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Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes [MG_U74Bv2]

ABSTRACT: The synthesis of fatty acids and cholesterol is regulated by three membrane-bound transcription factors: sterol regulatory element-binding proteins (SREBP)-1a, -1c, and -2. Their function in liver has been characterized in transgenic mice that overexpress each SREBP isoform and in mice that lack all three nuclear SREBPs because of gene knockout of SREBP cleavage-activating protein (SCAP) required for nuclear localization of SREBPs. Here, we use oligonucleotide arrays hybridized with RNA from livers of three lines of mice (transgenic for SREBP-1a, transgenic for SREBP-2, and knockout for SCAP) to identify genes that are likely to be direct targets of SREBPs in liver. Application of stringent combinatorial criteria to the transgenic/knockout approach allows identification of genes whose activities are likely controlled directly by the SREBPs.

ORGANISM(S): Mus musculus

PROVIDER: GSE102257 | GEO | 2017/08/05

SECONDARY ACCESSION(S): PRJNA397145

REPOSITORIES: GEO

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Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes [MG_U74Cv2]

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Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes [MG_U74Av2]

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Deletion of Scap in Alveolar Type II Cells Influences Lung Lipid Homeostasis and Identifies a Compensatory Role for Pulmonary Lipofibroblasts

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2011-01-08 | E-GEOD-26496 | biostudies-arrayexpress

Examination of hepatic SREBP-2 binding using ChIP-Seq

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Examination of hepatic SREBP-2 binding using ChIP-Seq

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A suite of haploid genetic screens identifies SPRING as a novel determinant of SREBP signaling and cholesterol metabolism

Project description:The sterol-regulatory element binding protein (SREBP) transcription factors are central transcriptional regulators of sterol- and fatty acid metabolism. Using a suite of human haploid genetic screens, we identify the SREBP Regulating Gene (SPRING; C12ORF49) as a novel regulator of this pathway. SPRING is a glycosylated Golgi-resident membrane protein. Genetic ablation of SPRING in human Hap1 cells, murine Hepa1-6 hepatoma cells, and in primary murine hepatocytes leads to a marked reduction in SREBP signaling. In mice, deletion of Spring results in embryonic lethality. However, we show that adenoviral-mediated silencing of hepatic Spring expression also attenuates the SREBP response. Mechanistically, we demonstrate that attenuated SREBP signaling in SPRINGKO cells is a result of reduced SREBP cleavage-activating protein (SCAP) and its mislocalization. Whereas in control cells SCAP cycles between the ER and the Golgi in a sterol-dependent manner, in SPRINGKO cells SCAP is trapped in the Golgi irrespective of the cellular sterol status. Consistent with limited functional SCAP in SPRINGKO cells, reintroducing SCAP restores SREBP-dependent signaling, cholesterol biosynthesis, and lipoprotein uptake. Consistent with SREBP signaling being required for cell growth and proliferation, a wide range of human tumor cell lines display dependency on SPRING expression. In conclusion, we identify SPRING as a previously unrecognized determinant of the SREBP pathway that is essential for proper SCAP function.

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