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December 2011

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Intramural papers of the month

By Robin Arnette, Raluca Dumitru, and Brant Hamel
December 2011

One apolipoprotein E allele associated with lower risk of Parkinson's

A recent study published in the journal Neurobiology of Aging suggested that apolipoprotein E (ApoE) epsilon4, a known risk allele for Alzheimer's disease, was associated with a lower risk of Parkinson's in non-Hispanic Caucasians. The data also indicated that epsilon4 tended to correspond to a 60 percent higher risk of dementia among Parkinson's patients. The work was a collaborative effort between scientists from NIEHS, Pennsylvania State University, the National Cancer Institute, and AARP.

The research team became interested in examining the connections between ApoE alleles and Parkinson's, because of the inconsistencies in the epidemiological literature, the clinical and epidemiological similarities between Parkinson's and Alzheimer's, and recent evidence that higher plasma cholesterol was associated with a lower risk for Parkinson's disease. The team performed this population-based case-control study using 786 Parkinson's patients from the Parkinson's, Genes, and Environment study, a case-control study within the large prospective NIH-AARP Diet and Health Study cohort. The study had 1537 healthy adults to serve as controls.

The investigators collected saliva samples from volunteers and contacted the patients' treating physicians to confirm a Parkinson's diagnosis. They extracted DNA from the saliva and genotyped two single nucleotide polymorphisms (SNPs) to determine ApoE alleles: epsilon3, epsilon4 or epsilon2. The team then conducted statistical analysis. Compared with epsilon3 carriers, participants that carried the epsilon4 allele had significantly lower odds of having Parkinson's, while epsilon2 carriers did not.

Citation: Gao J, Huang X, Park Y, Liu R, Hollenbeck A, Schatzkin A, Mailman RB, Chen H(http://www.ncbi.nlm.nih.gov/pubmed/21741729) Exit NIEHS. 2011. Apolipoprotein E genotypes and the risk of Parkinson disease. Neurobiol Aging 32(11):2106.e1-6.

Effects of endothelial CYP2C8 epoxygenase on cardiac recovery

A new collaborative effort between investigators at NIEHS, Oregon Health and Science University, and the University of North Carolina at Chapel Hill defines, for the first time, the role that endothelial-derived versus cardiomyocyte-derived epoxyeicosatrienoic acids (EETs) play in cardioprotection following ischemia/reperfusion (IR) injury.

Conflicting reports link EETs with beneficial, as well as detrimental, effects on cardiac recovery after IR injury. Expression of CYP2J2 in cardiomyocytes was previously shown to improve the functional recovery and reduce the infarct size after ischemia. Endothelial EETs are known to increase blood flow and reduce inflammation. However, other studies demonstrated that inhibition of CYP2C reduces infarct size after IR in isolated rat hearts.

To address the discrepancy, the investigators generated transgenic mice with increased endothelial EET biosynthesis (Tie2-CYP2C8 and Tie2-CYP2J2) or EET hydrolysis (Tie2-sEH) and compared them to mice with increased EET biosynthesis in cardiomyocytes (alphaMHC-CYP2J2) and wild-type (WT) mice. Compared to WT, the alphaMHC-CYP2J2 hearts had increased functional recovery and decreased infarct size after IR. In contrast, the Tie2-CYP2C8 hearts exhibited decreased functional recovery, due to increased production of reactive oxygen species and toxic linoleic acid metabolites.

These data confirm that CYP2J2 expression in cardiomyocytes is protective against IR injury, while endothelial-derived EETs have little effect. In contrast, the expression of CYP2C8 in endothelium has detrimental effects, which outweigh the potential benefits of increased EET biosynthesis.

Citation: Edin ML, Wang Z, Bradbury JA, Graves JP, Lih FB, DeGraff LM, Foley JF, Torphy R, Ronnekleiv OK, Tomer KB, Lee CR, Zeldin DC(http://www.ncbi.nlm.nih.gov/pubmed/21697548) Exit NIEHS. 2011. Endothelial expression of human cytochrome P450 expoxygenase CYP2C8 increases susceptibility to ischemia-reperfusion injury in isolated mouse heart. FASEB J 25(10):3436-3447.

Aprataxin structure links DNA repair mechanism to neurodegenerative disease

Using X-ray crystallography, NIEHS researchers have uncovered how the protein aprataxin recognizes and reverses damaged DNA. Aprataxin is a eukaryotic protein that is involved in the cellular response to genotoxic stress, and mutations in the human gene encoding the protein (APTX) cause a debilitating neurological disorder known as ataxia with oculomotor apraxia (AOA1). Until now, scientists weren't sure how these mutations affected aprataxin function.

Aprataxin normally acts to repair DNA as a DNA ligase proofreader in the cell by removing 5'-adenylated DNA left by aborted DNA ligation reactions. Using high-throughput robotics to screen a large number of crystallization conditions, the scientists crystallized a quaternary complex containing aprataxin, DNA, the DNA damage lesion 5'-adenosine monophosphate (AMP), and the metal cofactor zinc.

The structure revealed the two major domains in the protein: the HIT domain, which contains the wedge that allows access to the damaged DNA termini and the zinc finger domain, which combined with the HIT domain, specifically recognizes the structure of damaged DNA. The zinc finger domain surprisingly utilized a novel C2H2 Zn-binding motif to recognize damaged DNA in a sequence independent manner. This motif is a derivative of the classical C2H2 binding fold, and the finding implied that zinc finger-containing proteins may be much more widespread in nature than previously thought. With the aprataxin molecular structure in hand, scientists now have a template for understanding how APTX mutations inactivate this important DNA damage repair enzyme.

Citation: Tumbale P, Appel CD, Kraehenbuehl R, Robertson PD, Williams JS, Krahn J, Ahel I, Williams RS(http://www.ncbi.nlm.nih.gov/pubmed/21984210) Exit NIEHS. 2011. Structure of an aprataxin-DNA complex with insights into AOA1 neurodegenerative disease. Nat Struct Mol Biol 18(11):1189-1195.

New algorithm identifies transcription factors and coregulators in ChIP-seq data

Biostatisticians from NIEHS have developed a new method that determines which ChIP-seq data has binding sites for the transcription factor being immunoprecipitated and coregulatory factors. Called coMOTIF, the computational tool simultaneously models the coexistence of the two sequence motifs using joint distribution. It uses a technique to reduce the sampling space in the expectation-maximization (EM) algorithm, making a large-scale genomic search of transcription factors and their accompanying coregulators easier to find in ChIP-seq data.

Transcription factors and their accompanying coreulators work together to regulate gene transcription, but before the creation of coMOTIF, scientists had to search each ChIP-seq sequence one at a time to determine if they contained one or both motifs. As a result, the research team developed the new finite mixture model, which uses two known position weight matrices (PMWs) as starting points for the EM algorithm to simultaneously determine the two motifs.

coMOTIF has been proven to be more effective than the standard MEME+, because it allows nine states compared to MEME+'s three. It was tested on 10 simulated ChIP-seq datasets and did a better job of predicting which sequences contained both motifs. The coMOTIF software is freely available at http://www.niehs.nih.gov/research/resources/software/biostatistics/comotif/index.cfm http://www.niehs.nih.gov/research/resources/software/biostatistics/comotif/index.cfm.

Citation: Xu M, Weinberg CR, Umbach DM, Li L(http://www.ncbi.nlm.nih.gov/pubmed/21775309) Exit NIEHS. 2011. coMOTIF: a mixture framework for identifying transcription factor and coregulator motif in ChIP-seq data. Bioinformatics 27(19):2625-2632.

(Raluca Dumitru, M.D., Ph.D., is an Intramural Research Training Award (IRTA) Fellow in the NIEHS Stem Cell Biology Group of the Laboratory of Molecular Carcinogenesis. Brant Hamel, Ph.D., is an IRTA Fellow in the NIEHS Molecular Endocrinology Group of the Laboratory of Signal Transduction.)

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