulators of gene expression. The enzymes responsible for these modifications along with the other non-histone proteins, remodeling factors and small RNAs modulate the chromatin dynamicity, which in turn directs the chromatin function. A concerted action of different modifying enzymes catalyzes these modifications, which are read by effector modules and converted to functional outcomes by various protein complexes. Several small molecules in the physiological system such as acetyl CoA, NAD+, and ATP are actively involved in regulating these functional outcomes. Recent understanding in the field of epigenetics indicate the possibility of the existence of a network, ‘the epigenetic language’ involving cross talk among different modifications that could regulate cellular processes like transcription, replication and repair. Hence, these modifications are essential for the cellular homeostasis, and any alteration in this balance leads to a pathophysiological condition or disease manifestation. Therefore, it is becoming more evident that modulators of these modifying enzymes could be an attractive therapeutic strategy, popularly referred to as ‘Epigenetic therapy.’ Although this field is currently monopolized by DNA methylation and histone deacetylase inhibitors, this review highlights the modulators of the other modifications namely histone acetylation, lysine methylation and arginine methylation and argues in favor of their therapeutic potential.

Research Highlights
► Histone modifications are important regulators of gene expression in both physiological and pathophysiological states.
► The histone modifications mainly acetylation, lysine methylation and arginine methylation together establish an epigenetic network.
► Histone acetylation aberrations have been reported in diseases such as cancer, diabetes, inflammatory disorders as well as neurodegenerative states.
► Acetylation inhibitors are showing great promise as potential therapeutic agents due to their anti-inflammatory, anti-cancer as well as anti-HIV properties.
► Since the epigenetic marks exist as a network, and there are evidences implicating their role in different diseases, potential therapeutic strategy should be towards combinatorial targeting of these modifications.