A short guide to histone deacetylases including recent progress on class II enzymes

Park and Kim Experimental & Molecular Medicine (2020) 52:204–212 https://doi.org/10.1038/s12276-020-0382-4 REVIEW ARTICLE Experimental & Molecular Medicine Open Access A short guide to histone deacetylases including recent progress on class II enzymes Suk-Youl Park1 and Jeong-Sun Kim 2 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Abstract The interaction between histones and DNA is important for eukaryotic gene expression. A loose interaction caused, for example, by the neutralization of a positive charge on the histone surface by acetylation, induces a less compact chromatin structure, resulting in feasible accessibility of RNA polymerase and increased gene expression. In contrast, the formation of a tight chromatin structure due to the deacetylation of histone lysine residues on the surface by histone deacetylases enforces the interaction between the histones and DNA, which minimizes the chance of RNA polymerases contacting DNA, resulting in decreased gene expression. Therefore, the balance of the acetylation of histones mediated by histone acetylases (HATs) and histone deacetylases (HDACs) is an issue of transcription that has long been studied in relation to posttranslational modification. In this review, current knowledge of HDACs is briefly described with an emphasis on recent progress in research on HDACs, especially on class IIa HDACs. Introduction Long eukaryotic DNA is wrapped around histone proteins, leading to compact chromosomes. The compact nucleosome structure resulting mainly from the ionic interaction between the highly positively charged histones and the negatively charged DNA backbone restricts the access of the transcriptional machinery. The tight nucleosomes can become loose when the positive charge of the lysine residues on the histone surface is neutralized by acetylation performed by histone acetylase (HAT), which increases the accessibility of RNA polymerase II, resulting in gene expression. On the other hand, the recovery of a positive charge on the lysine side chain of the histone surface resulting from the action of histone deacetylase (HDAC) restores a compact chromatin structure, rendering access by RNA polymerase difficult, and thereby decreasing gene repression (Fig. 1). This mediation of gene expression by the acetylation and Correspondence: Jeong-Sun Kim () 1 Pohang Accelerator Laboratory, Pohang University of Science and Technology, 80 Jigokro-127-Beongil, Nam-gu, Pohang, Gyeongbuk 37673, Republic of Korea 2 Department of Chemistry, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Republic of Korea deacetylation of histones (a type of posttranslational modification) is a major gene expression regulation system in many eukaryotes, commonly referred to as the epigenetic control of eukaryotic gene transcription. The disruption of the balance between HAT and HDAC activities can result in the aberrant expression of a specific gene that ultimately leads to the instability of chromatic structure and epigenetic diseases1,2. Hence, the precise control of the activities of HATs and HDACs is important for the exact and timely expression of various genes associated with signal transduction and cell growth and death2. An imbalance between HAT and HDAC activities can also be caused by the repression of the intrinsic enzyme activity of HAT or HDAC. When HAT activity is inhibited, the timely expression of a target gene is hindered. On the other hand, the inhibition of HDAC activity keeps a continuous expression of a target gene. In this context, the control of HDAC activity by HDAC inhibitors has been targeted for the development of anticancer strategies as well as therapies for human diseases derived from cardiovascular, metabolic, and neurodegenerative disorders3–8. Eighteen human HDACs are grouped into four classes based on their primary homology to yeast HDACs. © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Korean Society for Biochemistry and Molecular Biology Park and Kim Experimental & Molecular Medicine (2020) 52:204–212 205 Fig. 1 Regulation of gene expression and repression by histone acetylase (HAT) and histone deacetylase (HDAC). Acetylation (AC) of histone lysine residues by HAT, opening up the chromatin structure, allows binding of RNA polymerase II (RNA Pol II), while deacetylation of the histone lysine residues by HDAC leads to the closed chromatin conformation to be unable to bind RNA Pol II. Histones are displayed with dark green spheres. DNA wound around the histones is shown as an orange tube. The histone lysine residues are drawn with thin and short gray tails on histone spheres. Among these groups, class I and II HDACs play a major role in the lysine deacetylation of N-terminal histone tails. HDACs interact with several partners through distinct domains. Both class I HDAC3 and IIa HDACs interact with two closely related corepressors: silencing mediator for retinoid and thyroid receptors (SMRT) and nuclear receptor corepressor (N-CoR). SMRT/N-CoR is associated with the sequence-specific DNA-binding domain of BCL6, which is involved in B-cell activation and differentiation, inflammation, and cell-cycle regulation9–11. Interestingly, HDAC3 and class IIa HDACs are catalytically inactive in their solitary state. However, when HDAC3 is bound to SMRT/N-CoR, it becomes enzymatically active regardless of the presence a class IIa HDAC12,13. In contrast, class IIa HDACs do not show any significant enhancement of lysine deacetylase activity after binding to the SMRT/N-CoR proteins. The SMRT/NCoR corepressors provide a structural link between active HDAC3 and inactive class IIa HDACs. Therefore, the role of class IIa HDACs and the biological relevance of these observations remain unclear. Chromatin remodeling via histone modification The human genome consists of a set of DNA compacted within 23 chromosome pairs containing approximately 6,469.66 megabase pairs, which encode over 20,000 genes. If the DNA from a single human cell was to be stretched out, it would be ~2 m long. The average human cell diameter is ~100 µm, and the nucleus is Official journal of the Kore (...truncated)