Showing papers by "Marla J. Berry published in 2014"

Selenoproteins in nervous system development and function.

Abstract: Selenoproteins are a distinct class of proteins that are characterized by the co-translational incorporation of selenium (Se) in the form of the 21st amino acid selenocysteine. Selenoproteins provide a key defense against oxidative stress, as many of these proteins participate in oxidation-reduction reactions neutralizing reactive oxygen species, where selenocysteine residues act as catalytic sites. Many selenoproteins are highly expressed in the brain, and mouse knockout studies have determined that several are required for normal brain development. In parallel with these laboratory studies, recent reports of rare human cases with mutations in genes involved in selenoprotein biosynthesis have described individuals with an assortment of neurological problems that mirror those detailed in knockout mice. These deficits include impairments in cognition and motor function, seizures, hearing loss, and altered thyroid metabolism. Additionally, due to the fact that oxidative stress is a key feature of neurodegenerative disease, there is considerable interest in the therapeutic potential of selenium supplementation for human neurological disorders. Studies performed in cell culture and rodent models have demonstrated that selenium administration attenuates oxidative stress, prevents neurodegeneration, and counters cell signaling mechanisms known to be dysregulated in certain disease states. However, there is currently no definitive evidence in support of selenium supplementation to prevent and/or treat common neurological conditions in the general population. It appears likely that, in humans, supplementation with selenium may only benefit certain subpopulations, such as those that are either selenium-deficient or possess genetic variants that affect selenium metabolism.

Nonsense-mediated decay factors are involved in the regulation of selenoprotein mRNA levels during selenium deficiency.

Abstract: Selenoproteins contain the unique amino acid selenocysteine (Sec), which is encoded by the triplet UGA. Since UGA also serves as a stop codon, it has been postulated that selenoprotein mRNAs are targeted for degradation by the nonsense-mediated mRNA decay pathway (NMD). Several reports have observed a hierarchy of selenoprotein mRNA expression when selenium (Se) is limiting, whereby the abundance of certain transcripts decline while others do not. We sought to investigate the role of NMD in this hierarchical response that selenoprotein mRNAs exhibit to environmental Se status. Selenoprotein mRNAs were categorized as being predicted sensitive or resistant to NMD based on the requirements held by the current model. About half of the selenoprotein transcriptome was predicted to be sensitive to NMD and showed significant changes in mRNA abundance in response to cellular Se status. The other half that was predicted to be resistant to NMD did not respond to Se status. RNA immunoprecipitation with essential NMD factor UPF1 revealed that the mRNAs that were the most sensitive to Se status were also the most enriched on UPF1 during Se deficiency. Furthermore, depletion of SMG1, the kinase responsible for UPF1 phosphorylation and NMD activation, abrogated the decline in transcript abundance of Se-responsive transcripts. Lastly, mRNA decay rates of Se-responsive transcripts were altered upon the addition of Se to resemble the slower decay rates of nonresponsive transcripts. Taken together, these results present novel evidence in support of a crucial role for the NMD pathway in regulating selenoprotein mRNA levels when Se is limiting.

Genome-wide hypermethylation coupled with promoter hypomethylation in the chorioamniotic membranes of early onset pre-eclampsia

Abstract: Pre-eclampsia is the leading cause of fetal and maternal morbidity and mortality. Early onset pre-eclampsia (EOPE) is a disorder that has severe maternal and fetal outcomes, whilst its etiology is poorly understood. We hypothesize that epigenetics plays an important role to mediate the development of EOPE and conducted a case-control study to compare the genome-wide methylome difference between chorioamniotic membranes from 30 EOPE and 17 full-term pregnancies using the Infinium Human Methylation 450 BeadChip arrays. Bioinformatics analysis tested differential methylation (DM) at CpG site level, gene level, and pathway and network level. A striking genome-wide hypermethylation pattern coupled with hypomethylation in promoters was observed. Out of 385 184 CpG sites, 9995 showed DM (2.6%). Of those DM sites, 91.9% showed hypermethylation (9186 of 9995). Over 900 genes had DM associated with promoters. Promoter-based DM analysis revealed that genes in canonical cancer-related pathways such as Rac, Ras, PI3K/Akt, NFκB and ErBB4 were enriched, and represented biological functional alterations that involve cell cycle, apoptosis, cancer signaling and inflammation. A group of genes previously found to be up-regulated in pre-eclampsia, including GRB2, ATF3, NFKB2, as well as genes in proteasome subunits (PSMA1, PMSE1, PSMD1 and PMSD8), harbored hypomethylated promoters. Contrarily, a cluster of microRNAs, including mir-519a1, mir-301a, mir-487a, mir-185, mir-329, mir-194, mir-376a1, mir-486 and mir-744 were all hypermethylated in their promoters in the EOPE samples. These findings collectively reveal new avenues of research regarding the vast epigenetic modifications in EOPE.

Isoform-specific Binding of Selenoprotein P to the -Propeller Domain of Apolipoprotein E Receptor 2 Mediates

Abstract: Background: ApoER2 facilitates uptake of Sepp1, but the binding mechanism has not been elucidated. Results: The two longest isoforms of Sepp1 bind to the YWTD β-propeller domain of apoER2, which functions as a Sepp1 receptor. Conclusion: Only longer Sepp1 isoforms with six or more selenocysteine residues can interact with a unique binding site of apoER2. Significance: ApoER2 takes up long isoform Sepp1 through its YWTD β-propeller domain. Sepp1 supplies selenium to tissues via receptor-mediated endocytosis. Mice, rats, and humans have 10 selenocysteines in Sepp1, which are incorporated via recoding of the stop codon, UGA. Four isoforms of rat Sepp1 have been identified, including full-length Sepp1 and three others, which terminate at the second, third, and seventh UGA codons. Previous studies have shown that the longer Sepp1 isoforms bind to the low density lipoprotein receptor apoER2, but the mechanism remains unclear. To identify the essential residues for apoER2 binding, an in vitro Sepp1 binding assay was developed using different Sec to Cys substituted variants of Sepp1 produced in HEK293T cells. ApoER2 was found to bind the two longest isoforms. These results suggest that Sepp1 isoforms with six or more selenocysteines are taken up by apoER2. Furthermore, the C-terminal domain of Sepp1 alone can bind to apoER2. These results indicate that apoER2 binds to the Sepp1 C-terminal domain and does not require the heparin-binding site, which is located in the N-terminal domain. Site-directed mutagenesis identified three residues of Sepp1 that are necessary for apoER2 binding. Sequential deletion of extracellular domains of apoER2 surprisingly identified the YWTD β-propeller domain as the Sepp1 binding site. Finally, we show that apoER2 missing the ligand-binding repeat region, which can result from cleavage at a furin cleavage site present in some apoER2 isoforms, can act as a receptor for Sepp1. Thus, longer isoforms of Sepp1 with high selenium content interact with a binding site distinct from the ligand-binding domain of apoER2 for selenium delivery.

Seafood consumption and umbilical cord blood mercury concentrations in a multiethnic maternal and child health cohort.

Abstract: Background: Fish consumption is common among the cultures of Hawaii, and given public health attention to mercury exposure in pregnancy, it is important to better understand patterns of fish consumption and mercury in pregnancy. This study examined the influence of maternal fish consumption during pregnancy on umbilical cord mercury (Hg) concentrations in a multiethnic cohort of women in Hawaii. Methods: This secondary analysis of a prospective cohort pilot study examined antenatal seafood consumption and neonatal outcomes in Hawaii. The first 100 eligible women who consented were enrolled. After delivery, umbilical cord blood and a dietary survey were obtained. Results: Most women (86%) consumed seafood during the month prior to delivery. Overall, 9% of women consumed more than the recommended limit of 12 ounces/week. Seafood consumption varied significantly by ethnicity and income, with 30% of poor women consuming more than the recommended limit. Seafood consumption did not vary by age or education. Umbilical cord blood Hg levels were 5 μg/L or more in 44% of women. Filipina were significantly less likely to have elevated Hg levels compared with non- Filipina (p < .05). Mercury levels did not vary by other demographic characteristics. Women reporting consumption exceeding 12 ounces fish per week were significantly more likely to have cord blood Hg levels of 5 μg/L or more, but mean Hg concentrations were not significantly higher (6.1 ± 3.3 v 5.0 ± 3.7). The odds ratio for elevated Hg, however, was significant among seafood-consumers compared with non-consumers (5.7; 95% confidence interval: 1.2, 27.1). Conclusions: Despite Environmental Protection Agency (EPA) guidelines, a significant portion of pregnant women consumed more than the recommended amount of seafood, which was associated with race and income. Further, almost half of study participants had cord blood Hg concentrations at or exceeding 5 μg/L.