Skill Learning Modulates RNA Pol II Poising at Immediate Early Genes in the Adult Striatum

A multilayered complexity of epigenetic and transcriptional regulatory mechanisms underlies neuronal activity-dependent gene transcription. The regulation of RNA Pol II progression along the transcription cycle, from promoter-proximal poising (with RNA Pol II paused at promoter-proximal regions, characterized by a Ser5P⁺-rich and Ser2P⁺-poor RPB1 CTD) to active elongation, has emerged as a major step in transcriptional regulation across several organisms, tissues, and developmental stages, including the nervous system. However, it is not known whether this mechanism is modulated by experience. We investigated the impact of learning a motor skill on RNA Pol II phosphorylation dynamics in the adult mouse striatum. We uncovered that learning modulates the in vivo striatal phosphorylation dynamics of the CTD of the RNA Pol II RPB1 subunit, leading to an increased poising index in trained mice. We found that this modulation occurs at immediate early genes (IEGs), with increased poising of RNA Pol II at both Arc and Fos genes but not at constitutively expressed genes. Furthermore, we confirmed that this was learning dependent, and not just regulated by context or motor activity. These experiments demonstrate a novel phenomenon of learning induced transcriptional modulation in adult brain, which may have implications for our understanding of learning, memory allocation, and consolidation.