Altered Histone Acetylation Is Associated with Age-Dependent Memory Impairment in Mice

Abstract

As the human life span increases, the number of people suffering from cognitive decline is rising dramatically. The mechanisms underlying age-associated memory impairment are, however, not understood. Here we show that memory disturbances in the aging brain of the mouse are associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation and fail to initiate a hippocampal gene expression program associated with memory consolidation. Restoration of physiological H4K12 acetylation reinstates the expression of learning-induced genes and leads to the recovery of cognitive abilities. Our data suggest that deregulated H4K12 acetylation may represent an early biomarker of an impaired genome-environment interaction in the aging mouse brain.

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Indirectly enhancing histone acetylation by chronic inhibition of histone deacetylases (HDACs) was able to reverse the cognitive deficits in AD mouse model (Kilgore et al, 2010) and also in aging mouse (Benito et al, 2015). This is consistent the dysregulation of H4K12ac being implicated to mediate cognitive impairment in aged mice (Peleg et al, 2010). Other histone markers are reviewed summarized elsewhere (Lardenoije et al, 2015).…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Genome-wide analyses revealed that H4K12 acetylation was associated with transcriptional modifications after learning, and the differential expression of 2,229 genes was been identified through chromatin immunoprecipitation sequencing. The expression of the formin 2 gene (an actin nucleator, important for synaptic plasticity and memory) was increased in a H4K12 acetylation-dependent manner [15]. The same year, we [180] also demonstrated that hippocampal-dependent spatial memory consolidation in the Morris Water Maze (MWM) increased H3K9K14 and H4K12 histone residues in the H2B N-terminus region.…”

“…This rise in histone acetylation was associated with an activation of both Nmethyl-D-aspartate receptors and the extracellular signal-regulated kinase (ERK) signaling pathway, which are upstream factors for the stabilization and the formation of LTM. In 2010, Peleg et al [15] revealed that CxFC causes an increase of several histones residues (H3K9K14, H4K5K8K12), as observed 1 h after exposure to the trial, in 3-month-old wild-type mice. Genome-wide analyses revealed that H4K12 acetylation was associated with transcriptional modifications after learning, and the differential expression of 2,229 genes was been identified through chromatin immunoprecipitation sequencing.…”

“…HDACi-based therapeutic strategies were first applied to models of polyglutamine (polyQ) diseases, such as Huntington's [8,9] and Kennedy's [10], and then subsequently revealed to be successful to some extent in several other animal models of neurodegenerative disease [5,6,11,12]. Importantly, this strategy has also been successfully applied in animals subjected to experimental brain damage [13,14] and recently shown to improve memory functions in aged mice [15]. HDACi are the only molecules used for increasing cellular acetylation, and two of these molecules have been approved for clinical use in cutaneous T cell lymphoma [16].…”

Epigenetic regulation of aging stem cells

“…HDACs can be divided into several classes based on sequence homology and cofactor dependency: class I, II and IV HDACs are classical HDACs requiring Zn 2 þ as a cofactor, whereas class III HDACs, also known as Sirtuins, require NAD þ as a cofactor (Imai et al, 2000;Haigis and Guarente, 2006;Yang and Seto, 2007). Control of histone acetylation is associated with longevity regulation in lower organisms (Kaeberlein et al, 1999;Tissenbaum and Guarente, 2001;Rogina and Helfand, 2004;Wood et al, 2004;Dang et al, 2009), and changes in histone acetylation in tissues, such as the brain and liver, correlate with age-dependent declines in tissue function (Oh and Conard, 1972;Shen et al, 2008;Kawakami et al, 2009;Peleg et al, 2010). However, the importance of histone acetylation in aging stem cells is less well studied.…”