Improved transcription and translation with L-leucine stimulation of mTORC1 in Roberts syndrome

BMC Genomics

Research Article

Baoshan Xu¹  Karin Gaudenz¹  Madelaine Gogol¹  Jennifer L. Gerton² 

[1] Stowers Institute for Medical Research, 1000 E 50th St, 64110, Kansas City, MO, USA;Stowers Institute for Medical Research, 1000 E 50th St, 64110, Kansas City, MO, USA;Department of Biochemistry and Molecular Biology, University of Kansas School of Medicine, 3901 Rainbow Blvd, 66160, Kansas City, KS, USA;

关键词: Ribosome profiling;    Gene expression;    Roberts syndrome (RBS);    mTORC1 pathway;    Translation;    Cohesin;   

DOI  :  10.1186/s12864-015-2354-y

 received in 2015-07-09, accepted in 2015-12-21,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundRoberts syndrome (RBS) is a human developmental disorder caused by mutations in the cohesin acetyltransferase ESCO2. We previously reported that mTORC1 signaling was depressed and overall translation was reduced in RBS cells and zebrafish models for RBS. Treatment of RBS cells and zebrafish RBS models with L-leucine partially rescued mTOR function and protein synthesis, correlating with increased cell division and improved development.ResultsIn this study, we use RBS cells to model mTORC1 repression and analyze transcription and translation with ribosome profiling to determine gene-level effects of L-leucine. L-leucine treatment partially rescued translational efficiency of ribosomal subunits, translation initiation factors, snoRNA production, and mitochondrial function in RBS cells, consistent with these processes being mTORC1 controlled. In contrast, other genes are differentially expressed independent of L-leucine treatment, including imprinted genes such as H19 and GTL2, miRNAs regulated by GTL2, HOX genes, and genes in nucleolar associated domains.ConclusionsOur study distinguishes between gene expression changes in RBS cells that are TOR dependent and those that are independent. Some of the TOR independent gene expression changes likely reflect the architectural role of cohesin in chromatin looping and gene expression. This study reveals the dramatic rescue effects of L-leucine stimulation of mTORC1 in RBS cells and supports that normal gene expression and translation requires ESCO2 function.

【 授权许可】

CC BY   
© Xu et al. 2015