Transcription factors implicated in substance use disorder, from immediate early genes to altered gene expression

Transcription factors (TFs) link external stimuli to altered gene expression in all cell types, tissues, and biological processes. Because addiction phenotypes, including substance use disorder (SUD) cause enormous human suffering, significant effort is ongoing to understand the molecular processes that underlie these conditions, including elucidating the genetic drivers of addiction. While immense progress has been made, the combination of complex, multilocus genetics, large numbers of inherited variants of small effect size, and heterogeneous cellular physiology has proved difficult to untangle. Despite these challenges, genome-wide association studies (GWAS) have provided evidence for the likely causative role for some genes and pathways, and neurobiological molecular studies have implicated some cellular and physiological processes. These mechanisms include how the substance itself is processed, the subsequent induced signals that activate neurobiological responses and influence behavioral changes, and corresponding epigenetic and structural alterations of brain circuitry. These mechanisms persist for some users, contributing to the addictive phenotype. Central to this response is the activation of several transcription factors and cofactors that are considered "immediate early genes" (IEGs), which communicate signals through neurotransmitter signaling pathways in the brain. In this review, we aggregate published evidence that links TFs to SUD and summarize the key TFs (such as CREB1, FOSB, E2F3A, and EGR1) involved in shared cellular processes emphasizing the role of IEGs. We also document shared connections across substances and model organisms, with an emphasis on known epigenetic interactions, GWAS links, and relevance to human biology.