Cell-autonomous transcriptional mechanism for enhancement of translation capacity in secretory cells [ChIP-Seq]

Translation is a basic cellular process and its capacity is adapted to cell function. In particular, secretory cells achieve high protein synthesis levels without triggering the protein stress response. It is unknown how and when translation capacity is increased during differentiation. Here, we show that the transcription factor Creb3l2 is a scaling factor for translation capacity in pituitary secretory cells and that it directly binds ~75% of regulatory and effector genes for translation. In parallel with this cell-autonomous mechanism, implementation of the physiological UPR pathway prevents triggering the protein stress response. The pituitary differentiation factor Tpit activates Creb3l2 expression, the Creb3l2-dependent regulatory network as well as the physiological UPR pathway. Thus, Creb3l2 implements high basal translation levels through direct targeting of translation effector genes acting downstream of signaling pathways that otherwise regulate protein synthesis. Expression of Creb3l2 may be a useful means to enhance production of therapeutic proteins. Overall design: ChIPseq in normal AtT-20 and Creb3l2 gain-of-function Tg corticotrope AtT-20 cells

翻译（Translation）是一项基础细胞生命过程，其翻译容量会随细胞功能状态进行适应性调整。具体而言，分泌细胞可在不触发蛋白质应激反应的前提下，实现高水平的蛋白质合成。目前学界尚不清楚细胞分化过程中翻译容量提升的具体机制与时序。本研究发现，转录因子（transcription factor）Creb3l2是垂体分泌细胞翻译容量的比例调控因子，其可直接结合约75%的翻译调控基因与效应基因。与该细胞自主调控机制协同的是，生理性未折叠蛋白反应（Unfolded Protein Response, UPR）通路的激活可避免蛋白质应激反应的触发。垂体分化因子Tpit可同时激活Creb3l2的表达、Creb3l2依赖的调控网络以及生理性未折叠蛋白反应通路。综上，Creb3l2可通过直接靶向原本参与调控蛋白质合成的信号通路下游的翻译效应基因，实现基础翻译水平的上调。Creb3l2的表达或可成为提升治疗性蛋白质生产效率的有效手段。整体实验设计：在正常AtT-20细胞与Creb3l2功能获得性转基因（Transgenic, Tg）促肾上腺皮质激素AtT-20细胞中开展染色质免疫共沉淀测序（Chromatin Immunoprecipitation sequencing, ChIP-seq）实验。