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GR and Klf15 regulate gene expression dynamics and integrate signals through feed forward circuitry

ABSTRACT: The glucocorticoid receptor (GR) regulates adaptive transcriptional programs that alter metabolism in response to stress. Network properties that allow GR to tune gene expression to match specific physiologic demands are poorly understood. We analyzed the transcriptional consequences of GR activation in murine lungs deficient for Klf15, a transcriptional regulator of amino acid metabolism that is induced by glucocorticoids and fasting

ORGANISM(S): Mus musculus

PROVIDER: GSE44695 | GEO | 2013/05/13

SECONDARY ACCESSION(S): PRJNA191037

REPOSITORIES: GEO

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GR and Klf15 regulate gene expression dynamics and integrate signals through feed forward circuitry

2013-05-13 | E-GEOD-44695 | biostudies-arrayexpress

The glucocorticoid receptor and KLF15 regulate gene expression dynamics and integrate signals through feed-forward circuitry.

Project description:The glucocorticoid receptor (GR) regulates adaptive transcriptional programs that alter metabolism in response to stress. Network properties that allow GR to tune gene expression to match specific physiologic demands are poorly understood. We analyzed the transcriptional consequences of GR activation in murine lungs deficient for KLF15, a transcriptional regulator of amino acid metabolism that is induced by glucocorticoids and fasting. Approximately 7% of glucocorticoid-regulated genes had altered expression in Klf15-knockdown (Klf15(-/-)) mice. KLF15 formed coherent and incoherent feed-forward circuits with GR that correlated with the expression dynamics of the glucocorticoid response. Coherent feed-forward gene regulation by GR and KLF15 was characterized by combinatorial activation of linked GR-KLF15 regulatory elements by both factors and increased GR occupancy, while expression of KLF15 reduced GR occupancy at the incoherent target, MT2A. Serum deprivation, which increased KLF15 expression in a GR-independent manner in vitro, enhanced glucocorticoid-mediated induction of feed-forward targets of GR and KLF15, such as the loci for the amino acid-metabolizing enzymes proline dehydrogenase and alpha-aminoadipic semialdehyde synthase. Our results establish feed-forward architecture as an organizational principle for the GR network and provide a novel mechanism through which GR integrates signals and regulates expression dynamics.

| S-EPMC3648070 | biostudies-literature

Comparison of glucocorticoid receptor (NR3C1) binding in wild type and Klf15-/- MEFs

Project description:The objective of this study was to dertemine GR binding patterns within wild type murine embryonic fibroblasts in comparison to embryonic fibroblasts derived from mice containing a null mutation for Klf15. This study utilized duplicate samples and the following conditions. Wild type cells treated with ethanol (pooled single sample secondary to low starting material); wild type cells treated with dexamethasone for 1 hour (2 samples); Klf15-/- cells treated with ethanol (2 samples); Klf15 -/- cells treated with dexamethasone (2 samples). Samples treated with ethanol served as controls.

2015-06-18 | E-GEOD-69947 | biostudies-arrayexpress

KLF15

Project description:KLF15

| PRJNA301030 | ENA

Genome-wide transcriptional targets of KLF15 in human airway smooth muscle

Project description:We previously demonstrated that the transcription factor, KLF15, is a glucocorticoid-regulated gene that represses primary human airway smooth muscle (ASM) proliferation. Here, we show that KLF15 also represses ASM hypertrophy. To uncover the mechanistic basis for these effects, we integrated transcriptome data from KLF15 over-expression with genome-wide analysis of RNA Polymerase II (RNAPII) and glucocorticoid receptor (GR) occupancy (i.e. ChIP-seq). This led us to identify PLCD1 as both a KLF15-regulated gene and a repressor of ASM hypertrophy.

2017-05-01 | GSE95397 | GEO

KLF15 and PPARδ cooperativity in the orchestration of lipid metabolism

Project description:We characterize the KLF15 cistrome in vivo in skeletal muscle and find that the majority of KLF15 binding is localized to distal intergenic regions and associated with genes related to circadian rhythmicity and lipid metabolism. We identify critical interdependence between KLF15 and the nuclear receptor PPARδ in the regulation of lipid metabolic gene programs. We further demonstrate that KLF15 and PPARδ co-localize genome-wide, interact, and are dependent on one another to exert their transcriptional effects on target genes.

2022-03-31 | GSE199547 | GEO

Comparison of glucocorticoid receptor (NR3C1) binding in wild type and Klf15-/- MEFs

2015-06-18 | GSE69947 | GEO

Effects of dexamethasone and KLF15 on genome-wide occupancy of the glucocorticoid receptor (NR3C1) and RNA polymerase II (RNAPII) in human airway smooth muscle

Project description:The objective of this study was to determine how dexamethasone and KLF15 modify GR and RNAPII occupancy in human airway smooth muscle on a genome-wide basis.

2017-08-31 | GSE95632 | GEO

ChIP-MS of GR and GR-DZn in mouse embryonic fibroblasts

Project description:The Glucocorticoid Receptor (GR) is both one of the most widely used clinical drug targets and a very potent metabolic regulator. GR belongs to the nuclear hormone receptor family of ligand-gated transcription factors that govern mammalian physiology. Upon ligand binding, GR enters the nucleus to regulate gene expression both positively and negatively. It is known to bind to consensus DNA sequences termed glucocorticoid response elements (GREs), but the mechanisms determining transcriptional activation versus repression remain an unresolved molecular paradox. Prevailing models suggest that tethering of GR to AP-1 or NF-κB via protein-protein interactions, rather than direct DNA binding, specifies negative regulation. However, here we show that the repression of inflammatory genes as well as all other glucocorticoid responses, require direct DNA binding of GR. Generating GR point mutant mice that retain the ability to tether via protein-protein interactions while unable to recognize DNA sequences, we demonstrate that response element recognition via the Zinc finger is absolutely required for both transcriptional activation and repression. We have used ChIP-Seq and RNA-Seq in inflammatory and metabolic cells and tissues together with proteomics to reveal that DNA binding of GR is necessary for the assembly of a functional SWI/SNF coregulator complex. Generally, the desired anti-inflammatory actions of GR are attributed to the silencing of inflammatory genes, while its adverse effects are believed to result from the transcriptional upregulation of metabolic targets. Our findings not only challenge classical models and dogmas of GR mediated gene regulation, but will provide an important basis for the development of novel immunosuppressants with reduced side effect profiles.

2020-07-07 | PXD013772 | Pride

KLF15 Cistromes Reveal a Hepatocyte Pathway Governing Plasma Corticosteroid Transport and Systemic Inflammation

Project description:Circulating corticosteroids orchestrate stress adaptation, including inhibition of inflammation. While pathways governing corticosteroid biosynthesis and intracellular signaling are understood, less is known about mechanisms controlling plasma corticosteroid transport. Here, we show hepatocyte KLF15 (Kruppel-like factor 15) controls plasma corticosteroid transport and inflammatory responses through direct transcriptional activation of Serpina6, which encodes corticosteroid binding globulin (CBG). Klf15-deficient mice have profoundly low CBG, reduced plasma corticosteroid binding capacity, and heightened mortality during inflammatory stress. These defects are completely rescued by reconstituting CBG, supporting that KLF15 works primarily through CBG to control plasma corticosterone homeostasis. To understand transcriptional mechanisms, we generated the first KLF15 cistromes using newly engineered Klf153xFLAG mice. Unexpectedly, liver KLF15 is predominantly promoter-enriched, including Serpina6, where it binds a palindromic GC-rich motif, opens chromatin, and transactivates genes with minimal associated gene repression. Overall, we provide new mechanistic insight into KLF15 function and identify a hepatocyte-intrinsic transcriptional module that potently regulates systemic corticosteroid transport and inflammation.

2021-12-28 | GSE166083 | GEO

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