Roles of the MYST Family in the Pathogenesis of Alzheimer's Disease via Histone or Non-histone Acetylation

Abstract

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and a major cause of death among elderly individuals. The etiology of AD involves a combination of genetic, environmental, and lifestyle factors. A number of epigenetic alterations in AD have recently been reported; for example, studies have found an increase in histone acetylation in patients with AD and the protective function of histone deacetylase inhibitors. The histone acetylases in the MYST family are involved in a number of key nuclear processes, such as gene-specific transcriptional regulation, DNA replication, and DNA damage response. Therefore, it is not surprising that they contribute to epigenetic regulation as an intermediary between genetic and environmental factors. MYST proteins also exert acetylation activity on non-histone proteins that are closely associated with the pathogenesis of AD. In this review, we summarized the current understanding of the roles of MYST acetyltransferases in physiological functions and pathological processes related to AD. Additionally, using published RNA-seq, ChIP-seq, and ChIP-chip data, we identified enriched pathways to further evaluate the correlation between MYST and AD. The recent research described in this review supports the importance of epigenetic modifications and the MYST family in AD, providing a basis for future functional studies.

Keywords: Alzheimer’s disease; Epigenetic; HBO1; MORF; MOZ; MYST; hMOF.

Figure 1.

Summarized diagram of Tip60 in AD. First, the complex composed of Fe65, AICD, and Tip60 can inhibit β-amyloid and Stathmin1 while Stathmin1 can promote tau phosphorylation. At the same time, Tip60 directly acetylates the H3/H4 histones and activates PTEN, thereby affecting the inflammatory pathogenesis of AD and phosphorylation of tau, respectively.

Figure 2.

Tip60-mediated target genes involved in AD. PANTHER pathway analyses of the differentially expressed genes determined by ChIP-seq using a Tip60 antibody in Drosophila melanogaster (A) and determined by RNA-seq in Tip60-mutant Drosophila melanogaster (B). The 20 most highly enriched pathway entries have been displayed.

Figure 3.

Involvement of MOZ and MORF in AD. MOZ binds to the promoter of p16INK4a and silences the p16INK4a expression, which in turn inhibits the self-renewal and proliferation of NSCs. The interaction of MOZ/p300 can acetylate tau or suppress the expression of Presenilin1 and BACE1. Additionally, the fusion genes of MORF and CBP can aggravate the pathogenesis of AD by either inhibiting the expression of the neuronal apoptosis factor (caspase-6) or promoting the abnormal accumulation of acetylated tau.

Figure 4.

MOZ-mediated target genes involved in AD. PANTHER pathway analyses of the differentially expressed genes in leukemic stem cells with the MOZ-TIF2 fusion gene (A), MOZ-knockdown in SUM-52 cells (B), and siRNA knockdown of MORF in the HEK 293 and HeLa cells (C). The 20 most highly enriched pathway entries have been displayed.

Figure 5.

HBO1-mediated target genes involved in AD. PANTHER pathway analyses based on ChIP-seq data obtained using an HBO1 antibody (A), ChIP-chip data using HBO1 antibodies in K562 cells (B), and a pathway enrichment analysis of ChIP-chip data for K562 cells (C). The 20 most highly enriched pathway entries have been displayed.

Figure 6.

The roles of MOF in AD. MOF can inhibit the degeneration of mitochondria and decrease AD induced by an oxidative phosphorylation. Acetylating H4K16 and MOF also activates Nox4 and MnSOD as well as decreases ROS. Finally, MOF activates lysosomes via LAMP1 and LAMP2.

Figure 7.

MOF-mediated target genes involved in AD. PANTHER pathway analysis of ChIP-seq data using an MOF antibody in the embryonic stem cells (A), and genes that were significantly altered in the MOF-deleted mouse embryonic fibroblasts (B). The 20 most highly enriched pathway entries have been displayed.