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Environmental Factor, June 2012

Intramural papers of the month

By Brant Hamel, Sonika Patial, Jeffrey Stumpf, and Sheetal Thakur

Chromatin structure changes during course of glucocorticoid receptor activation

A new study from scientists at NIEHS mapped alterations in the chromatin landscape at glucocorticoid receptor (GR) responsive regions during the course of hormone activation. The findings point to a more nuanced view of chromatin structure and its response to physiological stimuli. The GR initially bound an inactive transitional state between fully open and closed, prior to inducing a transition to an open and transcriptionally active structure.

The researchers measured the degree to which chromatin was open at over 50 sites across the genome, using the formaldehyde-assisted isolation of regulatory elements (FAIRE) technique. Prior to receptor activation, all GR-responsive regions had similar FAIRE signals, indicating common chromatin architecture for GR recruitment, which was confirmed across the genome utilizing next generation sequencing. After receptor activation, the FAIRE signal increased dramatically, though the degree of chromatin opening varied between responsive chromatin regions.

The team found significant changes in chromatin structure as far as 1,000 base pairs away from the site of receptor recruitment, indicating that altered chromatin structure can exist across multiple nucleosomes. Chromatin remodeling was dependent on the activity of the switch/sucrose nonfermentable (SWI/SNF) complex because depletion of Brg-1, a component of the complex, led to significant decreases in FAIRE signal in response to hormone. (BH)

CitationBurd CJ, Ward JM, Crusselle-Davis VJ, Kissling GE, Phadke D, Shah RR, Archer TK. 2012. Analysis of chromatin dynamics during glucocorticoid receptor activation. Mol Cell Biol 32(10):1805-1817.

Novel assay measures DNA breaks in human cells exposed to tumor inhibitors

In a recent issue of PNAS, NIEHS scientists report a method to accurately measure the number of DNA breaks that can be induced in human cells. Pioneered by members of the Chromosome Stability Group, they utilized this technique to determine how certain cancer inhibitors modulate DNA break repair.

The study used human cells containing a circular minichromosome from the Epstein-Barr virus. Like any circular DNA, the minichromosome is expected to be supercoiled if there are no breaks. A single-strand break (SSB) relaxes the DNA and a double-strand break (DSB) generates a linear molecule. Lead author Wenjian Ma, Ph.D., exposed cells to ionizing radiation and was able to separate the different configurations of the minichromosome, in order to measure how many molecules contained each type of DNA break and how quickly the DNA was repaired.

The researchers focused on a single class of chemotherapeutic agents that inhibit the poly(ADP-ribose) polymerase (PARP). PARP inhibitors can kill particular types of cancer cells that are defective in DSB repair and recombination processes. The study shows that while reducing PARP protein expression does not affect break repair, some PARP inhibitors impede SSB repair, but not DSB repair. The complexity of chemotherapeutic effects on repairing DNA emphasizes the importance of this novel technique and subsequent findings, in future studies to understand the connections between cancer treatment and DNA repair. (JS)

CitationMa W, Halweg CJ, Menendez D, Resnick MA. 2012. Differential effects of poly(ADP-ribose) polymerase inhibition on DNA break repair in human cells are revealed with Epstein-Barr virus. Proc Natl Acad U S A 109(17):6590-6595.

Mechanism for endocrine disrupting chemicals is dose and cell type specific

NIEHS researchers have uncovered the mechanisms by which endocrine disrupting chemicals (EDCs) initiate adverse effects on human cells. They found that bisphenol A (BPA) and bisphenol AF (BPAF), two synthetic chemicals found in polycarbonate plastics and electronic materials, and Zearalenone, an estrogenic mycotoxin found in cereal crops and bread, can function as both agonists and antagonist EDCs. Since EDCs are widely present in the environment, this study may help scientists understand the impact of environmental exposure on human health and wildlife populations. Previous experimental studies have shown that the antagonistic effects of BPA at low concentrations inhibit key adipokines, which are thought to protect humans from complex diseases, such as the induction of metabolic syndrome.

Researchers used three different human cell lines with low endogenous expression of estrogen receptor (ER) alpha to assess the estrogenic actions of the three EDCs. The results showed that both BPA and BPAF act as antagonists for ER alpha and ER beta at low concentrations, less than 10 nanomolar, but act as agonists at higher concentrations, greater than 10 nanomolar, in a cell specific manner. The findings may help explain the tissue selective actions. Moreover, these EDCs not only activate endogenous ER alpha target genes, but can also mediate rapid action responses, such as the activation of p44/p42 mitogen-activated protein kinase (MAPK) pathway, which indicates their mechanisms of action may also involve not only gene responses, but also extranuclear cell signaling activities. (SP)

CitationLi Y, Burns KA, Arao Y, Luh CJ, Korach KS. 2012. Differential estrogenic actions of endocrine-disrupting chemicals bisphenol A, bisphenol AF, and Zearalenone through estrogen receptor alpha and beta in vitro. Environ Health Perspect; doi:10.1289/ehp.1104689 [Online 11 April 2012].

SIRT1 is a crucial regulator of mammalian metabolic homeostasis

In a new study from NIEHS, scientists demonstrated that SIRT1, a highly-conserved nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, is an essential factor in the regulation of systemic energy and steroid hormone homeostasis. Mice lacking one copy of the SIRT1 gene showed compromised handling of metabolic stress following a high fat diet. Since SIRT1 has been implicated in a variety of metabolic disorders, such as obesity, diabetes, and related inflammatory disorders, this work strengthens the understanding of the role of SIRT1 in metabolic dysfunctions and identifies it as a potential therapeutic target.

Using metabolomic and biochemical tests on a heterozygous SIRT1 mouse model, the scientists showed that these mice were susceptible to metabolic abnormalities, such as obesity and high blood glucose, in response to a high fat diet. Furthermore, SIRT1 insufficient mice demonstrated significant alterations in free fatty acid recycling in the liver and increased testosterone levels. The observed increase was attributed to impaired hepatic inactivation and clearance of testosterone in these mice.

This study further establishes SIRT1 as a crucial modulator of metabolic equilibrium and may help in the development of novel therapeutic interventions that target SIRT1 in metabolic disorders, such as type 2 diabetes and obesity. (ST)

CitationPurushotham A, Xu Q, Li X. 2012. Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding. FASEB J 26(2):656-667.

(Brant Hamel, Ph.D., is an Intramural Research Training Award (IRTA) fellow in the NIEHS Laboratory of Signal Transduction. Sonika Patial, D.V.M., Ph.D., is a visiting fellow in the NIEHS Laboratory of Signal Transduction. Jeffrey Stumpf, Ph.D., is a research fellow in the NIEHS Laboratory of Molecular Genetics. Sheetal Thakur, Ph.D., is an IRTA fellow in the NIEHS/NTP Toxicology Branch.)

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