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Environmental Factor, March 2012

Intramural Papers of the Month

By Sonika Patial and Ian Thomas

Tet1 is essential for pluripotency in mouse embryonic stem cells

In a new study, researchers at NIEHS and the University of New York School of Medicine found that acute short term depletion of Tet1 results in the loss of mouse embryonic stem cell (mESC) identity. The finding is in contrast to genetic deletion of Tet1, which has been previously shown to have no effect on the maintenance of embryonic stem cells in an undifferentiated state. The conclusions help scientists better understand how embryonic stem cells sustain their pluripotency or the ability to differentiate into specialized cells in the body.

Tet1 is an enzyme that catalyzes the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and promotes DNA demethylation. Investigators used RNA interference to deplete the levels of Tet1 in mESCs and measured the expression levels of genes involved in the maintenance of an undifferentiated state, genes involved in differentiation, and levels of 5hmC. The results showed that depletion of Tet1 in mESCs led to a reduction in 5hmC and the expression levels of genes involved in maintaining the pluripotent state with a simultaneous increase in the expression of genes known to induce differentiation. The study also goes on to show dependence of LIF/Stat3 signaling on Tet1.

The data support the hypothesis that an acute short-term depletion of Tet1 induces reduction in 5hmC, and uncovers a molecular mechanism by which Tet1 regulates the pluripotency state.

CitationFreudenberg JM, Ghosh S, Lackford BL, Yellaboina S, Zheng X, Li R, Cuddapah S, Wade PA, Hu G, Jothi R. 2011. Acute depletion of Tet1-dependent 5-hydroxymethylcytosine levels impairs LIF/Stat3 signaling and results in loss of embryonic stem cell identity. Nucleic Acids Res; doi:10.1093/nar/gkr1253 [Online 30 December 2011].

EET research may help in the fight against cancer

Researchers have found that the removal of small molecules produced in the body called epoxyeicosatrienoic acids (EETS) may prevent the formation of blood vessels that feed tumor cells. A collaborative team, made up of scientists from NIEHS and other institutions, made the discovery and published the findings in the Journal of Clinical Investigation. Their paper was also the first to demonstrate that EETs work with a protein known to induce blood vessel growth, called vascular endothelial growth factor (VEGF), to promote metastasis or the spread of cancer.

High levels of EETs are beneficial in patients with diseases, such as hypertension, heart attack, and stroke, because the molecules cause blood vessels to dilate. This action reduces the pressure in the vascular system, and protects against cell death. However, lots of EETs in the body also make tumor cells grow faster. To determine the role EETs played in cancer, the team developed four strains of mice, three with high levels of EETs and one with low levels of EETs.

The team determined that EETs in the healthy tissue surrounding the tumors activate blood vessel formation which feed the tumors. The mice with higher EETs also produced more metastatic tumors than the mice with lower EETs. These results have important implications for the development of new cancer therapies.

CitationPanigrahy D, Edin ML, Lee CR, Huang S, Bielenberg DR, Butterfield CE, Barnés CM, Mammoto A, Mammoto T, Luria A, Benny O, Chaponis DM, Dudley AC, Greene ER, Vergilio JA, Pietramaggiori G, Scherer-Pietramaggiori SS, Short SM, Seth M, Lih FB, Tomer KB, Yang J, Schwendener RA, Hammock BD, Falck JR, Manthati VL, Ingber DE, Kaipainen A, D'Amore PA, Kieran MW, Zeldin DC. 2012. Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. J Clin Invest 122(1):178-191. Story

Early-life soy exposure and gender-role play behavior in children

According to scientists from NIEHS and the University of North Carolina Gillings School of Global Public Health, early-life soy exposure is associated with play behavior that is less typically female in girls at 42 months of age. The team did not observe similar changes in boys. The work represents an important issue in children’s health, because soy-based infant formula contains isoflavones, estrogen-like compounds that can induce changes in gender-typical behavior in experimental animals if they are exposed to high doses at a young age.

In this study, scientists examined parents’ reports of gender-typical play behavior in 3,664 boys and 3,412 girls at 30, 42 and 57 months of age, in relation to their exposure to soy-based and non-soy-based infant feeding methods, categorized as primarily breast-fed, early formula-fed, early soy-fed, and late soy-fed.

While less feminine behavior was found in early soy-fed girls, defined as those introduced to soy at or before 4 months of age, the researchers emphasize that these girls were not outside the normal range for typical female behavior.  Additionally, this finding was not observed at 30 and 57 months, suggesting that the influence of an environmental factor, such as soy, may become more or less important over time.

CitationAdgent MA, Daniels JL, Edwards LJ, Siega-Riz AM, Rogan WJ. 2011. Early-life soy exposure and gender-role play behavior in children. Environ Health Perspect 119(12):1811-1816.

The role of CD103(+) dendritic cells in allergic lung inflammation

NIEHS researchers determined that a specific subset of dendritic cells (DC) expressing the integrin CD103, induces T helper type 2 (Th2) responses to inhaled allergens, such as cockroach antigen and allergens present in house dust extracts. This novel finding could lead to improved therapies for preventing allergic sensitization to common indoor allergens.

The researchers prepared DCs from lungs of allergen-treated mice and separated the cells into subsets based on their expression of specific cell surface markers. These purified DC subsets were then cultured with naïve, allergen-specific CD4(+) T cells. The results showed that CD103(+) cells primed Th2 differentiation, whereas a different DC subset, expressing CD11b, primed Th1 differentiation. Mice lacking CD103(+) dendritic cells showed substantially reduced allergic responses to inhaled allergens.

The results of this study demonstrate that CD103(+) dendritic cells play an essential role in inducing Th2 type immune response to inhaled allergens. The paper not only provides insight into the roles of the two subsets of resident lung dendritic cells in allergic inflammation, but it might also reveal novel opportunities to reduce the severity of allergic inflammation.

CitationNakano H, Free ME, Whitehead GS, Maruoka S, Wilson RH, Nakano K, Cook DN. 2012. Pulmonary CD103(+) dendritic cells prime Th2 responses to inhaled allergens. Mucosal Immunol 5(1):53-65.

(Sonika Patial, D.V.M., Ph.D., is a visiting fellow in the NIEHS Laboratory of Signal Transduction. Ian Thomas is a public affairs specialist with the NIEHS Office of Communications and Public Liaison, and a regular contributor to the Environmental Factor.)

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