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Intramural Papers of the Month

By Robin Arnette
May 2008

More Dietary Fiber May Protect Against COPD

According to researchers from NIEHS and the University of North Carolina at Chapel Hill, greater intake of dietary fiber may protect against deterioration of lung function and possibly against chronic obstructive pulmonary disease (COPD). Data from previous research suggested that fiber consumption protected adults against the development of chronic bronchitis, but no other study had examined fiber intake in relation to pulmonary function and COPD.

Trained interviewers administered a 66-item food frequency questionnaire to approximately 15,000 middle-aged men and women from four U.S. communities during the Atherosclerosis Risk in Communities (ARIC) Study. At baseline and three years later, participants were asked about respiratory diseases and symptoms and underwent lung function testing. Each participant's daily intake of nutrients was computed by multiplying the daily servings of each food item by its nutrient content. Fiber intake and lung function measurements were statistically analyzed using linear regression, multiple logistic regression and median-value quintiles.

The team found that a diet high in fiber, particularly from cereal and fruit, was related to better lung function. This result was the same regardless of sex, ethnicity or smoking status. The benefits were also independent of antioxidant vitamin ingestion or other dietary patterns. This investigation is the first to provide evidence that dietary fiber is independently associated with better pulmonary function and reduced prevalence of COPD.

Citation: Kan H, Steven J, Heiss G, Rose KM, London SJ.( Exit NIEHS Website 2008. Dietary fiber, lung function, and chronic obstructive pulmonary disease in the atherosclerosis risk in communities study. Am J Epidemiol 167(5):570-578.

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A Novel Approach for Indentifying Transcription Factor Binding Sites

NIEHS investigators have developed a novel method for identifying transcription factor binding sites in a set of sequences. The approach, called fdrMotif, is faster and has a higher sensitivity than MEME, a commonly-used de novo motif discovery program.

To identify transcription factor biding sites in chromatin immunoprecipitation (ChIP) sequences, the majority of de novo motif identification methods use a two-stage approach that (1) optimizes the motif model and (2) tests the statistical significance of the motif score. However, the two-stage approach has several disadvantages such as the need to specify or model the abundance parameter, uncontrolled errors for multiple comparisons and arbitrary P-values and Z-scores.

The authors improved on standard identification methods in their development of fdrMotif, which uses an E-step and the maximization (M)-step in model optimization like MEME, but also utilizes a new normalization procedure in the E-step that combines model optimization and significance testing during each iteration. When tested, fdrMotif identified 93.2 percent of the p53 binding sites in ChIP sequences. When fdrMotif and MEME were tested on 500 sets of simulated ChIP sequences with embedded known p53 binding sites, fdrMotif performed better.

In summary, fdrMotif is a simple approach that doesn't require a motif abundance parameter or post-analysis statistical significance test. It is a unique and useful tool for motif identification.

Citation: Li L, Bass RL, Liang Y.( Exit NIEHS Website 2008. fdrMotif: Identifying cis-elements by an EM algorithm coupled with false discovery rate control. Bioinformatics 24(5):629-636.

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17β-estradiol Enhances Nucleosome Remodeling Independent of Estrogen Receptors

According to NIEHS investigators, 17β-estradiol (E2) induces remodeling of a nucleosome strategically located within the hormone response regulatory region of the estrogen-related receptor alpha (ERRα) gene promoter and enhances ERR? gene expression. The team was surprised to discover that E2-dependent remodeling of the specific nucleosome can occur independently of the estrogen receptor (ER).

ERRα is closely related to the ER (α and β). Recent evidence suggests that ERRα is a negative prognostic marker for breast cancer survival, being highly expressed in breast cancer cells lacking ER. Based on the knowledge that nucleosomes strategically located at hormone response elements (HREs) prevent transcription-factor binding within the regulatory region, the investigators sought to understand the role of chromatin architecture in estrogen dependent regulation of the ERRα gene in breast cancer cells.

Using various biochemical assays, the investigators examined the effect of E2 on the chromatin architecture in ER-positive MCF-7 and ER-negative SKBR3 breast cancer cells. They found that estrogen led to changes in chromatin architecture at the HRE as exhibited by increased restriction enzyme hypersensitivity and enhanced histone H3 and H4 acetylation. These changes were attenuated by the estrogen antagonist ICI 182 780 in ER-positive, but not ER-negative cells.

Since current evidence suggests that ERRα promotes local production of estrogen in aggressive breast tumors, this study highlights the importance of estrogen regulation of ERRα gene expression independent of the estrogen receptor. This and other clinically-important findings suggest that ERRα may play a role in the estrogen-dependent breast cancer.

Citation: Hu P, Kinyamu HK, Wang L, Martin J, Archer TK, Teng C.( Exit NIEHS Website 2008. Estrogen induces estrogen-related receptor α gene expression and chromatin structural changes in estrogen receptor (ER)-positive and ER-negative breast cancer cells. J Biol Chem (11):6752-6763.

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Synaptic Elimination in Rat Hippocampal Neurons

Changes in spine size and long-term depression (LTD)-a process in which low-frequency synaptic stimulation causes the weakening of glutamatergic synapses in the hippocampus-lead to the elimination of synapses, according to NIEHS researchers. Their work sheds light on the association between neuronal activity during development and maturation of brain circuitry.

Previous studies had determined that LTD was associated with dendritic spine enlargement or shrinkage. However, the team wanted to know whether LTD could lead to separation of synaptic structures when the spine shrank or was lost. The team cultured rat hippocampal cells on multi-electrode arrays and labeled the neurons with genes that encoded red or green fluorescent proteins to visualize presynaptic and postsynaptic processes.

LTD-inducing stimulation led to a reduction in the synaptic red and green co-localization and often induced a complete separation of the presynaptic bouton from the dendritic spine. They also found that spine shrinkage following LTD occurs independently of synapse elimination. Further investigations using this experimental model may provide information about the molecular mechanisms of brain circuitry during development.

Citation: Bastrikova N, Gardner GA, Reece JM, Jeromin A, Dudek SM.( Exit NIEHS Website 2008. Synapse elimination accompanies functional plasticity in hippocampal neurons. Proc Natl Acad Sci USA 105(8):3123-3127.

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