Repetitive CREB-DNA interactions at gene loci predetermined by CBP induce activity-dependent gene expression in human cortical neurons

• Published in: Cell reports (Cambridge) Vol. 43; no. 1; p. 113576
• Main Authors: Atsumi, Yuri, Iwata, Ryohei, Kimura, Hiroshi, Vanderhaeghen, Pierre, Yamamoto, Nobuhiko, Sugo, Noriyuki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.01.2024
• Subjects: activity-dependent gene; BRD4; CBP; CREB; histone acetylation; human cortical neuron; neuronal activity; RNAPII; single-molecule imaging; CBP; CREB; CP: Neuroscience; neuronal activity; single-molecule imaging; CP: Molecular biology; human cortical neuron; RNAPII; activity-dependent gene; histone acetylation; BRD4
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113576

Neuronal activity-dependent transcription plays a key role in plasticity and pathology in the brain. An intriguing question is how neuronal activity controls gene expression via interactions of transcription factors with DNA and chromatin modifiers in the nucleus. By utilizing single-molecule imaging in human embryonic stem cell (ESC)-derived cortical neurons, we demonstrate that neuronal activity increases repetitive emergence of cAMP response element-binding protein (CREB) at histone acetylation sites in the nucleus, where RNA polymerase II (RNAPII) accumulation and FOS expression occur rapidly. Neuronal activity also enhances co-localization of CREB and CREB-binding protein (CBP). Increased binding of a constitutively active CREB to CBP efficiently induces CREB repetitive emergence. On the other hand, the formation of histone acetylation sites is dependent on CBP histone modification via acetyltransferase (HAT) activity but is not affected by neuronal activity. Taken together, our results suggest that neuronal activity promotes repetitive CREB-CRE and CREB-CBP interactions at predetermined histone acetylation sites, leading to rapid gene expression. [Display omitted] •Single-molecule imaging shows CREB and CBP dynamics in human cortical neurons•Neuronal activity induces CREB-CBP repetitive emergence at histone acetylation sites•RNAPII accumulates at the repetitive emergence sites, leading to gene expression•Histone acetylation sites are predetermined by CBP HAT activity Atsumi et al. show spatiotemporal dynamics of CREB and CBP in neuronal gene regulation by imaging techniques in human ESC-derived cortical neurons. Histone acetylation is preprepared by CBP at activity-dependent gene loci, while neuronal activity induces gene expression at the acetylation sites by promoting emergence of CREB, CBP, and RNAPII.