Roles of Histone Deacetylase 4 in the Inflammatory and Metabolic Processes

Abstract

Histone deacetylase 4 (HDAC4), a class IIa HDAC, has gained attention as a potential therapeutic target in treating inflammatory and metabolic processes based on its essential role in various biological pathways by deacetylating non-histone proteins, including transcription factors. The activity of HDAC4 is regulated at the transcriptional, post-transcriptional, and post-translational levels. The functions of HDAC4 are tissue-dependent in response to endogenous and exogenous factors and their substrates. In particular, the association of HDAC4 with non-histone targets, including transcription factors, such as myocyte enhancer factor 2, hypoxia-inducible factor, signal transducer and activator of transcription 1, and forkhead box proteins, play a crucial role in regulating inflammatory and metabolic processes. This review summarizes the regulatory modes of HDAC4 activity and its functions in inflammation, insulin signaling and glucose metabolism, and cardiac muscle development.

Keywords: Histone deacetylases; Inflammation; Metabolism; Transcription factors.

Fig. 1.

The histone deacetylase (HDAC) superfamily. Green bars indicate the zinc-dependent deacetylase domain; Blue bars indicate the nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase domain; Yellow bars indicate the myocyte enhancer factor 2 (MEF2) binding domain; Pink bars indicate the nuclear localization signal; Brown bars indicate the nuclear export signal; Purple bar indicates the zinc finger domain. SIRT, sirtuin.

Fig. 2.

Summary of the regulatory modes of histone deacetylase 4 (HDAC4) expression and activity. The transcriptional level of HDAC4 is regulated by transcription factors, specificity protein 1 (Sp1) and Sp3, by directly binding to consensus GC-rich sequences in the HDAC4 promoter. miRNAs regulate HDAC4 expression at the post-transcriptional level of HDAC4 through mRNA degradation or inhibition of translation, while HDAC4 can also regulate the expression of miRNAs by altering the acetylation states of their promoter. The post-translational level of HDAC4 regulation includes its subcellular localization and interaction with other proteins as repressors, substrates, or structures. As HDAC4 undergoes several post-translational modifications, there might conflict with each other for the regulation of HDAC4, which influence the localization of HDAC4. The modifications in HDAC4 are involved in a wide range of biological processes by regulating the acetylation state.

Fig. 3.

The role of histone deacetylase 4 (HDAC4) in the regulation of histone and non-histone proteins. The acetylation state at the lysine residue regulates the function of histone and non-histone proteins. Histone deacetylation by HDAC4 condenses chromatin structure, which controls the binding of transcription factors to DNA for transcriptional repression. HDAC4 interacts with non-histone proteins, including transcription factors, as a transcriptional corepressor. In particular, HDAC4 plays a role in metabolic and inflammatory pathways by regulating myocyte enhancer factor 2 (MEF2), hypoxia-inducible factor 1 (HIF1), signal transducer and activator of transcription 1 (STAT1), and forkhead box O 1 (FOXO1) transcription factors. The modifications of histone and non-histone proteins are involved in a wide range of biological processes by regulating gene transcription.