Chromatin architecture defines the glucocorticoid response

Burd, Craig J.; Archer, Trevor

doi:10.1016/j.mce.2013.03.020

Cited by 40 publications

(30 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…47−49 Other factors influencing glucocorticoid action and which may differ between glial cell types include the following: GR chaperones/cochaperones, transcriptional coregulators, and chromatin remodelling complexes; 47 transcription factors such as AP-1, NF-KB, and STATs that participate in protein−protein interaction with (and are modulated by) the GR; 47−49 the lncRNA GAS5 which acts as a decoy glucocorticoid response element to riborepress the GR; 50 and chromatin architecture. 51 CS are undoubtedly highly effective immunosuppressive agents that assist recovery in a range of pathologies. However, we consider that elucidation of the mechanisms of adverse effects of CS based immunotherapies is essential given the intimate relationship between myelination and axonal function/ survival.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Jenkins

Pickard

Khong

et al. 2013

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Corticosteroid (CS) therapy is used widely in the treatment of a range of pathologies, but can delay production of myelin, the insulating sheath around central nervous system nerve fibers. The cellular targets of CS action are not fully understood, that is, "direct" action on cells involved in myelin genesis [oligodendrocytes and their progenitors the oligodendrocyte precursor cells (OPCs)] versus "indirect" action on other neural cells. We evaluated the effects of the widely used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes, employing complementary histological and transcriptional analyses. Histological assessments showed no DEX effects on OPC proliferation or oligodendrocyte genesis/maturation (key processes underpinning myelin genesis). Immunostaining and RT-PCR analyses show that both cell types express glucocorticoid receptor (GR; the target for DEX action), ruling out receptor expression as a causal factor in the lack of DEX-responsiveness. GRs function as ligand-activated transcription factors, so we simultaneously analyzed DEX-induced transcriptional responses using microarray analyses; these substantiated the histological findings, with limited gene expression changes in DEX-treated OPCs and oligodendrocytes. With identical treatment, microglial cells showed profound and global changes post-DEX addition; an unexpected finding was the identification of the transcription factor Olig1, a master regulator of myelination, as a DEX responsive gene in microglia. Our data indicate that CS-induced myelination delays are unlikely to be due to direct drug action on OPCs or oligodendrocytes, and may occur secondary to alterations in other neural cells, such as the immune component. To the best of our knowledge, this is the first comparative molecular and cellular analysis of CS effects in glial cells, to investigate the targets of this major class of anti-inflammatory drugs as a basis for myelination deficits.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 99%

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Jenkins

Pickard

Khong

et al. 2013

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Only a small fraction of GREs across the genome are actually occupied by the receptor, and these sites of GR binding vary in a tissue-specific manner due to differences in chromatin landscape that regulate the accessibility of the GRE (51). Genome-wide analyses have also found that the majority of GR binding sites do not reside in the promoter of glucocorticoid responsive genes but rather in intergenic or intragenic regions that can be great distances away from the transcription start site (52). The GRE-bound receptor undergoes conformational changes that lead to the recruitment of coregulators and chromatin remodeling complexes that regulate RNA polymerase II activity and thereby alter the transcription rates of target genes (53–55).…”

Section: 0 Glucocorticoid Signalingmentioning

confidence: 99%

Glucocorticoid signaling in the heart: A cardiomyocyte perspective

Oakley

Cidlowski

2015

The Journal of Steroid Biochemistry and Molecular Biology

103

View full text Add to dashboard Cite

Heart failure is one of the leading causes of death in the Western world. Glucocorticoids are primary stress hormones that regulate a vast array of biological processes, and synthetic derivatives of these steroids have been mainstays in the clinic for the last half century. Abnormal levels of glucocorticoids are known to negatively impact the cardiovascular system; however, surprisingly little is known about the direct role of glucocorticoid signaling in the heart. The actions of glucocorticoids are mediated classically by the glucocorticoid receptor (GR). In certain cells, such as cardiomyocytes, glucocorticoid occupancy and activation of the mineralocorticoid receptor (MR) may also contribute to the observed response. Recently, there has been a surge of reports investigating the in vivo function of glucocorticoid signaling in the heart using transgenic mice that specifically target GR or MR in cardiomyocytes. Results from these studies suggest that GR signaling in cardiomyocytes is critical for the normal development and function of the heart. In contrast, MR signaling in cardiomyocytes participates in the development and progression of cardiac disease. In the following review, we discuss these genetic mouse models and the new insights they are providing into the direct role cardiomyocyte glucocorticoid signaling plays in heart physiology and pathophysiology.

show abstract

“…In hormonal signaling, different cell types can respond in distinct ways if their signal transduction components and chromatin states are cell type-specific [reviewed in 57], but the hormone’s spatial distribution is systemic and effectively uniform. In contrast, the specificity of the morphogen signaling proteins appears to be achieved by physically pairing particular cells.…”

Section: Long Distance Signaling In Non-neuronal Tissuesmentioning

confidence: 99%

Communicating by touch – neurons are not alone

Kornberg

Roy

2014

Trends in Cell Biology

View full text Add to dashboard Cite

Summary Long distance cell-cell communication is essential for organ development and function. Whereas neurons communicate at long distances by transferring signals at sites of direct contact (i.e. at synapses), it has been presumed that the only way other cell types signal is by dispersing signals through extracellular fluid - indirectly. Recent evidence from Drosophila suggests that non-neuronal cells also exchange signaling proteins at sites of direct contact, even when long distances separate the cells. Here, we review contact-mediated signaling in neurons and discuss how this signaling mechanism is shared by other cell types.

show abstract

Chromatin architecture defines the glucocorticoid response

Cited by 40 publications

References 75 publications

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Glucocorticoid signaling in the heart: A cardiomyocyte perspective

Communicating by touch – neurons are not alone

Contact Info

Product

Resources

About