Acetyltransferases (HATs) as targets for neurological therapeutics

Abstract

The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen long-term events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

Fig. 1

Histone acetyletransferase (HAT) and histone deacetylase (HDAC) families. Illustration of chromatin conformation according to the HAT/HDAC balance. The acetylation levels of nucleosome histone tails, at lysine residues, are determined through the interplay between acetylation and deacetylation mechanisms engaged respectively through HATs and HDACs enzymes. The different families and classes of enzymes are noted. Ac = Acetyl; CBP = cyclic adenomonophosphate response element-binding (CREB) binding protein; GNAT = Gcn5-related N-acetyltransferases; hGCN5 = human general control of amino acid synthesis protein 5-like 2; PCAF = p300/CBP-associated factor; ELP3 = elongation protein 3; MYST = MOZ/YBF2/SAS2/TIP60; TIP60 = TAT interacting proteins 60; TFIIIC90 = transcription factor IIIC 90kDa; TAF1 = TATA Box Binding Protein-Associated Factor, SRC1 = steroid receptor coactivator 1; ACTR = SRC-3, steroid receptor coactivator/AIB-1, Activated In Breast cancer-1/TRAM-1, thyroid hormone receptor activator molecule 1/ NCOA3, nuclear receptor coactivator 3

Fig. 2

Role of acetylation in different lineage determination. The neural stem cells (NSCs) exist in a niche, which can be differentially modulated to specific neuronal lineages. A differential recruitment of specific transcription factors (TF) to the same acetyltransferases determine specific neural cell fates from the NSCs. Cyclic adenomonophosphate response element-binding (CREB) binding protein (CBP)/p300 histone acetyletransferases (HATs) interact with STAT and SMAD activating glial fibrillary acidic protein (GFAP) expression, thus specifying the glial lineage. Increased expression of neurogenin (Ngn1) titrates this complex, thus leading to the release of STAT, blocking GFAP expression. The new Ngn1–CBP/p300–SMAD complex subsequently binds to the E box elements, which results in a neuron cell type due to the activation of NeuroD1 expression [53]. CBP/p300 when bound to retinoic acid receptor (RAR) and neurogenin 2 (Ngn2) leads to a differentiation of the motor neuron cells. The deacetylases histone deacetylases (HDACs) HDAC1 and HDAC2 act as a general repressor, blocking the transcription factor and thereby resulting in oligodendrocyte specification

Fig. 3

Histone acetyltransferase (HAT) activation as a therapeutic strategy. Illustration of the beneficial effects of the use of a HAT activator at the cellular level (see ‘HAT Activation vs HDAC Inhibition as a Therapeutic Strategy’). The activation of the HAT preserves the “acetylation code” of nuclear and cytoplasmic proteins (1–3), along with a proper positioning at gene loci (4) and recruitment of coactivators (5). Importantly, this strategy will preserve the histone deacetylase (HDAC) activity surrounding gene loci (6), otherwise impaired when following an HDAC inhibition strategy. Therefore, as both HAT and HDAC activities are present, a correct acetylation turn-over is possible, allowing transcriptional proceedings, see [217]. Ac = Acetyl; NFκB = nuclear factor kappa B; UBF-1 = upstream binding factor-1; CoAct = coactivator; CoRep = co-repressor; TF = transcription factor; RNApolII = RNA polymerase II

Fig. 4

Effects of histone acetyltransferase (HAT) activator molecules on brain functions and their potential therapeutic use in diseases. In rodent models, the described effects of different HAT activators [SPV106 for p300/cyclic adenomonophosphate response element-binding (CREB)-associated factor (PCAF) [219] or carbon nanosphere (CSP)-TTK21 for CREB-binding protein (CBP)/p300 [72] are depicted]. The drawings represent the effect of CSP-TTK21 on newly generated (doublecortin-positive) neurons with increased dendritic branching measured in the hippocampus of adult mice 3 days after CSP-TTK21 injection. For spatial memory, CSP (−)- or CSP-TTK21 (+)-injected mice were tested in the Morris water maze and retention was evaluated 2 days (recent, 2d) or 16 days (long-term, 16d) after a weak protocol of acquisition. The retention index indicates significant retention of the platform location in the CSP-TTK21 injected group at long delays without effect on recent memory (*p < 0.05). For further details see [72]. The potential applications in diseases are summarized in the boxes (see text). NSC = neural stem cells; AD = Alzheimer’s disease; RTS = Rubinstein Taybi syndrome