Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses

Slonim, Donna K.; Koide, Kazunori; Johnson, Kirby L.; Tantravahi, Umadevi; Cowan, Janet M.; Jarrah, Zina; Bianchi, Diana W.

doi:10.1073/pnas.0903909106

Cited by 111 publications

(159 citation statements)

References 46 publications

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“…Alterations in chromosome number, particularly trisomy 21, have been associated with elevated mitochondrial ROS, oxidative damage, diminished metabolism, and compromised resilience (Busciglio & Yankner, 1995; Coskun et al, 2016; Slonim et al, 2009; Zis et al, 2012) Here, we show that human DS HF and mouse Dp16 MEF display compromised mitochondrial function, oxidative stress, and activated Nrf2 antioxidant response. Furthermore, our results demonstrate that sustained Nrf2 stabilization is vital to maintain cell function in both DS and Dp16.…”

Section: Discussionmentioning

confidence: 49%

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Zamponi

Coşkun

et al. 2018

Aging Cell

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SummaryMounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2‐mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCδdependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria‐targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2‐mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial‐specific interventions as a key aspect of antioxidant and antiaging therapies.

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Section: Discussionmentioning

confidence: 49%

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Zamponi

Coşkun

et al. 2018

Aging Cell

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“…3). The RNA was extracted, amplified, labeled and hybridized to either the Affymetrix U133A expression microarray (Larrabee et al 2005) or the Affymetrix GeneChip Human Genome U133 Plus 2.0 expression microarray (Slonim et al 2009;Koide et al 2011;Hui et al 2012aHui et al ,b, 2013aEdlow et al 2014;Massingham et al 2014). Despite the availability of more sophisticated expression microarrays, the U133 Plus 2.0 was chosen because of the need for compatibility with an essential downstream in silico tool, the Connectivity Map (Lamb et al 2006).…”

Section: Methodsmentioning

confidence: 99%

“…In 2009, work from Slonim et al began to compare the development of second trimester fetuses with DS (caused by a full trisomy 21, T21) to that of healthy euploid fetuses (Slonim et al 2009). Expression microarray studies revealed a set of genes significantly differentially regulated between the seven age-and sexmatched pairs of fetuses.…”

Section: Genetic Disorders: Down Syndromementioning

confidence: 99%

The Amniotic Fluid Transcriptome as a Guide to Understanding Fetal Disease

Zwemer

Bianchi

2015

Cold Spring Harbor Perspectives in Medicine

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Section: Full Transcriptmentioning

confidence: 99%

“…She finds that gene activity is abnormal across the whole genome, not just on the extra chromosome, and even in genes needed for brain development 9 . She's also found that cells of fetuses with Down's incur damage from the by-products of metabolism, a condition known as oxidative stress 10 .This raises the provocative possibility of treating fetuses in the womb to ameliorate the cognitive impairment associated with Down's. To explore this, Bianchi's team compared transcriptome data from fetuses …”

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confidence: 99%

Secrets of life in a spoonful of blood

Ainsworth¹

2017

Nature

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L ife starts with a puzzle. Out of sight in a mother's womb, 3 billion letters of DNA code somehow turn into 3D bodies, all in the space of a mere 40 weeks. Fetuses form eyes, brains, hearts, fingers and toes -in processes that are meticulously coordinated in both time and space. Biologists have pieced together parts of this puzzle, but many gaps remain. Now, a crop of molecular technologies is giving scientists tantalizing hints about how to fill in those gaps. Improved ways of reading and interpreting the information in fetal genetic material are uncovering a raft of genes involved in human development, and letting researchers eavesdrop on the hum of gene activity before birth. They can see which genes turn on or off at pivotal moments, and sense how the environment nurtures or intrudes on this.Even the vital life-support system that we jettison at birth -the Womb with a viewThe intricate development of the fetus is yielding its long-held secrets to stateof-the-art molecular technologies. © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . BY C L A I R E A I N S W O R T HILLUSTRATIONplacenta -is laying bare its secrets. "It really is this great mystery in reproduction, " says Zev Williams, a reproductive endocrinologist and infertility specialist at the Albert Einstein College of Medicine in New York City. "It's obviously such a critical part of human development, but it's been so understudied. " Until now, much of the work has relied on amniotic or placental samples obtained during routine invasive tests such as amniocentesis. But scientists are eyeing the next step: studies that are non-invasive for the fetus and are done on a teaspoonful of blood drawn from a pregnant woman's arm. In this way, researchers could monitor fetuses as they develop and, down the line, develop non-invasive tests for a broad range of conditions, in both fetus and mother.Physicians are already moving towards treating fetuses in the womb on the basis of such diagnoses. "It's an exciting time, " says Mark Kilby, a fetal-medicine specialist at the University of Birmingham, UK.But it won't be plain sailing. The technologies are developing so quickly that scientists are struggling to interpret the information they yield and are facing knotty ethical quandaries. What, for example, should doctors do if non-invasive prenatal testing (NIPT) reveals a DNA sequence that sometimes causes disease -but not always? "That is what we have to discuss as a whole community, " says clinician and geneticist Dennis Lo of the Chinese University of Hong Kong, who was the first to find fetal DNA in a mother's blood 1 . DEVELOPMENT WORKProbing fetal development starts, naturally enough, with DNA, the recipe for life. Developmental biologists have already gathered a trove of information here, through studies of laboratory animals from worms to mice, identifying many genes and processes that have human equivalents. Painstaking detective work on families with inherited gene...

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Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses

Cited by 111 publications

References 46 publications

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

The Amniotic Fluid Transcriptome as a Guide to Understanding Fetal Disease

Secrets of life in a spoonful of blood

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