ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression

Abstract

ΔFOSB is a uniquely stable member of the FOS family of immediate early gene AP1 transcription factors. Its accumulation in specific cell types and tissues in response to a range of chronic stimuli is associated with biological phenomena as diverse as memory formation, drug addiction, stress resilience, and immune cell activity. Causal connections between ΔFOSB expression and the physiological and behavioral sequelae of chronic stimuli have been established in rodent and, in some cases, primate models for numerous healthy and pathological states with such preclinical observations often supported by human data demonstrating tissue-specific ΔFOSB expression associated with several specific syndromes. However, the viability of ΔFOSB as a target for therapeutic intervention might be questioned over presumptive concerns of side effects given its expression in such a wide range of cell types and circumstances. Here, we summarize numerous insights from the past three decades of research into ΔFOSB structure, function, mechanisms of induction, and regulation of target genes that support its potential as a druggable target. We pay particular attention to the potential for targeting distinct ΔFOSB isoforms or distinct ΔFOSB-containing multiprotein complexes to achieve cell type or tissue specificity to overcome off-target concerns. We also cover critical gaps in knowledge that currently limit the exploitation of ΔFOSB’s therapeutic possibilities and how they may be addressed. Finally, we summarize both current and potential future strategies for generating small molecules or genetic tools for the manipulation of ΔFOSB in the clinic.

Cell-type-specific whole-genome landscape of ΔFOSB binding in nucleus accumbens after chronic cocaine exposure

“…The induction of ΔFOSB in NAc has been demonstrated in humans with substance use disorders as well as in rodents after chronic exposure to cocaine or other drugs of abuse 1,2 . In addition, viral or genetic bidirectional manipulation of ΔFOSB activity in rodent NAc neurons controls the development of addiction-related behaviors 1,2,27 .…”

“…The induction of ΔFOSB in NAc has been demonstrated in humans with substance use disorders as well as in rodents after chronic exposure to cocaine or other drugs of abuse 1,2 . In addition, viral or genetic bidirectional manipulation of ΔFOSB activity in rodent NAc neurons controls the development of addiction-related behaviors 1,2,27 . However, it has been challenging to identify the direct genomic targets of ΔFOSB, beyond studies of a small number of candidate genes, due to technical limitations of using ChIP-seq to interrogate transcription factors in micro-dissected brain tissue.…”

“…ΔFOSB has long been considered a key player in the development of drug addiction, but it has also been implicated in numerous other brain functions and neuropsychiatric disorders, including stress susceptibility and resilience, learning and memory, Alzheimer’s disease, and epilepsy, among others 2,3,46-49 . Accordingly, there is interest in developing small molecule potentiators or inhibitors of ΔFOSB as possible imaging agents for diagnostic purposes or even as novel therapeutic approaches 2,50 . The present study expands our understanding of ΔFOSB’s molecular functions and will assist strategies to control ΔFOSB’s transcriptional machinery.…”

“…All drugs of abuse induce ΔFOSB selectively in D1 MSNs, whereas opioids uniquely induce ΔFOSB equally in both D1 and D2 MSNs 6 . Overexpressing ΔFOSB selectively in D1 MSNs, by use of viral-mediated gene transfer or of inducible genetic mutant mice, increases an animal’s sensitivity to the rewarding effects of cocaine and certain other drugs of abuse, while antagonizing ΔFOSB action via expression of a dominant-negative antagonist exerts the opposite effect 1,2 . The consequences of ΔFOSB induction in D2 MSNs have not yet been characterized.…”

Virtual Special Issue: Epigenetics 2022

“…In this joint virtual special issue, you will see contributions spanning the neuro­epigentic landscape from some of the top authors in the field. Of particular note are several exceptional Perspective and Review papers covering epigenetic mechanisms of memory, activity-dependent brain plasticity, neuro­degeneration, and chronic pain . Beyond this, you will find new research that points to the therapeutic potential of epigenetic regulation in a number of disease contexts.…”