Myeloid BAF60a Deficiency Alters Metabolic Homeostasis and Exacerbates Atherosclerosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA932023 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23353300_1.fastq.gz | Fastqsanger.gz | |||
| SRR23353300_2.fastq.gz | Fastqsanger.gz | |||
| SRR23353301_1.fastq.gz | Fastqsanger.gz | |||
| SRR23353301_2.fastq.gz | Fastqsanger.gz | |||
| SRR23353302_1.fastq.gz | Fastqsanger.gz |
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Project description:Atherosclerosis, a leading health concern, stems from the dynamic involvement of immune cells in vascular plaques. Despite its significance, the interplay between chromatin remodeling and transcriptional regulation in plaque macrophages is understudied. We discovered the reduced expression of Baf60a, a component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, in macrophages from advanced plaques. Myeloid-specific Baf60a deletion compromised mitochondrial integrity and heightened adhesion, apoptosis, and plaque development. BAF60a preserves mitochondrial energy homeostasis under pro-atherogenic stimuli by retaining nuclear respiratory factor 1 (NRF1) accessibility at critical genes. Overexpression of BAF60a rescued mitochondrial dysfunction in an NRF1-dependent manner. This study illuminates the BAF60a-NRF1 axis as a mitochondrial function modulator in atherosclerosis, proposing the rejuvenation of perturbed chromatin remodeling machinery as a potential therapeutic target.
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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.
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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.
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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.
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