CRTC1 mediates preferential transcription at neuronal activity-regulated CRE/TATA promoters

• Published in: Scientific reports 2017-12, Vol.7 (1), p.18004-18004, Article 18004
• Main Authors: Parra-Damas, Arnaldo, Rubió-Ferrarons, Laura, Shen, Jie, Saura, Carlos A.
• Format: Article
• Language: English
• Subjects: 38; 45; 45/90; 631/378/87; 631/45/882; 82/80; 96/109; 96/95; Animals; Brain - metabolism; c-Fos protein; Chromatin; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; Dephosphorylation; Depolarization; Gene expression; Gene Expression Regulation; Humanities and Social Sciences; Immunoprecipitation; Mice; Molecular modelling; multidisciplinary; Neurons - metabolism; Nuclear transport; Presenilin 1; Presenilin 2; Promoter Regions, Genetic; Promoters; Science; Science (multidisciplinary); Signal transduction; Transcription activation; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Translocation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-18215-y

Gene expression mediated by the transcription factor cAMP-responsive element-binding protein (CREB) is essential for a wide range of brain processes. The transcriptional coactivartor CREB-regulated transcription coactivator-1 (CRTC1) is required for efficient induction of CREB target genes during neuronal activity. However, the mechanisms regulating induction of specific CREB/CRTC1-dependent genes during neuronal activity remain largely unclear. Here, we investigated the molecular mechanisms regulating activity-dependent gene transcription upon activation of the CREB/CRTC1 signaling pathway in neurons. Depolarization and cAMP signals induce preferential transcription of activity-dependent genes containing promoters with proximal CRE/TATA sequences, such as c-fos , Dusp1 , Nr4a1 , Nr4a 2 and Ptgs2 , but not genes with proximal CRE/TATA-less promoters (e.g. Nr4a 3 , Presenilin-1 and Presenilin-2 ). Notably, biochemical and chromatin immunoprecipitation analyses reveal constitutive binding of CREB to target gene promoters in the absence of neuronal activity, whereas recruitment of CRTC1 to proximal CRE/TATA promoters depends on neuronal activity. Neuronal activity induces rapid CRTC1 dephosphorylation, nuclear translocation and binding to endogenous CREB. These results indicate that neuronal activity induces a preferential binding of CRTC1 to the transcriptional complex in CRE/TATA-containing promoters to engage activity-dependent transcription in neurons.