Transcription factors Lef1 and Rest stimulate recovery from depressive states.

The depressive state, a hallmark of major depressive disorder (MDD) and frequently observed alongside various neurological diseases, is often characterized by the dysregulation of multiple genes, reflecting a complex and multifaceted pathology underlying its symptoms. To gain deeper insights into the role of transcription factors (TFs) in mediating depressive states, we performed a detailed analysis of transcription factor activity profiles (TFAPs) in mouse brains, employing a TF-activity reporter battery that enables evaluation of transcriptional activities of multiple TFs and endogenous gene expression patterns within the same samples. This approach identified two critical TFs, T-cell factor/lymphoid enhancer factor (TCF/LEF) and RE1-silencing transcription factor (REST), whose activities were closely associated with a depressive phenotype and the transcriptomic alterations observed in mice subjected to chronic social defeat stress. We also found significant alterations in genes downstream of both TCF/LEF and REST in the brains of human patients with MDD. Pharmacological assessment in mice revealed that the neuropsychiatric agents, lithium and sertraline, modulate TCF/LEF and REST activities both in vitro and in vivo. Genetic and pharmacological manipulations of TCF/LEF and REST activities in stress-exposed mice influenced the recovery from depressive states, with combined modulation of both TFs enhancing therapeutic outcomes. These findings underscore the critical roles of TCF/LEF and REST in driving the transcriptomic changes observed in the brain during recovery from a depressive state. TFAP analysis deepens our understanding of the molecular underpinnings of chronic disorders and offers the potential for novel therapeutic interventions.