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. Acting through the glucocorticoid receptor (GR), glucocorticoids directly repress inflammatory responses at transcriptional and epigenetic levels in macrophages. A major unanswered question relates to the sequence of events that result in the formation of repressive regions. In this study, we identify bromodomain containing 9 (BRD9), a component of SWI/SNF chromatin remodeling complex, as a modulator of glucocorticoid responses in macrophages. Inhibition, degradation, or genetic depletion of BRD9 in bone marrow-derived macrophages significantly attenuated their responses to both liposaccharides and interferon inflammatory stimuli. Notably, BRD9-regulated genes extensively overlap with those regulated by the synthetic glucocorticoid dexamethasone. Pharmacologic inhibition of BRD9 potentiated the antiinflammatory responses of dexamethasone, while the genetic deletion of BRD9 in macrophages reduced high-fat diet-induced adipose inflammation. Mechanistically, BRD9 colocalized at a subset of GR genomic binding sites, and depletion of BRD9 enhanced GR occupancy primarily at inflammatory-related genes to potentiate GR-induced repression. Collectively, these findings establish BRD9 as a genomic antagonist of GR at inflammatory-related genes in macrophages, and reveal a potential for BRD9 inhibitors to increase the therapeutic efficacies of glucocorticoids.
β cell dysfunction and failure are driving forces of type 2 diabetes mellitus (T2DM) pathogenesis. Investigating the underlying mechanisms of β cell dysfunction may provide novel targets for the development of next generation therapy for T2DM. Epigenetics is the study of gene expression changes that do not involve DNA sequence changes, including DNA methylation, histone modification, and non-coding RNAs. Specific epigenetic signatures at all levels, including DNA methylation, chromatin accessibility, histone modification, and non-coding RNA, define β cell identity during embryonic development, postnatal maturation, and maintain β cell function at homeostatic states. During progression of T2DM, overnutrition, inflammation, and other types of stress collaboratively disrupt the homeostatic epigenetic signatures in β cells. Dysregulated epigenetic signatures, and the associating transcriptional outputs, lead to the dysfunction and eventual loss of β cells. In this review, we will summarize recent discoveries of the establishment and disruption of β cell-specific epigenetic signatures, and discuss the potential implication in therapeutic development.
Pregnancy and childbirth are both natural occurring events, but still little is known about the signaling mechanisms that induce contractions. Throughout the world, premature labor occurs in 12% of all pregnancies with 36% of infant deaths resulting from preterm related causes [1]. Even though the cause of preterm labor can vary, understanding alternative signaling pathways which affect muscle contraction could provide additional treatment options in stopping premature labor. The uterus is composed of smooth muscle which is innervated with a plexus of nerves that cover the muscle fibers. Smooth muscle can be stimulated or modulated by many sources such as neurotransmitters [dopamine], hormones [estrogen], peptides [oxytocin] and amines. In this study, we are focusing on the biogenic monoamine tyramine which is produced in the tyrosine catecholamine biosynthesis pathway. Tyramine is known to be associated with peripheral vasoconstriction, increased cardiac output, increased respiration, elevated blood glucose and the release of norepinephrine. Our research has found tyramine, and its specific receptor TAAR1 [2], to be localized within mouse uterus and that this monoamine can induce uterine contractions at levels similar to oxytocin.Research that focuses on reproduction commonly use techniques involving immunohistochemistry or histological staining to identify localization of key modulators and receptors or they observe general morphology in fixed whole or sectioned tissue [ Fig. 1]. In studies involving muscle tissue, force transduction measurements allow the researcher to quantify differences in contractile force. These methods can be used with the addition of agonists and antagonists which help decipher the mechanisms that may modulate the contraction. A drawback of these methods is that muscle contraction is a complex system that relies on feedback mechanisms and without observing the tissue in real time, the researcher would be making interpretations based on random snapshots in time. To overcome this limitation, we have developed an imaging technique that can observe muscle signaling dynamics in real time.This protocol was approved through the IACUC protocol 15-1388T at Arizona State University and the mouse uterine tissues were derived from GFP LifeAct transgenic mice [3]. These mice contain a transgene encoding a 17-amino acid peptide called LifeAct, which binds F-actin. This peptide is coexpressed with GFP which enables the actin cytoskeleton to be imaged both in vivo and in vitro. Actin is a key component of muscle tissue and this transgenic model allows researchers the ability to visualize muscle contractions. Combining this tissue with the TAAR1 receptor antibody conjugated to a fluorescent probe [antibody labeling kit, Thermo Fisher, #A20186] is a tool that can be used to visualize the actual response and timing of a receptor mediated event. Imaging was conducted using a dipping lens on a Leica SP5 confocal microscope which allowed the tissue to continue normal peristaltic contractile activity. Time-...
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