Transcription factor Creb3l1 maintains proteostasis in neuroendocrine cells.
Transcription factor Creb3l1 maintains proteostasis in neuroendocrine cells.
复制标题
DOI：
10.1016/j.molmet.2022.101542
复制
发表时间：
2022-09
影响因子：
8.1
通讯作者：
Greenwood, Michael P.
中科院分区：
文献类型：
--
作者：
Greenwood, Mingkwan;Gillard, Benjamin T.;Farrukh, Rizwan;Paterson, Alex;Althammer, Ferdinand;Grinevich, Valery;Murphy, David;Greenwood, Michael P.
Dynamic changes to neuropeptide hormone synthesis and secretion by hypothalamic neuroendocrine cells is essential to ensure metabolic homeostasis. The specialised molecular mechanisms that allow neuroendocrine cells to synthesise and secrete vast quantities of neuropeptides remain ill defined. The objective of this study was to identify novel genes and pathways controlled by transcription factor and endoplasmic reticulum stress sensor Creb3l1 which is robustly activated in hypothalamic magnocellular neurones in response to increased demand for protein synthesis. We adopted a multiomic strategy to investigate specific roles of Creb3l1 in rat magnocellular neurones. We first performed chromatin immunoprecipitation followed by genome sequencing (ChIP-seq) to identify Creb3l1 genomic targets and then integrated this data with RNA sequencing data from physiologically stimulated and Creb3l1 knockdown magnocellular neurones. The data converged on Creb3l1 targets that code for ribosomal proteins and endoplasmic reticulum proteins crucial for the maintenance of cellular proteostasis. We validated genes that compose the PERK arm of the unfolded protein response pathway including Eif2ak3, Eif2s1, Atf4 and Ddit3 as direct Creb3l1 targets. Importantly, knockdown of Creb3l1 in the hypothalamus led to a dramatic depletion in neuropeptide synthesis and secretion. The physiological outcomes from studies of paraventricular and supraoptic nuclei Creb3l1 knockdown animals were changes to food and water consumption. Collectively, our data identify Creb3l1 as a comprehensive controller of the PERK signalling pathway in magnocellular neurones in response to physiological stimulation. The broad regulation of neuropeptide synthesis and secretion by Creb3l1 presents a new therapeutic strategy for metabolic diseases. A multiomic investigation of transcription factor Creb3l1 in the hypothalamus. Creb3l1 targets ER and ribosomal genes to preserve cellular proteostasis. Identification of Creb3l1 as a major controller of the PERK arm of the UPR pathway. Knockdown of Creb3l1 in the PVN and SON inhibits hormone synthesis and secretion. Hypothalamic Creb3l1 expression regulates food and water intake.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
4.2
作者：
Greenwood MP;Greenwood M;Romanova EV;Mecawi AS;Paterson A;Sarenac O;Japundžić-Žigon N;Antunes-Rodrigues J;Paton JFR;Sweedler JV;Murphy D
通讯作者：
Murphy D
影响因子：
3.2
作者：
通讯作者：
--
影响因子：
3.7
作者：
Greenwood M;Greenwood MP;Paton JF;Murphy D
通讯作者：
Murphy D
影响因子：
4
作者：
Garcia, Iris A.;Torres Demichelis, Vanina;Alvarez, Cecilia
通讯作者：
Alvarez, Cecilia