Syntaxin 1A (Stx1a) is primarily involved in the docking of synaptic vesicles at active zones in neurons. Its gene is a TATA-less gene, with several transcription initiation sites, which is activated by the binding of Sp1 and acetylated histone H3 (H3) in the core promoter region (CPR) through the derepression of class I histone deacetylase (HDAC). In the present study, to clarify the factor characterizing Stx1a gene expression via the protein kinase A (PKA) pathway inducing the Stx1a mRNA, we investigated whether the epigenetic process is involved in the Stx1a gene transcription induced by PKA signaling. We found that the PKA activator forskolin induced Stx1a expression in non-neuronal cells, FRSK and 3Y1, which do not endogenously express Stx1a, unlike PC12. HDAC8 inhibition by shRNA knockdown and specific inhibitors induced Stx1a expression in FRSK. The PKA inhibitor H89 suppressed HDAC8-Ser39 phosphorylation, H3 acetylation and Stx1a induction by forskolin in FRSK cells. Finally, we also found that forskolin led to the dissociation of HDAC8-CPR interaction and the association of Sp1 and Ac-H3 to CPR in FRSK. The results of the current study suggest that forskolin phosphorylates HDAC8-Ser39 via the PKA pathway and increases histone H3 acetylation in cells expressing HDAC8, resulting in the induction of the Stx1a gene.
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The polyamine biosynthetic enzyme arginine decarboxylase has emerged multiple times from different proteins folds by convergent evolution, and has also emerged independently, at different times, from the same protein fold by pseudoconvergent evolution. In some cases, the enzyme cofactor is an internally produced pyruvoyl group, in others it is pyridoxal 5'-phosphate. The origin of this enzyme from such diverse structural classes and with different catalytic mechanisms indicates that the emergence of polyamine biosynthesis on Earth was, and is, inevitable. For more information, please see review article, “Evolution of Biosynthetic Diversity” by Anthony J. Michael, pages 2277–2299.
Transcription regulation mechanism of the syntaxin 1A gene via protein kinase A
Takahiro Nakayama, Kimio Akagawa; Transcription regulation mechanism of the syntaxin 1A gene via protein kinase A. Biochem J 15 July 2017; 474 (14): 2465–2473. doi: https://doi.org/10.1042/BCJ20170249
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