Intramural papers of the month
By Robin Arnette, Tara Ann Cartwright, Deacqunita Diggs, Ernie Hood, and Qing Xu
- NTP finds that chronic cobalt metal exposure leads to lung tumors in rodents
- Bidirectional transcription facilitates gene responsiveness
- Nonmotor symptoms are sign of early Parkinson’s disease
- NIEHS scientists decipher the conformational maturation of an HIV enzyme
- Preterm births are not strongly linked to seasons of the year
NTP finds that chronic cobalt metal exposure leads to lung tumors in rodents
Scientists in the National Toxicology Program (NTP) found a high incidence of Kras mutations and lower incidences of Egfr and Tp53 mutations in cobalt metal dust (CMD)-induced rodent lung tumors, compared to those arising spontaneously. Furthermore, the Ames assay, a test for bacterial mutagenicity, yielded positive results, indicating a carcinogenic potential for CMD. These findings are significant because the genetic alterations are similar to those seen in human lung cancer.
The majority of the Kras mutations in CMD-induced rodent lung tumors consisted of exon 1 codon 12 G to T transversions, while the lung tumors arising spontaneously usually harbor codon 12 G to A transitions. G to T transversions are commonly associated with oxidative damage to DNA and are one of the most common Kras mutations in human lung cancers. In addition, results of the Ames assay demonstrated the capacity of cobalt (II) ions to induce mutations at G:C base pairs. These results support the CMD-induced lung tumor mutation data.
This study suggests that differential mutation spectra may be used to potentially distinguish between lung tumors resulting from chemical exposures and those arising spontaneously. The data may also be used to compare mutations between rodent and human cancers. (DD)
Citation: Hong HH, Hoenerhoff MJ, Ton TV, Herbert RA, Kissling GE, Hooth MJ, Behl M, Witt KL, Smith-Roe SL, Sills RC, Pandiri AR. 2015. Kras, Egfr, and Tp53 mutations in B6C3F1/N mouse and F344/NTac rat alveolar/bronchiolar carcinomas resulting from chronic inhalation exposure to cobalt metal. Toxicol Pathol; doi:10.1177/0192623315581192 [Online 9 June 2015].
Bidirectional transcription facilitates gene responsiveness
NIEHS researchers have shed new light on the regulatory landscape surrounding mammalian protein-coding genes, enhancing the understanding of the basic mechanisms of how cells respond to stresses from their environment. The scientists reported that bidirectional promoters contributed to an optimized environment for recruitment of transcription factors and the transcription machinery.
Using bone marrow-derived macrophages from C57BL/6 mice, high-throughput sequencing of transcription start site (TSS)-associated RNAs was performed to precisely annotate both sense and anti-sense TSSs near mouse mRNA genes. Bidirectional promoter architecture was found to be widespread, as anti-sense TSSs were observed at more than 75 percent of active promoters. The study revealed two previously unappreciated features of promoter architecture that affect both resting and stimulus-responsive transcription, as seen during immune challenge.
First, the distance between protein-coding sense and noncoding, upstream anti-sense (TSSs) is related to the size of the nucleosome-depleted region, the level of signal-dependent transcription factor binding, and gene activation. Second, a group of anti-sense TSSs with an enhancer-like chromatin signature was seen in the macrophages. The scientists propose that anti-sense promoters serve as platforms for transcription factor binding and establishment of active chromatin to further regulate or enhance sense-strand mRNA expression. (EH)
Citation: Scruggs BS, Gilchrist DA, Nechaev S, Muse GW, Burkholder A, Fargo DC, Adelman K. 2015. Bidirectional transcription arises from two distinct hubs of transcription factor binding and active chromatin. Mol Cell 58(6):1101-1112.
Nonmotor symptoms are sign of early Parkinson’s disease
Scientists from the NIEHS Epidemiology Branch and the Biostatistics and Computational Biology Branch have determined that the presence of several nonmotor symptoms of Parkinson’s disease could effectively differentiate patients with early Parkinson’s from healthy controls. They also found differences between men and women in the presentation of nonmoter symptoms. In one of the largest analyses to date, researchers examined five major areas of nonmotor symptoms — sleep, olfactory, neurobehavioral, autonomic, and neuropsychological domains.
Parkinson’s is a progressive neurodegenerative disorder that is clinically diagnosed by the presence of cardinal motor dysfunction. However, patients with Parkinson’s also suffer from a range of nonmotor symptoms, such as sense of smell loss, depression, sleep disorders, constipation, pain, and cognitive dysfunction.
In addition to finding that nonmotor symptoms differentiate Parkinson’s patients from healthy volunteers, the study indicated potential sex differences among Parkinson’s patients with nonmotor symptoms. For example, male patients with Parkinson’s performed significantly worse than female patients with regard to odor identification. Female patients outperformed their male counterparts on global cognition and memory domain, but experienced higher trait anxiety, which is sustained worry or nervousness in response to a perceived threat.
Since many Parkinson’s nonmotor symptoms may develop years before disease diagnosis, research on these symptoms may eventually help identify individuals at risk for the disease and help scientists understand the disease origin. (TAC)
Citation: Liu R, Umbach DM, Peddada SD, Xu Z, Troster AI, Huang X, Chen H. 2015. Potential sex differences in nonmotor symptoms in early drug-naive Parkinson disease. Neurology 84(21):2107-2115.
NIEHS scientists decipher the conformational maturation of an HIV enzyme
NIEHS researchers have analyzed the molecular changes that occur during the maturing of human immunodeficiency virus (HIV) reverse transcriptase (RT), a key enzyme in the life cycle of the virus that causes acquired immunodeficiency syndrome (AIDS). The authors anticipate that their new understanding of the maturation pathway may lead to the development of alternate inhibition strategies that interfere with the process.
The mature form of RT, a target of pharmaceutical compounds used to treat AIDS, consists of a catalytic p66 subunit and a structural p51 subunit. Both subunits are derived from a single peptide chain that is present in the HIV virion, or the entire viral particle. Unfortunately, the high mutagenic rate of HIV allows it to develop mutated forms of RT that can escape drug inhibition.
Maturation of RT from the single polypeptide to form the active, two subunit enzyme is a complex process that until now has been largely uncharacterized. Using isotopic labeling in combination with nuclear magnetic resonance, the research team found that a key feature of the maturation is a metamorphic polymerase domain, which is similar to a puzzle that has two alternate solutions. (QX)
Citation: Zheng X, Perera L, Mueller GA, DeRose EF, London RE. Asymmetric conformational maturation of HIV-1 reverse transcriptase. eLife; doi:10.7554/eLife.06359.001.
Preterm births are not strongly linked to seasons of the year
A research team led by scientists at NIEHS explored possible seasonal effects on risk of preterm birth in Norway. While earlier studies from other groups suggested huge effects of season on preterm birth, the more careful analysis by the NIEHS-led group showed that season has little effect on preterm birth in the country. Their findings cast doubt on previous studies that suggested that spring conception produces shorter pregnancies.
Preterm birth is a common pregnancy complication that endangers both the survival and the long-term health of the infant. Understanding seasonal effects on preterm birth could implicate environmental causes that could be modified to reduce risk. Norway experiences strong seasonal variation and has also maintained an excellent birth registry. Therefore, it provides an ideal source of population-level data for studying effects of season on reproductive health. Couples often plan their pregnancies with attention to season, meaning that the mix of planned and unplanned pregnancies and the gestational age distribution of the fetuses that are at risk of early birth also change through the seasons. Consequently, the statistical analysis must be done carefully to avoid confounding biases.
The authors offered that the remaining risk pattern observed, with somewhat increased risk for conceptions occurring during early January and early July, could be a behavior-mediated effect of seasonal holidays in Norway, and unintentional conceptions during those times. The peaks coincide with New Year’s Day and the start of summer break in Norway. (RA)
Citation: Weinberg CR, Shi M, DeRoo LA, Basso O, Skjaerven R. 2015. Season and preterm birth in Norway: a cautionary tale. Int J Epidemiol; doi:10.1093/ije/dyv100 [Online 4 June 2015].
(Robin Arnette, Ph.D., is a science writer and editor in the NIEHS Office of Communications and Public Liaison. Tara Ann Cartwright, Ph.D., is a former postdoctoral fellow in the NIEHS Intracellular Regulation Group. Deacqunita Diggs, Ph.D., is a National Health and Environmental Effects Laboratory fellow in the U.S. Environmental Protection Agency Developmental Toxicity Branch. Ernie Hood is a contract writer with the NIEHS Office of Communications and Public Liaison. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)