Lab of Molecular Neurobiology, Institute of Higher Nervous Activity and Neurophysiology of RAS, 5A Butlerova st, Moscow, 117485, Russia.
Lab of Cellular Neurobiology of Learning, Institute of Higher Nervous Activity and Neurophysiology of RAS, 5A Butlerova st, Moscow, 117485, Russia.
Sci Rep. 2019 Mar 13;9(1):4332. doi: 10.1038/s41598-019-40823-z.
It is widely accepted that memory consolidation requires de-novo transcription of memory-related genes. Epigenetic modifications, particularly histone acetylation, may facilitate gene transcription, but their potential molecular targets are poorly characterized. In the current study, we addressed the question of epigenetic control of atypical protein kinases (aPKC) that are critically involved in memory consolidation and maintenance. We examined the patterns of expression of two aPKC genes (Prkci and Prkcz) in rat cultured cortical neurons treated with histone deacetylase inhibitors. Histone hyperacetylation in the promoter region of Prkci gene elicited direct activation of transcriptional machinery, resulting in increased production of PKCλ mRNA. In parallel, histone hyperacetylation in the upstream promoter of Prkcz gene led to appearance of the corresponding PKCζ transcripts that are almost absent in the brain in resting conditions. In contrast, histone hyperacetylation in the downstream promoter of Prkcz gene was accompanied by a decreased expression of the brain-specific PKMζ products. We showed that epigenetically-triggered differential expression of PKMζ and PKCζ mRNA depended on protein synthesis. Summarizing, our results suggest that genes, encoding memory-related aPKC, may represent the molecular targets for epigenetic regulation through posttranslational histone modifications.
人们普遍认为，记忆巩固需要记忆相关基因的从头转录。表观遗传修饰，特别是组蛋白乙酰化，可能有助于基因转录，但它们的潜在分子靶点尚未得到很好的描述。在本研究中，我们探讨了组蛋白去乙酰化酶抑制剂处理的培养皮质神经元中异常蛋白激酶（aPKC）的表观遗传控制问题。我们研究了两种 aPKC 基因（Prkci 和 Prkcz）在大鼠培养皮质神经元中的表达模式。Prkci 基因启动子区域的组蛋白过度乙酰化引发了转录机制的直接激活，导致 PKCλ mRNA 的产生增加。同时，Prkcz 基因上游启动子的组蛋白过度乙酰化导致了相应的 PKCζ 转录本的出现，而在静息状态下，这些转录本在脑中几乎不存在。相比之下，Prkcz 基因下游启动子的组蛋白过度乙酰化伴随着脑特异性 PKMζ 产物表达的减少。我们表明，PKMζ 和 PKCζ mRNA 的表观遗传触发的差异表达依赖于蛋白质合成。总之，我们的结果表明，编码记忆相关 aPKC 的基因可能是通过翻译后组蛋白修饰进行表观遗传调控的分子靶点。
