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Environmental Factor, November 2012

Extramural papers of the month

By Nancy Lamontagne

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Non-coding DNA variants may link early exposures with later health problems

Researchers, supported in part by NIEHS, report that genetic differences linked to a variety of diseases are activated during fetal development. These findings could help explain why some early environmental exposures increase disease risk years or even decades later.

The researchers investigated whether variants in noncoding regions of DNA regulate gene expression, by looking at thousands of these variants identified in genome-wide association studies (GWAS). They mapped regions that are sensitive to DNase I cleavage, because these hypersensitivity sites mark regions that actively regulate gene expression.

They found that more than 76 percent of noncoding GWAS variants were in, or very near, DNase I hypersensitivity sites, indicating that most of the noncoding variants in these samples regulate genes. In addition, 88 percent of the variants in regulatory DNA regions are active in fetal development, including variants associated with adult-onset disease. This suggests that environmental exposures during this period could influence risk for a large number of diseases.

The researchers also identified the genes regulated by hundreds of GWAS variants, including genes associated with blood platelet counts, amyotrophic lateral sclerosis (ALS), Crohn’s disease, breast and ovarian cancer, and schizophrenia. Almost 80 percent of GWAS variants in regulatory DNA were connected to genes that were not the closest ones to the variant, which is probably why previous attempts to link GWAS variants with target genes have been so difficult.

CitationMaurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, Reynolds AP, Sandstrom R, Qu H, Brody J, Shafer A, Neri F, Lee K, Kutyavin T, Stehling-Sun S, Johnson AK, Canfield TK, Giste E, Diegel M, Bates D, Hansen RS, Neph S, Sabo PJ, Heimfeld S, Raubitschek A, Ziegler S, Cotsapas C, Sotoodehnia N, Glass I, Sunyaev SR, Kaul R, Stamatoyannopoulos JA. 2012. Systematic localization of common disease-associated variation in regulatory DNA. Science 337(6099):1190-1195.

Reversible epigenetic changes associated with bee behavior

Researchers studying honeybees report what could be the first evidence of reversible epigenetic changes associated with behavior. The research may shed light on problems that people have with learning, memory, stress response, and mood disorders, which all involve interactions between genetic and epigenetic components. The work was supported by an NIH Director’s Pioneer Award.

Although all worker honeybees are genetically identical within the same hive, they carry out different roles. For example, some bees nurse larvae, while others forage for food. Since genetics isn’t responsible for the differing behaviors, epigenetic changes are likely involved. Epigenetic changes, such as DNA methylation, modify gene expression without changing the genetic code.

To study the role of epigenetic changes in bee behavior, the researchers used a method known as comprehensive high-throughput arrays for relative methylation (CHARM) to locate methylated DNA in the brains of bees. They found no differences in DNA methylation between worker and queen bees, roles that are irreversible. However, they saw substantial differences between nurses and forager bees. Reverting foragers back to nurses reestablished methylation levels for a majority of genes, providing evidence of reversible epigenetic changes that are associated with behavior.

CitationHerb BR, Wolschin F, Hansen KD, Aryee MJ, Langmead B, Irizarry R, Amdam GV, Feinberg AP. 2012. Reversible switching between epigenetic states in honeybee behavioral subcastes. Nat Neurosci 15(10):1371-1373.

Fetal BPA exposure harms reproductive health in primates

A new primate study from NIEHS grantees adds more evidence that exposure to bisphenol A (BPA) can be disruptive to female reproductive systems. Although the study involved only a small group of animals, the findings support those from rodent studies and raise concerns about current levels of human exposure to BPA.

BPA is found in polycarbonate plastics and epoxy resins, and exposure can occur through consuming foods or beverages kept in packaging made with BPA. The researchers looked at how maternal levels of BPA, similar to those reported in humans, would affect the fetal ovary of rhesus monkeys. They assessed various durations and routes of exposure to BPA, including single daily doses of BPA and sustained low-level exposure.

The study’s findings suggest that, like mice, the fetal primate ovary is sensitive to BPA. Specifically, the researchers found that when second trimester monkeys were exposed to BPA at the beginning of fetal egg cell meiosis, the egg cells failed to divide properly during the earliest stage of development. In monkeys exposed continuously, the researchers also observed complications in the third trimester, noting that the eggs in the fetus were not packaged appropriately in follicles. The problems with fetal egg development could potentially affect later reproductive success and longevity.

CitationHunt PA, Lawson C, Gieske M, Murdoch B, Smith H, Marre A, Hassold T, Vandevoort CA. 2012. Bisphenol A alters early oogenesis and follicle formation in the fetal ovary of the rhesus monkey. Proc Natl Acad Sci U S A 109(43):17525-17530.

Assay quantifies effects of DNA damage on transcription

A new assay, developed by NIEHS grantees, could help explain how DNA damage from environmental chemicals leads to development of cancer and other diseases. The competitive transcription and adduct bypass (CTAB) assay quantifies how DNA damage effects the rate and fidelity of transcription, the process that converts DNA’s genetic information into proteins. Using this information, investigators can assess how DNA damage hinders protein synthesis, leading to mutant proteins.

The researchers demonstrated the assay by showing how oxidative-induced DNA damage affected transcription in vitro and in mammalian cells. They say that the CTAB assay should be applicable for studying other types of DNA damage. It can also be used to examine proteins involved in DNA repair.

CitationYou C, Dai X, Yuan B, Wang J, Wang J, Brooks PJ, Niedernhofer LJ, Wang Y.  2012. A quantitative assay for assessing the effects of DNA lesions on transcription. Nat Chem Biol; doi:10.1038/nchembio.1046. [Online 19 August 2012]. Story

(Nancy Lamontagne is a science writer with MDB, Inc., a contractor for the NIEHS Division of Extramural Research and Training, Superfund Research Program, and Worker Education and Training Program.)

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