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Environmental Factor, July 2012

Intramural papers of the month

By Anshul Pandya, Sonika Patial, Sheetal Thakur, and Sheila Yong

Pol II pausing modulates basal gene expression in signal transduction cascades

NIEHS scientists have revealed that RNA polymerase II (Pol II) pausing does not necessarily lead to higher gene expression upon induction of stimulus-responsive networks. Rather, it is important in modulating basal gene expression. The research offers a new model for understanding how paused Pol II impacts gene expression in resting cells.

Using the systems biology approach in Drosophila S2 cells and focusing primarily on the immune response pathways, they found that many downstream target genes were rapidly induced, despite not harboring paused Pol II at their promoters prior to pathogenic challenge. Instead, they observed a higher prevalence of Pol II pausing at promoters of genes whose expression levels were more modest. Genes in the latter category encode regulatory components and receptor ligands that either initiate or dampen the signaling cascade.

The scientists also knocked down the expression of NELF, a component required for Pol II pausing, and found that the magnitude of the overall immune response was diminished, regardless of whether the genes experienced Pol II pausing or not. Their findings indicate that, although the regulatory components are more modestly expressed in response to immune challenge, their basal expression in resting cells is more tightly regulated so that these cells are better poised to rapidly initiate the immune response cascade as needed. (SY)

CitationGilchrist DA, Fromm G, dos Santos G, Pham LN, McDaniel IE, Burkholder A, Fargo DC, Adelman K. 2012. Regulating the regulators: the pervasive effects of Pol II pausing on stimulus-responsive gene networks. Genes Dev 26(9):933-944.

Clustered mutations attributed to body’s natural defenses

A collaborative team, comprised of scientists from NIEHS, The Broad Institute, and the University of North Carolina at Chapel Hill, has identified DNA regions with a high number of nonrandom mutations in yeast and some human cancers. The findings may represent one of the mechanisms of cancer development.

Researchers subjected yeast cells to the DNA damaging agent methyl methanesulfonate and then sequenced the genomes. They found that certain patches of DNA sequence contained clusters with more mutations than in the rest of the genome. The data challenged the traditionally held view that mutations occur randomly. Further analysis suggested that these mutations occurred at the same time in stretches of abnormally long single-stranded DNA.

The research team developed bioinformatics tools to determine if human cancers contained similar mutation clusters and, surprisingly, nearly half of them did. These mutations, however, were not caused by environmental damage, but by a specific set of proteins known as APOBEC cytosine-deaminases. APOBEC proteins, which are part of the human immune system, attack viruses that enter the body.

The results of this study suggest that several antiviral drugs, capable of stimulating APOBEC genes, should be considered potential mutagens as they relate to mutation clusters. (SP)

CitationRoberts SA, Sterling J, Thompson C, Harris S, Mav D, Shah R, Klimczak LJ, Kryukov GV, Malc E, Mieczkowski PA, Resnick MA, Gordenin DA. 2012. Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol Cell 46(4):424-435. Story

STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children

A new study, conducted by NIEHS scientists, provides evidence that the polymorphisms in STAT6, signal transducer and activator of transcription-6, and LRP1, low-density lipoprotein receptor–related protein-1, genes are associated with sensitization to food allergens in asthmatic patients. Asthmatic patients are at increased risk for sensitization to food allergens, so the results may not be completely generalizable to the entire population.

Prior to the publication of this paper, epidemiologists had identified family history as a risk factor for food allergies, but no genetic variants had been conclusively identified for food sensitization or clinical food allergies. Therefore, the research team examined the associations between food allergen sensitization and single nucleotide polymorphisms (SNPs) in five autosomal candidate genes: CD14, IL10, IL13, SPINK5, and STAT6.

The study included 162 asthmatic children from the Mexico City Childhood Asthma Study, who tested positive to at least one food allergen using skin prick tests, and their parents, using the case-parent triad design. The research team found that several SNPs in or near STAT6, and two more in the nearby LRP1 gene, were associated with sensitization to food allergens. (AP)

CitationHancock DB, Romieu I, Chiu GY, Sienra-Monge JJ, Li H, Estela Del Rio-Navarro B, London SJ. 2012. STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children. J Allergy Clin Immunol 129(6):1673-1676.

Socioeconomic adversity in early life impacts the future risk of rheumatoid arthritis

Epidemiologists from NIEHS report that women with lower childhood socioeconomic status are more likely to develop rheumatoid arthritis (RA) in adulthood. The study is the first to describe an association of multiple childhood socioeconomic factors, such as household education, income, and maternal age, with adult onset RA.

The researchers analyzed information from more than 50,000 women aged 35-74 from the NIEHS Sister Study cohort. Participants were asked about perinatal factors, demographics, residential history, lifestyle, medical history, and medication use. The study showed that women who were raised in a household with lower education, lower income, food insecurity, and young maternal age were at higher risk of developing RA as adults. The impact of childhood socioeconomic adversity on RA was the most apparent in women with lower adult educational attainment. Women with fathers who smoked three months prior to conception also had a higher risk of RA, regardless of socioeconomic factors.

These emerging results are an important step toward investigating the role of developmental, environmental, and social factors on the risk for RA in women. (ST)

CitationParks CG, D’Aloisio AA, DeRoo LA, Huiber K, Rider LG, Miller FW, Sandler DP. 2012. Childhood socioeconomic factors and perinatal characteristics influence development of rheumatoid arthritis in adulthood. Ann Rheum Dis; doi:10.1136/annrheumdis-2011-201083 [Online 14 May 2012].

(Anshul Pandya, Ph.D., is an Intramural Research Training Award [IRTA] fellow in the NIEHS Laboratory of Neurobiology. Sonika Patial, D.V.M., Ph.D., is a visiting fellow in the NIEHS Laboratory of Signal Transduction. Sheetal Thakur, Ph.D., is an IRTA fellow in the NTP Toxicology Branch. Sheila Yong, Ph.D., is a visiting fellow in the NIEHS Laboratory of Signal Transduction.)

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