Multi-Faceted Role of Histone Methyltransferase Enhancer of Zeste 2 (EZH2) in Neuroinflammation and Emerging Targeting Options

Abstract

Neuroinflammation, a complex nervous system response to brain injury and other pathological stimuli, exhibits a common denominator role in the pathogenesis of neurological disorders and their progression. Among several regulators of neuroinflammation, epigenetic mechanisms with particular emphasis on histone methylation have a prominent role by altering the expression of specific genes involved in the onset and progression of neuroinflammation. The Enhancer of Zeste 2 (EZH2) histone lysine methyltransferase is a multi-faceted and context-dependent regulator of immune response and neural cell function, significantly involved in the underlying mechanisms of neuroinflammation, such as inflammatory gene expression, astrocyte function, microglial activation, BBB integrity, and interactions with non-coding RNAs. Herein, we explore the intricate implication of EZH2 activity in the onset of neuroinflammation and associated pathological conditions, and discuss its potential as a therapeutic target. Currently available EZH2 inhibitors with neuroprotective effects are also addressed in an effort to reveal novel strategies for managing neuroinflammatory conditions, and potentially improving neurological health.

Keywords: DZNep; EPZ-6438; EZH2 inhibitors; H3K27me3; epigenetic; histone methylation; neuroinflammation.

Figure 1

EZH2 gene structure and PRC2 complex components. (A) Structure of EZH2 indicating the regulatory (SBD, EID, BAM, SAL, SRM, and SANT1) and catalytic domains (MCSS, SANT2, CXC and SET). (B) PRC2 complex composition indicating the core subunits: EZH2 (enhancer of zeste homolog 2), EED (embryonic ectoderm development), SUZ12 (suppressor of zeste 12 homolog), RbAp46/48 (retinoblastoma binding protein 4) and non-core subunits: JARID2 (jumonji, AT-rich interactive domain 2), PCL (polycomb-like proteins), AEBP2 (adipocyte enhancer-binding protein 2). (C) Crystal structure of the PRC2 complex with the EZH2 subunit in green, EED in red, SUZ12 in blue, and JARID2 in yellow. (D) Two-dimensional structure of EZH2 subunit. The structure was obtained from the Protein Data Bank (PDB ID: [5LS6], [4MI0]), and the image was generated using ChimeraX (version 1.10) [23].

Figure 2

Role of EZH2 in the regulation of inflammatory gene expression.

Figure 3

Main EZH2-induced mechanisms of neuroinflammation.