The Contribution of Systematic Approaches to Characterizing the Proteins and Functions of the Endoplasmic Reticulum

Schuldiner, Maya; Weissman, Jonathan S.

doi:10.1101/cshperspect.a013284

Cited by 13 publications

(14 citation statements)

References 157 publications

(146 reference statements)

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“…This relied upon the assumption that genes which are part of a common functional pathway (in this case, lipid metabolism) should be regulated similarly. This approach has been used to great effect in yeast, and more recently in cultured mammalian cells, to expose previously hidden components of the secretory apparatus and other pathways of interest (Schuldiner and Weissman, 2013). Here, our goal was to infer hidden transcriptional regulators using temporal patterns of gene expression as an output.…”

Section: Resultsmentioning

confidence: 99%

Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network

Arensdorf¹,

McCabe²,

Kaufman³

et al. 2013

Front. Genet.

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The unfolded protein response (UPR) responds to disruption of endoplasmic reticulum (ER) function by initiating signaling cascades that ultimately culminate in extensive transcriptional regulation. Classically, this regulation includes genes encoding ER chaperones, ER-associated degradation factors, and others involved in secretory protein folding and processing, and is carried out by the transcriptional activators that are produced as a consequence of UPR activation. However, up to half of the mRNAs regulated by ER stress are downregulated rather than upregulated, and the mechanisms linking ER stress and UPR activation to mRNA suppression are poorly understood. To begin to address this issue, we used a “bottom-up” approach to study the metabolic gene regulatory network controlled by the UPR in the liver, because ER stress in the liver leads to lipid accumulation, and fatty liver disease is the most common liver disease in the western world. qRT-PCR profiling of mouse liver mRNAs during ER stress revealed that suppression of the transcriptional regulators C/EBPα, PPARα, and PGC-1α preceded lipid accumulation, and was then followed by suppression of mRNAs encoding key enzymes involved in fatty acid oxidation and lipoprotein biogenesis and transport. Mice lacking the ER stress sensor ATF6α, which experience persistent ER stress and profound lipid accumulation during challenge, were then used as the basis for a functional genomics approach that allowed genes to be grouped into distinct expression profiles. This clustering predicted that ER stress would suppress the activity of the metabolic transcriptional regulator HNF4α—a finding subsequently confirmed by chromatin immunopreciptation at the Cebpa and Pgc1a promoters. Our results establish a framework for hepatic gene regulation during ER stress and suggest that HNF4α occupies the apex of that framework. They also provide a unique resource for the community to further explore the temporal regulation of gene expression during ER stress in vivo.

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Section: Resultsmentioning

confidence: 99%

Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network

Arensdorf¹,

McCabe²,

Kaufman³

et al. 2013

Front. Genet.

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“…Here, the continued application of functional genomics (see Schuldiner and Weissman 2013) and transgenic mouse models are likely to have a key role. Inspiration may also be taken from the rich set of tools available for manipulating and monitoring phosphoinositide lipids (Várnai and Balla 2008;Chang-Ileto et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Breslow

2013

Cold Spring Harbor Perspectives in Biology

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Sphingolipids are a diverse group of lipids that have essential cellular roles as structural components of membranes and as potent signaling molecules. In recent years, a detailed picture has emerged of the basic biochemistry of sphingolipids-from their initial synthesis in the endoplasmic reticulum (ER), to their elaboration into complex glycosphingolipids, to their turnover and degradation. However, our understanding of how sphingolipid metabolism is regulated in response to metabolic demand and physiologic cues remains incomplete. Here I discuss new insights into the mechanisms that ensure sphingolipid homeostasis, with an emphasis on the ER as a critical regulatory site in sphingolipid metabolism. In particular, Orm family proteins have recently emerged as key ER-localized mediators of sphingolipid homeostasis. A detailed understanding of how cells sense and control sphingolipid production promises to provide key insights into membrane function in health and disease.

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“…However, the ER proteome and the topology of ER enzymes are poorly characterized [126], and to date, only the oxidases discussed here have been implicated as major determinants of ER redox conditions through luminal hydrogen peroxide production.…”

Section: Formation and Elimination Of Hydrogen Peroxide In The Ermentioning

confidence: 99%

Composition of the redox environment of the endoplasmic reticulum and sources of hydrogen peroxide

Margittai

Enyedi

Csala

et al. 2015

Free Radical Biology and Medicine

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The Contribution of Systematic Approaches to Characterizing the Proteins and Functions of the Endoplasmic Reticulum

Cited by 13 publications

References 157 publications

Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network

Temporal clustering of gene expression links the metabolic transcription factor HNF4α to the ER stress-dependent gene regulatory network

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Composition of the redox environment of the endoplasmic reticulum and sources of hydrogen peroxide

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