Genome-wide coactivation screen identifies BAF60a as a regulator of lipid metabolism through PGC-1alpha
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE9523 | GEO | 2008/08/01
SECONDARY ACCESSION(S): PRJNA103329
REPOSITORIES: GEO
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Project description:Impaired mitochondrial function has been implicated in the pathogenesis of type 2 diabetes, heart failure and neurodegeneration as well as during aging. Studies with the PGC-1 transcriptional coactivators have demonstrated that these factors are key components of the regulatory network that controls mitochondrial function in mammalian cells. Here we describe a genome-wide coactivation assay to globally identify the transcriptional partners for PGC-1α. These analyses revealed a molecular signature of the PGC-1α transcriptional network, and identified BAF60a (Smarcd1), a subunit of the SWI/SNF chromatin-remodeling complex, as a critical regulator of lipid homeostasis. Adenoviral-mediated expression of BAF60a stimulates fatty acid β-oxidation in cultured hepatocytes and reduces hepatic triglyceride levels in diet-induced obese mice. BAF60a physically interacts with PGC-1α and is recruited to PPARα target genes in the fasted liver. Liver-specific RNAi knockdown of BAF60a impairs fatty acid oxidation and results in severe hepatic steatosis following starvation. These results define a role for the SWI/SNF complexes in the regulation of hepatic lipid metabolism, and reveal a potential target for therapeutic intervention. Experiment Overall Design: Primary hepatocytes were isolated from C57/Bl6J mice (10 weeks old) and transduced with recombinant adenoviruses expressing GFP or BAF60a for 40 hrs. Total RNA was isolated for array analysis.
2008-10-20 | E-GEOD-9523 | biostudies-arrayexpress
Project description:Dietary nutrients interact with the gene networks to orchestrate adaptive responses during metabolic stress. Tissue metabolic reprogramming is frequently linked to induction of pathways with pathophysiological consequences. Here we identified Baf60a as a diet-sensitive subunit of the SWI/SNF chromatin-remodeling complexes in the liver that links the consumption of fat- and cholesterol-rich diet to elevated plasma cholesterol levels. The expression of Baf60a in the liver was elevated following western diet feeding. Hepatocyte-specific inactivation of Baf60a reduced bile acid production and intestinal cholesterol absorption, and attenuated diet-induced hypercholesterolemia and atherosclerosis in mice. At the mechanistic level, Baf60a stimulates the expression of hepatic genes involved in bile acid synthesis, modification, and transport through a CAR/Baf60a feedforward regulatory loop. Baf60a is required for the recruitment of the SWI/SNF chromatin-remodeling complexes to facilitate an activating epigenetic switch on the CAR target genes. These studies elucidate an unexpected regulatory pathway that mediates the hyperlipidemic and atherogenic effects of western diet consumption. We used microarrays to elucidate the role of hepatic Baf60a in the regulation of lipid metabolism.
2015-10-03 | GSE73709 | GEO
Project description:Transcriptional coactivator PGC-1α and its splice variant NT-PGC-1α play crucial roles in regulating cold-induced thermogenesis in brown adipose tissue (BAT). PGC-1α and NT-PGC-1α are highly induced by cold in BAT and subsequently bind to and coactivate many different transcription factors to regulate expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, respiration and thermogenesis. To identify the complete repertoire of PGC-1α and NT-PGC-1α target genes in BAT, we analyzed genome-wide DNA-binding and gene expression profiles. We find that PGC-1α-/NT-PGC-1α binding broadly associates with cold-mediated transcriptional activation. In addition to their known target genes in mitochondrial biogenesis, fatty acid oxidation, respiration and thermogenesis, PGC-1α and NT-PGC-1α target to a broad spectrum of genes involved in diverse biological pathways including ubiquitin-dependent protein catabolism, ribonucleoprotein complex biosynthesis, phospholipid biosynthesis, angiogenesis, glycogen metabolism, phosphorylation, and autophagy. Our findings expand the number of genes and biological pathways that may be regulated by PGC-1α and NT-PGC-1α and provide further insight into the transcriptional regulatory network in which PGC-1α and NT-PGC-1α coordinate a comprehensive transcriptional response in BAT in response to cold.
2018-05-22 | GSE110053 | GEO
Project description:Transcriptional coactivator PGC-1α and its splice variant NT-PGC-1α play crucial roles in regulating cold-induced thermogenesis in brown adipose tissue (BAT). PGC-1α and NT-PGC-1α are highly induced by cold in BAT and subsequently bind to and coactivate many different transcription factors to regulate expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, respiration and thermogenesis. To identify the complete repertoire of PGC-1α and NT-PGC-1α target genes in BAT, we analyzed genome-wide DNA-binding and gene expression profiles. We find that PGC-1α-/NT-PGC-1α binding broadly associates with cold-mediated transcriptional activation. In addition to their known target genes in mitochondrial biogenesis, fatty acid oxidation, respiration and thermogenesis, PGC-1α and NT-PGC-1α target to a broad spectrum of genes involved in diverse biological pathways including ubiquitin-dependent protein catabolism, ribonucleoprotein complex biosynthesis, phospholipid biosynthesis, angiogenesis, glycogen metabolism, phosphorylation, and autophagy. Our findings expand the number of genes and biological pathways that may be regulated by PGC-1α and NT-PGC-1α and provide further insight into the transcriptional regulatory network in which PGC-1α and NT-PGC-1α coordinate a comprehensive transcriptional response in BAT in response to cold.
2018-05-22 | GSE110055 | GEO
Project description:The β-adrenergic receptor signaling pathway is a major component of adaptive thermogenesis in brown and white adipose tissue during cold acclimation. The β-AR activation highly induces transcriptional coactivator PGC-1α and its splice variant N-terminal (NT)-PGC-1α, promoting the transcription program of mitochondrial biogenesis and thermogenesis. In the present study, we evaluated the role of NT-PGC-1α in brown adipocyte energy metabolism by genome-wide profiling of NT-PGC-1α-responsive genes. Canonical pathway analysis revealed that a number of genes upregulated by NT-PGC-1α are highly enriched in mitochondrial pathways including fatty acid transport and β-oxidation, TCA cycle and electron transport system, thus reinforcing the crucial role of NT-PGC-1α in the enhancement of mitochondrial function. Moreover, gene expression profiling of NT-PGC-1α revealed activation of distinct metabolic pathways such as glucose, lipid and nucleotide metabolism and of signaling pathways such as RAR and PPAR-γ/RXRα activation in brown adipocytes. Together, our data strengthen our previous findings that NT-PGC-1α is a key regulator of mitochondrial oxidative metabolism and thermogenesis in brown adipocytes and further suggest that NT-PGC-1α influences a broader spectrum of thermogenic processes to meet cellular needs for adaptive thermogenesis. Two samples from two groups: NT-PGC-1α overexpression and empty vector. There are technical replicates (A and B) for each group. Two RNA samples were pooled for each group.
2015-08-07 | E-GEOD-71774 | biostudies-arrayexpress
Project description:Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. Lipin 1 appears to be highly involved in the control of fatty acid metabolism. Lipin 1 is most often located in the nucleus, but other studies suggest that lipin also has effects in the cytoplasm. However, the molecular function of lipin 1 is unclear. To evaluate the effects of activation of the lipin 1 system in liver, lipin 1beta was overexpressed in mouse liver using an adenoviral vector. We found that lipin 1 overexpression increased the expression of many genes involved in mitochondrial fatty acid oxidation while repressing expression of genes involved in lipogenesis. We believe that lipin is a transcriptional coactivator of the peroxisome proliferator-activated receptor (PPAR) complex. However, the many molecular aspects of its function remain unclear. Abstract of published manuscript follows:; Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway.Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE, Lawrence JC Jr, Kelly DP. Center for Cardiovascular Research and Washington University School of Medicine, St. Louis, Missouri 63110; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110. Perturbations in hepatic lipid homeostasis are linked to the development of obesity-related steatohepatitis. Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. However, the molecular function of lipin 1 is unclear. Herein, we demonstrate that the expression of lipin 1 is induced by peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha), a transcriptional coactivator controlling several key hepatic metabolic pathways. Gain-of-function and loss-of-function strategies demonstrated that lipin selectively activates a subset of PGC-1alpha target pathways, including fatty acid oxidation and mitochondrial oxidative phosphorylation, while suppressing the lipogenic program and lowering circulating lipid levels. Lipin activates mitochondrial fatty acid oxidative metabolism by inducing expression of the nuclear receptor PPARalpha, a known PGC-1alpha target, and via direct physical interactions with PPARalpha and PGC-1alpha. These results identify lipin 1 as a selective physiological amplifier of the PGC-1alpha/PPARalpha-mediated control of hepatic lipid metabolism. Experiment Overall Design: Adult male C57BL6 mice were injected with adenovirus driving expression of mouse lipin 1beta or green fluorescent protein (GFP). Mice were recovered and sacrificed 6 days after injection. Total RNA was isolated and analyzed using Affymetrix microarray.
2008-06-13 | E-GEOD-5538 | biostudies-arrayexpress
Project description:Brown and beige fat share a remarkably similar transcriptional program that supports fuel oxidation and thermogenesis. The chromatin-remodeling machinery that governs genome accessibility and renders adipocytes poised for thermogenic activation remains elusive. Here we found that BAF60a, a subunit of the SWI/SNF chromatin-remodeling complexes, serves an indispensible role in cold-induced thermogenesis in brown fat. BAF60a maintains chromatin accessibility for key thermogenic genes in close proximity to PPARg and EBF2 binding sites. Surprisingly, fat-specific BAF60a inactivation triggers more pronounced browning of inguinal white adipose tissue that is linked to induction of MC2R, a receptor for the pituitary hormone ACTH. Elevated MC2R expression sensitizes adipocytes and BAF60a-deficient adipose tissue to thermogenic activation in response to ACTH stimulation. These observations reveal an unexpected dichotomous role of BAF60a-mediated chromatin remodeling in transcriptional control of brown and beige gene programs and illustrate a pituitary-adipose signaling axis in the control of thermogenesis.
2020-02-20 | GSE128747 | GEO
Project description:The β-adrenergic receptor signaling pathway is a major component of adaptive thermogenesis in brown and white adipose tissue during cold acclimation. The β-AR activation highly induces transcriptional coactivator PGC-1α and its splice variant N-terminal (NT)-PGC-1α, promoting the transcription program of mitochondrial biogenesis and thermogenesis. In the present study, we evaluated the role of NT-PGC-1α in brown adipocyte energy metabolism by genome-wide profiling of NT-PGC-1α-responsive genes. Canonical pathway analysis revealed that a number of genes upregulated by NT-PGC-1α are highly enriched in mitochondrial pathways including fatty acid transport and β-oxidation, TCA cycle and electron transport system, thus reinforcing the crucial role of NT-PGC-1α in the enhancement of mitochondrial function. Moreover, gene expression profiling of NT-PGC-1α revealed activation of distinct metabolic pathways such as glucose, lipid and nucleotide metabolism and of signaling pathways such as RAR and PPAR-γ/RXRα activation in brown adipocytes. Together, our data strengthen our previous findings that NT-PGC-1α is a key regulator of mitochondrial oxidative metabolism and thermogenesis in brown adipocytes and further suggest that NT-PGC-1α influences a broader spectrum of thermogenic processes to meet cellular needs for adaptive thermogenesis.
2015-08-07 | GSE71774 | GEO
Project description:Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. Lipin 1 appears to be highly involved in the control of fatty acid metabolism. Lipin 1 is most often located in the nucleus, but other studies suggest that lipin also has effects in the cytoplasm. However, the molecular function of lipin 1 is unclear. To evaluate the effects of activation of the lipin 1 system in liver, lipin 1beta was overexpressed in mouse liver using an adenoviral vector. We found that lipin 1 overexpression increased the expression of many genes involved in mitochondrial fatty acid oxidation while repressing expression of genes involved in lipogenesis. We believe that lipin is a transcriptional coactivator of the peroxisome proliferator-activated receptor (PPAR) complex. However, the many molecular aspects of its function remain unclear. Abstract of published manuscript follows: Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway.Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE, Lawrence JC Jr, Kelly DP. Center for Cardiovascular Research and Washington University School of Medicine, St. Louis, Missouri 63110; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110. Perturbations in hepatic lipid homeostasis are linked to the development of obesity-related steatohepatitis. Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. However, the molecular function of lipin 1 is unclear. Herein, we demonstrate that the expression of lipin 1 is induced by peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha), a transcriptional coactivator controlling several key hepatic metabolic pathways. Gain-of-function and loss-of-function strategies demonstrated that lipin selectively activates a subset of PGC-1alpha target pathways, including fatty acid oxidation and mitochondrial oxidative phosphorylation, while suppressing the lipogenic program and lowering circulating lipid levels. Lipin activates mitochondrial fatty acid oxidative metabolism by inducing expression of the nuclear receptor PPARalpha, a known PGC-1alpha target, and via direct physical interactions with PPARalpha and PGC-1alpha. These results identify lipin 1 as a selective physiological amplifier of the PGC-1alpha/PPARalpha-mediated control of hepatic lipid metabolism. Keywords: response to lipin 1 activation
2006-08-16 | GSE5538 | GEO
Project description:The effect of PGC-1α overexpression using adenovirus (PGC-1α-Ad) on hepatic gene expression was studied in mice primary hepatocytes.
2019-04-10 | GSE114485 | GEO