Bromodomain containing 9 (BRD9) regulates macrophage inflammatory responses by potentiating glucocorticoid receptor activity.

In macrophages, homeostatic and immune signals induce distinct sets of transcriptional responses, defining cellular identity and functional states. The activity of lineage-specific and signal-induced transcription factors are regulated by chromatin accessibility and other epigenetic modulators. Glucocorticoids are potent antiinflammatory drugs; however, the mechanisms by which they selectively attenuate inflammatory genes are not yet understood.

Niche-Specific Reprogramming of Epigenetic Landscapes Drives Myeloid Cell Diversity in Nonalcoholic Steatohepatitis.

Tissue-resident and recruited macrophages contribute to both host defense and pathology. Multiple macrophage phenotypes are represented in diseased tissues, but we lack deep understanding of mechanisms controlling diversification. Here, we investigate origins and epigenetic trajectories of hepatic macrophages during diet-induced non-alcoholic steatohepatitis (NASH).

Circadian clock cryptochrome proteins regulate autoimmunity.

The circadian system regulates numerous physiological processes including immune responses. Here, we show that mice deficient of the circadian clock genes and [ double knockout (DKO)] develop an autoimmune phenotype including high serum IgG concentrations, serum antinuclear antibodies, and precipitation of IgG, IgM, and complement 3 in glomeruli and massive infiltration of leukocytes into the lungs and kidneys. Flow cytometry of lymphoid organs revealed decreased pre-B cell numbers and a higher percentage of mature recirculating B cells in the bone marrow, as well as increased numbers of B2 B cells in the peritoneal cavity of DKO mice.

Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBα Degradation.

Defects in circadian rhythm influence physiology and behavior with implications for the treatment of sleep disorders, metabolic disease, and cancer. Although core regulatory components of clock rhythmicity have been defined, insight into the mechanisms underpinning amplitude is limited. Here, we show that REV-ERBα, a core inhibitory component of clock transcription, is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7.

Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs.

Enhancers are critical genomic elements that define cellular and functional identity through the spatial and temporal regulation of gene expression. Recent studies suggest that key genes regulating cell type-specific functions reside in enhancer-dense genomic regions (i.e.

Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β.

The circadian clock acts at the genomic level to coordinate internal behavioural and physiological rhythms via the CLOCK-BMAL1 transcriptional heterodimer. Although the nuclear receptors REV-ERB-α and REV-ERB-β have been proposed to form an accessory feedback loop that contributes to clock function, their precise roles and importance remain unresolved. To establish their regulatory potential, we determined the genome-wide cis-acting targets (cistromes) of both REV-ERB isoforms in murine liver, which revealed shared recognition at over 50% of their total DNA binding sites and extensive overlap with the master circadian regulator BMAL1.

PPARdelta regulates multiple proinflammatory pathways to suppress atherosclerosis.

Lipid homeostasis and inflammation are key determinants in atherogenesis, exemplified by the requirement of lipid-laden, foam cell macrophages for atherosclerotic lesion formation. Although the nuclear receptor PPARdelta has been implicated in both systemic lipid metabolism and macrophage inflammation, its role as a therapeutic target in vascular disease is unclear. We show here that orally active PPARdelta agonists significantly reduce atherosclerosis in apoE(-/-) mice.

PPAR-gamma regulates osteoclastogenesis in mice.

Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. Regulation of osteoclast function is central to the understanding of bone diseases such as osteoporosis, rheumatoid arthritis and osteopetrosis. Although peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to inhibit osteoblast differentiation, its role, if any, in osteoclasts is unknown.

Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense.

Macrophage activation by the proinflammatory cytokine interferon-gamma (IFN-gamma) is a critical component of the host innate response to bacterial pathogenesis. However, the precise nature of the IFN-gamma-induced activation pathway is not known. Here we show using genome-wide expression and chromatin-binding profiling that IFN-gamma induces the expression of many nuclear genes encoding mitochondrial respiratory chain machinery via activation of the nuclear receptor ERR alpha (estrogen-related receptor alpha, NR3B1).

Maternal PPAR gamma protects nursing neonates by suppressing the production of inflammatory milk.

Lactation is a highly demanding lipid synthesis and transport process that is crucial for the development of newborn mammals. While PPAR gamma is known to promote adipogenesis and lipogenesis in adipose tissue, its role in the lactating mammary gland is unexplored. Here, we report that a targeted deletion of PPAR gamma in mice results in the production of "toxic milk" containing elevated levels of inflammatory lipids.

PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis.

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1beta (PGC-1beta) is believed to control mitochondrial oxidative energy metabolism by activating specific target transcription factors including estrogen-related receptors and nuclear respiratory factor 1, yet its physiological role is not yet clearly understood. To define its function in vivo, we generated and characterized mice lacking the functional PGC-1beta protein [PGC-1beta knockout (KO) mice]. PGC-1beta KO mice are viable and fertile and show no overt phenotype under normal laboratory conditions.

PPARdelta regulates glucose metabolism and insulin sensitivity.

The metabolic syndrome is a collection of obesity-related disorders. The peroxisome proliferator-activated receptors (PPARs) regulate transcription in response to fatty acids and, as such, are potential therapeutic targets for these diseases. We show that PPARdelta (NR1C2) knockout mice are metabolically less active and glucose-intolerant, whereas receptor activation in db/db mice improves insulin sensitivity.

Peroxisome proliferator-activated receptor delta promotes very low-density lipoprotein-derived fatty acid catabolism in the macrophage.

Significant attention has focused on the role of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, recent advances have identified triglyceride-rich lipoproteins [e.g.

Pregnane X receptor prevents hepatorenal toxicity from cholesterol metabolites.

Efficient detoxification and clearance of cholesterol metabolites such as oxysterols, bile alcohols, and bile acids are critical for survival because they can promote liver and cardiovascular disease. We report here that loss of the nuclear xenobiotic receptor PXR (pregnane X receptor), a regulator of enterohepatic drug metabolism and clearance, results in an unexpected acute lethality associated with signs of severe hepatorenal failure when mice are fed with a diet that elicits accumulation of cholesterol and its metabolites. Induction of a distinct drug clearance program by a high-affinity ligand for the related nuclear receptor, the constitutive androstane receptor, does not overcome the lethality, indicating the unique requirement of PXR for detoxification.