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Intramural Papers of the Month

By Laura Hall and Omari Bandele
March 2010

Reciprocal Epigenetic Modifications of Histone H2B in Apoptosis

NIEHS scientists have discovered that histone H2B in chromatin has two adjacent amino acids - serine at position 14 (S14) and lysine at position 15 (K15) -- that are epigenetically modified during apoptosis. In normal non-apoptotic cells, K15 is acetylated and there is little S14 phosphorylation. In apoptotic cells, however, there is a switch to deacetylation of K15 and phosphorylation of S14.

The researchers found that deacetylation of K15 is necessary to allow S14 phosphorylation and inhibiting K15 deacetylation inhibits internucleosomal DNA degradation -- the second of two major steps of DNA degradation during apoptosis.

Apoptosis plays a critical role in eliminating unhealthy cells from the body. Improperly controlled apoptosis can lead to diseases such as cancer if cells that should be eliminated remain, or neurodegenerative disorders if too many healthy cells are killed. During apoptosis, a programmed series of biochemical events in the cell leads to cell death -- with accompanying changes in cell structure. These changes include fragmentation of chromosomal DNA in the form of internucleosomal DNA degradation.

The authors had previously shown that H2B was phosphorylated at S14 during the induction of apoptosis. This study showed that the acetylation state of K15 regulates apoptosis-specific S14 phosphorylation.

Citation: Ajiro K, Scoltock AB, Smith LK, Ashasima M, Cidlowski JA. ( NIEHS 2010. Reciprocal epigenetic modification of histone H2B occurs in chromatin during apoptosis in vitro and in vivo. Cell Death Differ doi:10.1038/cdd2009.199 [Epub ahead of print].

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Obese Male Mice Have Reduced Fertility and Increased Sensitivity to Environmental Chemicals

Male mice, obese from eating a high-fat diet, have significantly reduced fertility and greater sensitivity to acrylamide (AA), a reproductive toxin, compared to their lean littermates. AA is a known carcinogen, mutagen, and neurotoxin, which is found in baked and fried carbohydrate-rich foods like potato chips, French fries, and bread.

Obesity is a global epidemic. Obese adults have an increased risk of heart disease, diabetes, cancer, and stroke. Studies have also suggested a relationship between obesity and human infertility.

NIEHS researchers compared fertility of male mice by mating males with control females. Female mice partnered with obese males showed lowered numbers of vaginal semen plugs indicating mating and pregnancies, one fifth as many as lean mice. Obese mice had sperm with decreased motility and reduced hyperactivated progression, an indicator of sperm viability and fertilization potential.

Both obese and lean mice treated with AA showed decreased fertility, but the deleterious effects of AA were greater in obese mice. This work suggested that obese men may be more susceptible to reproductive toxins and possibly other environmental chemicals.

NIEHS scientists also found that the obese mice had five-fold greater leptin and insulin levels and significant differences in the mRNA of several genes in their testes compared to lean mice - changes clearly indicative of diabetes in diet-induced obese mice.

Citation: Ghanayem BI, Bai R, Kissling GE, Travlos G, Hoffler U. ( NIEHS 2010. Diet-induced obesity in male mice is associated with reduced fertility and potentiation of acrylamide-induced reproductive toxicity. Biol Reprod 82(1):96-104.

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Acetaminophen-Induced Transcriptional Changes Predict Liver Injury

A collaborative research effort led by NIEHS scientists demonstrated that non-toxic doses of acetaminophen induce transcriptional changes in humans similar to those observed in overdose patients and rats exposed to toxic doses of the drug. These findings reveal potential biomarkers that may indicate early signs of drug-induced liver injury (DILI).

Acetaminophen is the most common cause of acute liver failure in the U.S. However, limitations in traditional clinical approaches have hampered the diagnosis of DILI. Paules and colleagues previously demonstrated in rats exposed to high doses of liver-damaging chemicals that transcriptional signatures in peripheral blood (PB) outperform traditional clinical markers in detecting the presence and severity of DILI.

The authors in the current study examined changes in human PB gene expression in response to a dose of acetaminophen that did not induce detectable levels of liver injury. They observed a distinct transcriptional signature - including downregulation of genes associated with oxidative phosphorylation - and metabolic changes that led to increased serum lactate levels.

The identification of acetaminophen-induced transcriptional and metabolic signatures in human PB may address the need for better biomarkers of DILI. These expression profiles may assist clinicians and provide more meaningful liver safety data in clinical trials of new drugs.

Citation: Fannin RD, Russo M, O'Connell TM, Gerrish K, Winnike JH, Macdonald J, et al. ( NIEHS 2010. Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation. Hepatology 51(1):227-236.

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Estrogen Receptor Enhances p53 Transcriptional Activity

Researchers from NIEHS have demonstrated that estrogen receptors (ER) can enhance the transcriptional activity of the p53 tumor suppressor by binding ER-specific sequences near p53-target sites. This study also reveals the ability of p53 to function at noncanonical sites - significantly expanding the p53 regulatory network.

p53 and ER are prominent sequence-specific transcription factors that directly regulate the expression of a variety of genes. p53-mediated transactivation involves binding to a well-defined consensus sequence composed of two decamers. Resnick and colleagues recently observed that within the promoter of the FLT gene, p53 could function at a noncanonical binding site in about 5 percent of the population, which contains only half the consensus sequence. In addition, transcriptional activity increased upon ER binding at a nearby site.

The authors further examined the generality of this p53/ER transactivation synergy by replacing the p53 site in the FLT promoter with a variety of canonical and noncanonical p53-target sequences. Luciferase reporter assays in human cancer cells revealed that p53 and ER could, indeed, cooperate to drive transactivation of p53-responsive sequences. The researchers also observed that ER displays a similar relationship with cancer-associated p53 mutants and other p53 family members, p63 and p73.

The identification of sequence-specific transcription factors that enhance p53 transactivation activity encourages further studies to identify additional transcription factors that modulate p53-mediated gene expression and suggests new roles for estrogen in p53-mediated human stress responses.

Citation: Menendez D, Inga A, Resnick MA. ( NIEHS 2010. Estrogen receptor acting in cis enhances WT and mutant p53 transactivation at canonical and noncanonical p53 target sequences. Proc Natl Acad Sci USA 107(4):1500-1505.

(Laura Hall is a biologist in the NIEHS Laboratory of Pharmacology currently on detail as a writer for the Environmental Factor. Omari J. Bandele, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Environmental Genomics Group.)

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