Eukaryotic DNA, histones and histone-like proteins are assembled into chromatin, a highly organized, dynamic nucleoprotein complex that plays a significant role(s) in the regulation of cellular homeostasis. The tails and the globular domains of nucleosomal histones can be modified by acetylation, phosphorylation, methylation, ubiquitination, sumoylation and, less commonly, by citrullination and ADP-ribosylation. These post-translational modifications can alter DNA–histone interactions or the binding of proteins, such as transcription factors, to chromatin. Histone acetylations represent one of the best characterized post-translational modifications with profound functional implications for a wide range of cellular processes.Acetylation and deacetylation are counteracting, post-translational modifications that affect a large number of histone and nonhistone proteins. Acetylation levels of histone tails are maintained by the opposing, yet well balanced, activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs
Two types of protein acetylation take place in the cell. N acetylation is the acetylation of the amino termini of newly synthesized proteins that mostly follows the removal of the first methionine residue. This type of acetylation is common in eukaryotes but also occurs to some extent in archaea. The second type of acetylation is a reversible modification that occurs on lysine residues of mature proteins, resulting in charge neutralization of these residues. The latter type of protein acetylation is catalyzed by a family of histone acetyltransferases (HATs) that function to transfer an acetyl group from acetyl-coenzyme A (acetyl-CoA) to the e-amino group of certain lysine side chains. The HAT family is composed of five enzyme subfamilies, of which the Gcn5-related N-acetyltransferase (GNAT) subfamily is the best characterized. Acetylation can occur on histones, DNA-binding TF (Transcription Factors), acetylases, nuclear import factors, non-nuclear proteins (Alpha-Tubulin) and proteins that shuttle from the nucleus to the cytoplasm, such as the Importin-Alpha family of nuclear import factors. Acetylation can modify the recognition of DNA, the stability of proteins and the interaction between proteins. Acetylation reactions catalyzed by HATs can be reversed by a family of histone deacetylases (HDACs
are divided into three classes: class I HDACs
are related to yeast Rpd3, class II HDACs
are related to yeast HdaI, and class III HDACs
are related to the yeast transcriptional repressor Sir2. Class I and class II HDACs
share some homology in their catalytic domains and hydrolyze the acetamide bond in similar manners, whereas class III HDACs
share no homology with class I and II HDACs
and employ a different enzymatic mechanism (Ref.2).
Protein lysine acetyltransferases (HATs or PATs) acetylate histones and other proteins, and are principally modeled as transcriptional coactivators. CREB binding protein (CBP, CREBBP) and its paralog p300 (EP300) constitute the KAT3 family of HATs in mammals, which has mostly unique sequence identity compared to other HAT families (Ref.3). Acetylation complexes such as PCAF (p300/CBP-Associated Factor), p300/CBP (CREBBP), TAFs (TBP-Associated Factors), SRC1 (Steroid Receptor Coactivator-1) and MOZ or deacetylation complexes such as HDACs (Histone Deacetylases) are recruited to DNA-bound TF in response to signaling pathways. A number of non-histone proteins act as substrates for PCAF and/or p300/CBP. Many of these substrates are involved in the regulation of transcription and include p53, E2F1, E2F1, EKLF (Kruppel-Like Factor-1), TCF, GATA1, GATA1 (High Mobility Group AT-Hook-1) and ACTR/NCOAR3. DNA-binding proteins such as HMGB1 (High-Mobility Group Box1) and even non-nuclear proteins such as Alpha-Tubulin are modified by acetylation. Deacetylases such as HDAC1 can deacetylate not only histones but also a TF, E2F1. The enzymatic activity of acetylases is regulated by proliferation and differentiation signals. The regulatory signal can come via phosphorylation or via hormonal signaling through coactivator function of SRC1 and ACTR with nuclear receptors, including PR (Progesterone Receptor), GR (Glucocorticoid Receptor), ER (Estrogen Receptor), TR (Thyroid hormone Receptor), and RXR (Retinoid X Receptor). Proliferation signals regulating acetylation comes from the HATs (Histone Acetyl-Transferases) activity of CBP stimulated at the G1-S phase. This effect is mediated by a phosphorylation event carried out by a Cyclin-E-CDK complex. The HAT activity is also responsive to DNA repair signals. The binding of the viral oncoprotein E1A to p300/CBP and PCAF also regulate the HAT activity of the enzyme (Ref.4). In addition, RNAP-II transcription PIC (Preinitiation Complex) is recruited to the promoter as a holoenzyme that includes a subset of the GTFs (General Transcription Factors) consisting of the TBP (TATA-Binding Protein), TFIIB, TFIIE-Beta, TFIIF, and TFIIH. This complex mediates the response to transcriptional activators as well as repressors that include TFIIA, which stabilizes DNA-TBP binding, and factors that affect nucleosome structure, including HATs and ATP-dependent chromatin remodeling complexes (Ref.5).
Histone hyperacetylation by HATs is associated with transcriptional activation, presumably by remodeling nucleosomal structure into an open conformation more accessible to transcription complexes. Conversely, histone deacetylation is associated with transcriptional repression reversing the chromatin remodeling process. In general, the deacetylation of histones results in transcriptional repression, whereas increases in histone acetylation lead to the enhancement of gene transcription. The repressor Mad/MAX dimmer interacts with Sin3(or NCOR2/SMRT, etc.), which recruits HDACs
to repress transcription. Since histone acetylation is maintained during mitosis, the acetylation pattern also contributes a heritable epigenetic imprint that influences gene transcription (Ref.6). Another function regulated by acetylation is protein stability. The acetylated version has a longer half-life.