BET bromodomains as novel epigenetic targets for brain health and disease

Abstract

Epigenetic pharmacotherapy for CNS-related diseases is a burgeoning area of research. In particular, members of the bromodomain and extra-terminal domain (BET) family of proteins have emerged as intriguing therapeutic targets due to their putative involvement in an array of brain diseases. With their ability to bind to acetylated histones and act as a scaffold for chromatin modifying complexes, BET proteins were originally thought of as passive epigenetic 'reader' proteins. However, new research depicts a more complex reality where BET proteins act as key nodes in lineage-specific and signal-dependent transcriptional mechanisms to influence disease-relevant functions. Amid a recent wave of drug development efforts from basic scientists and pharmaceutical companies, BET inhibitors are currently being studied in several CNS-related disease models, but safety and tolerability remain a concern. Here we review the progress in understanding the neurobiological mechanisms of BET proteins and the therapeutic potential of targeting BET proteins for brain health and disease.

Keywords: Addiction; Alzheimer's disease; BET; BRD4; Brain cancer; Bromodomain; Epigenetic readers; Learning and memory; Neuroepigenetics; Neurological disorders; Substance use disorder.

Figure 1.. Yearly publications (2006–2019) for the PubMed search terms BRD2, BRD3, and BRD4.

Note the rise in publications (particularly for BRD4) following the discovery of JQ1 and I-BET.

Figure 2.. Interactions with BRD4 domains:

BRD4 contains tandem bromodomains (BD1 and BD2) that bind to acetylated histone and non-histone proteins, an extra-terminal domain (ET) that interacts with several chromatin regulators, and a C-terminal domain (CTM) that interacts with P-TEFb to facilitate transcription elongation. Several transcription factors have also been found to associate with BRD4-associated complexes. CK2, PKA, and IKK-epsilon phosphorylate BRD4 to alter its binding to acetylated proteins and PP2A removes the phosphorylation sites. Also listed are examples of BD1/BD2, BD1-selective, and BD2-selective BET inhibitions and key genes altered by BET inhibition in specific cell types.

Figure 3.. Heatmap of Brd2, Brd3, and Brd4 mRNA expression in mouse neuronal cell types.

Each row compares relative expression of Brd2, Brd3, and Brd4 mRNA within a cell type cluster from the specified brain region. RNA expression is compared using normalized mean log values obtained from DropVis single-cell RNAseq database (http://dropviz.org/). The heatmap was generated using Morpheous tool provided by the Broad Institute (https://software.broadinstitute.org/morpheus/). Red indicates higher expression levels and blue indicates lower expression levels. Note that these are baseline expression levels and that specific disease states may augment Brd2, Brd3, Brd4 levels in a cell type-specific manner.