Identification of novel genes and pathways regulating SREBP transcriptional activity.
BACKGROUND
Lipid metabolism in mammals is orchestrated by a family of transcription factors called sterol regulatory element-binding proteins (SREBPs) that control the expression of genes required for the uptake and synthesis of cholesterol, fatty acids, and triglycerides. SREBPs are thus essential for insulin-induced lipogenesis and for cellular membrane homeostasis and biogenesis. Although multiple players have been identified that control the expression and activation of SREBPs, gaps remain in our understanding of how SREBPs are coordinated with other physiological pathways.


METHODS
To identify novel regulators of SREBPs, we performed a genome-wide cDNA over-expression screen to identify proteins that might modulate the transcription of a luciferase gene driven from an SREBP-specific promoter. The results were verified through secondary biological assays and expression data were analyzed by a novel application of the Gene Set Enrichment Analysis (GSEA) method.


CONCLUSIONS
We screened 10,000 different cDNAs and identified a number of genes and pathways that have previously not been implicated in SREBP control and cellular cholesterol homeostasis. These findings further our understanding of lipid biology and should lead to new insights into lipid associated disorders.
Chatterjee
Sandipan
S
Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Szustakowski
Joseph D
JD
Nanguneri
Nirmala R
NR
Mickanin
Craig
C
Labow
Mark A
MA
Nohturfft
Axel
A
Dev
Kumlesh K
KK
Sivasankaran
Rajeev
R
D001483:Base Sequence; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D018076:DNA, Complementary; D006706:Homeostasis; D006801:Humans; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
D018076:DNA, Complementary; D051779:Sterol Regulatory Element Binding Proteins; D002784:Cholesterol