The Hypersensitive Glucocorticoid Response Specifically Regulates Period 1 and Expression of Circadian Genes

HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 07/2012; 32(18):3756-67. DOI: 10.1128/MCB.00062-12
Source: PubMed


Glucocorticoids regulate gene expression by binding and activating the glucocorticoid receptor (GR). While ligand affinity
determines the global sensitivity of the response, additional proteins act on the genome to tune sensitivity of some genes.
However, the genomic extent and specificity of dose-specific glucocorticoid responses are unknown. We show that dose-specific
glucocorticoid responses are extraordinarily specific at the genomic scale, able to distinctly express a single gene, the
circadian rhythm gene for Period 1 (PER1), at concentrations consistent with the nighttime nadir of human cortisol. We mapped the PER1 response to a single GR binding site. The specific GR binding sequence did not impact sensitivity, and we instead attributed
the response to a combination of additional transcription factors and chromatin accessibility acting in the same locus. The
PER1 hypersensitive response element is conserved in the mouse, where we found similar upregulation of Per1 in pituitary cells. Targeted and transient overexpression of PER1 led to regulation of additional circadian rhythm genes hours later, suggesting that hypersensitive expression of PER1 impacts circadian gene expression. These findings show that hypersensitive GR binding occurs throughout the genome, drives
targeted gene expression, and may be important to endocrine mediation of peripheral circadian rhythms.

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    • "The innermost circle shows the motif occurrences in the mitochondrial genome for each factor as black vertical bars. (A) CREB; (B) STAT3; (C) GR in A549 cells treated with different concentrations of dexamethasone (Dex) [60], [61]; (D) ERα in untreated (DMSO) ECC1 cells and ECC1 cells treated with bisphenol A (BPA), genistein (Gen) or 17β-estradiol (E2) [31]; (E) IRF3; (F) NFκB in GM12878 cells treated with TNFα [37]. The reads per million (RPM) tracks are shown, scaled to the maximum signal level (for both strands) for each dataset. "
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    ABSTRACT: Mitochondria contain their own circular genome, with mitochondria-specific transcription and replication systems and corresponding regulatory proteins. All of these proteins are encoded in the nuclear genome and are post-translationally imported into mitochondria. In addition, several nuclear transcription factors have been reported to act in mitochondria, but there has been no comprehensive mapping of their occupancy patterns and it is not clear how many other factors may also be found in mitochondria. Here we address these questions by using ChIP-seq data from the ENCODE, mouseENCODE and modENCODE consortia for 151 human, 31 mouse and 35 C. elegans factors. We identified 8 human and 3 mouse transcription factors with strong localized enrichment over the mitochondrial genome that was usually associated with the corresponding recognition sequence motif. Notably, these sites of occupancy are often the sites with highest ChIP-seq signal intensity within both the nuclear and mitochondrial genomes and are thus best explained as true binding events to mitochondrial DNA, which exist in high copy number in each cell. We corroborated these findings by immunocytochemical staining evidence for mitochondrial localization. However, we were unable to find clear evidence for mitochondrial binding in ENCODE and other publicly available ChIP-seq data for most factors previously reported to localize there. As the first global analysis of nuclear transcription factors binding in mitochondria, this work opens the door to future studies that probe the functional significance of the phenomenon.
    PLoS ONE 01/2014; 9(1):e84713. DOI:10.1371/journal.pone.0084713 · 3.23 Impact Factor
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    • "via glucocorticoid-dependent plasticity in circuits involved in endocrine regulation as well as learning and memory (de Kloet et al., 2005) and response selection. Because of its lower affinity, the GR gets substantially occupied at hormone levels reached at the circadian peak (Reddy et al., 2012) and after stress. Accordingly, it is the receptor most prominently involved in the transcriptional consequences of stressinduced elevation of glucocorticoid levels. "
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    ABSTRACT: Glucocorticoid hormones exert crucial effects on the brain in relation to physiology, endocrine regulation, mood and cognition. Their two receptor types, glucocorticoid and mineralocorticoid receptors (MR and GR), are members of the nuclear receptor superfamily and act in large measure as transcription factors. The outcome of MR/GR action on the genome depends on interaction with members from different protein families, which are of crucial importance for cross-talk with other neuronal and hormonal signals that impinge on the glucocorticoid sensitive circuitry. Relevant interacting proteins include other transcription factors that may either tether the receptor to the DNA, or that bind in the vicinity of GR and MR to tune the transcriptional response. In addition, transcriptional coregulator proteins constitute the actual signal transduction pathway to the transcription machinery. We review the current evidence for involvement of individual coregulators in GR-dependent effects on stress responses, and learning and memory. We discuss the use of in vitro and in silico tools to predict those coregulators that are of importance for particular brain processes. Finally, we discuss the potential of selective receptor modulators that may only allow a subset of all interactions, thus allowing more selective targeting of glucocorticoid-dependent processes in the brain.
    Neuroscience 03/2013; 242. DOI:10.1016/j.neuroscience.2013.03.038 · 3.36 Impact Factor
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    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. Approximately 7% of glucocorticoid-regulated genes had altered expression in 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 amino acid metabolizing enzymes PRODH and AASS. 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.
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