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

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2354-y) contains supplementary material, which is available to authorized users.

Methionine Regulates mTORC1 via the T1R1/T1R3-PLCβ-Ca2+-ERK1/2 Signal Transduction Process in C2C12 Cells

“…AA stimulation, such as l -leucine can improve the transcription and translation of mTORC1 [31,32]. Previous studies focused on the mechanism by which the activity of some AA transporters may modulate the size and composition of the intracellular AA pool and the effects of such an activity [21].…”

How many roads lead to cohesinopathies?

“…As in the rad21, smc3 , and nipbl morphants, reduced 4EBP1 phosphorylation and mTOR activity are observed in esco2 morphants. Remarkably, L‐leucine ameliorates the developmental defects otherwise present in esco2 morphants, thus providing support of the role of esco2 in ribosome biogenesis and translation (Xu et al, 2013; Xu et al, ; Xu et al, ; Zakari et al, ). These studies provide a second example through which mechanism‐based boundaries are bridged between CdLS and RBS.…”

“…There is compelling evidence that cohesion pathway factors regulate gene transcription (Dorsett and Krantz, ; Cucco and Musio, ; Dorsett, ). While microarray analyses of individual cohesion pathway gene knockdowns often reveal limited overlap in gene deregulation (Rhodes et al, ; Monnich et al, ; Muto et al, ; Muto et al, ), new studies provide a growing body of evidence that RBS models, similar to those of CdLS, exhibit significant changes in gene expression (Banerji et al, ; Choi et al, ; Leem et al, ; Monnich et al, ; Xu et al, ; Rahman et al, ). This unifying model may appear to be challenged by disparate findings regarding NIPBL, cohesin, and CTCF residency on chromatin (Misulovin et al, ; Kagey et al, ; Muto et al, ; Zuin et al, ; Minamino et al, ; Rahman et al, ).…”

“…For example, there is evidence that mutations in genes associated with CdLS cause apoptosis through mitotic failure (Kaur et al, ; Ghiselli, ; Fazio et al, ; Schuster et al, ; Pistocchi et al, ). Furthermore, there is evidence that mutations in esco2 impact transcription regulation (Leem et al, , Choi et al, , Banerji et al, , Xu et al, ). One possibility is that the few observed differences between CdLS and RBS phenotypes are based on the effective dosage of the cohesion pathway genes.…”

Cohesin facilitates zygotic genome activation in zebrafish

“…These processes are also compromised by disrupting cohesin function in yeast and mammalian cells (Bose et al, 2012). Xu et al previously demonstrated that translational defects in zebrafish and mammalian cell cohesin mutants were chemically rescued by L-Leucine stimulation of the TOR pathway (Xu et al, 2016; Xu et al, 2015). Our data are consistent with these observations that translational mechanisms require normal cohesin function.…”