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Page 4 of 18 Yelton et al. Neuroimmunol Neuroinflammation 2018;5:46 I http://dx.doi.org/10.20517/2347-8659.2018.58
Table 1. Characteristics of the human histone deacetylase enzymes and their similarity to yeast proteins
HDAC enzyme class HDAC enzymes* Protein family Required catalytic Resembled yeast
cofactor protein sequence
I HDAC1, HDAC2, HDAC3, and HDAC8 Histone deacetylase Zn 2+ Rpd3
II HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10 Histone deacetylase Zn 2+ Hda1
III SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7 Sir2 regulator NAD + Sir2
IV HDAC11 Histone deacetylase Zn 2+ Class I and II HDACs
*HDAC enzymes have been divided into four classes based on their similarity in sequence and function to well-described yeast proteins.
Class I enzymes include HDAC 1, 2, 3, and 8 that belong to the classical HDAC family, require a Zn for their catalytic action, and are
2+
similar to the yeast protein Rpd3. Class II enzymes contain HDAC 4, 5, 6, 7, 9, and 10 that also belong to the classical HDAC family, also
2+
require a Zn for their catalytic action, and are similar to the yeast protein Hda1. Class III enzymes differ most significantly from their
+
HDAC counterparts, containing SIRT 1, 2, 3, 4, 5, 6, and 7 that belong to the distinct Sir2 regulator family, require NAD as an essential
catalytic cofactor, and are similar to the yeast protein Sir2. Finally, class IV contains only HDAC11 that is also part of the classical HDAC
family, requires a Zn for its catalytic action as well, and most resembles the class I and II HDAC enzymes. These enzymes are numbered
2+
in the order in which they were discovered. HDAC: histone deacetylase; SIRT: sirtuin
sequence similarity to a yeast protein, which is called the reduced potassium dependency 3 (Rpd3). HDAC4,
HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10 are all class II proteins with sequence similarity to the yeast
protein histone deacetylase-A 1 (Hda1). Class I HDACs are ubiquitously expressed in all tissues while class II
[26]
HDACs are tissue-specifically expressed . Sirtuin is a word coined from its founding member Sir2 in the
yeast Saccharomyces cerevisiae. Sirtuin 1 (SIRT1), SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7 in humans
are all class III proteins with sequence similarity to the S. cerevisiae protein known as the Sir2. Finally,
HDAC11 is the lone member of class IV and shares sequence similarity to both the class I and class II HDACs.
These enzymes, for the most part, were numbered according to the order in which they were discovered.
HDACs in classes I, II, and IV are in the superfamily of proteins known as the arginase/deacetylase
superfamily, which contains the arginase-like amidino hydrolases and the HDACs. The HDAC enzymes
2+
in classes I, II, and IV belong to the classical HDAC family and require a zinc ion (Zn ) for their catalytic
action to take place. HDACs in class III, however, belong to the deoxyhypusine synthase-like nicotinamide
adenine dinucleotide (NAD)/flavin adenine dinucleotide-binding-domain superfamily of proteins, which
contain the Sir2 proteins as well as many other sequence-similar enzyme families. In contrast to the
+
classical HDAC family of enzymes, class III enzymes require NAD as a cofactor for enzyme activity
instead of a Zn 2+[27] . While there are subtle differences in the classification scheme of these enzymes, they
play an essential functional role in maintaining the balance between histone acetylation and deacetylation.
This balance ultimately mediates access of transcriptional machinery to the chromatin of the cell, with
downstream consequences such as alteration in gene transcription. However, functionality of these enzymes
is much more complicated than one HDAC per one histone (or non-histone) protein. These enzymes as a
superfamily are biologically essential due to their opposition of the effects of HAT enzymes, where a defect
in this balance leads to epigenetic changes in the aberrant tissue [Figure 1].
A change in the cellular balance between HAT and HDAC enzyme activity modifies gene expression and
translation of mRNA transcripts into protein products. However, this cellular balance is very delicate and
[28]
has been classically shown that “minor” histone modifications can greatly influence gene transcription .
In fact, in one genome-wide mapping study, HDACs were observed to be bound to chromatin at actively
[29]
transcribed genes, but not silent genes . These HDACs are believed to be able to reset active chromatin,
silencing the gene after making the desired protein product by the cell. Additionally, non-histone proteins
are also subject to cellular changes through acetylation. Noteworthy non-histone proteins that can cause
great cellular change include transcription factors, chaperone proteins, viral proteins, and proteins involved
in DNA repair, recombination, and replication . These non-histone proteins have been implicated in
[30]
essential cellular processes such as chromatin remodeling, cell cycle regulation, apoptosis, autophagy, and
actin nucleation . The HDACs have been implicated in pathology as well, where their dysregulation halts
[31]
the repression of active genes in the cell, leading to an abnormal expression of certain protein products.