Noninvasive in vivo monitoring of tissue-specific global gene expression in humans

Koh, Winston; Pan, Wenying; Gawad, Charles; Fan, H. Christina; Kerchner, Geoffrey A.; Wyss‐Coray, Tony; Blumenfeld, Yair J.; El‐Sayed, Yasser Y.; Quake, Stephen R.

doi:10.1073/pnas.1405528111

Cited by 276 publications

(278 citation statements)

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“…Previous maternal plasma transcriptomic profiling studies have shown that certain trophoblast-specific transcripts and the overall fractional placental contribution increase with gestation (20,39,40). The fraction of fetal-derived RNA increases from only 3.7% in early pregnancy to 11.28% in late pregnancy (19,20).…”

Section: Noninvasive Elucidation Of Placental Cellular Dynamics Durinmentioning

confidence: 95%

“…Significantly elevated levels of total cell-free DNA and selected placenta-specific RNA transcripts have also been reported in the maternal plasma of women with PE (8)(9)(10)(11), restricted fetal growth (12), and preterm birth (13)(14)(15), supporting a role for cell-free nucleic acids as a noninvasive tool for placental monitoring. Previous studies have attempted to provide a comprehensive assessment of maternal plasma nucleic acids by microarray analysis, massively parallel transcriptomic, or methylomic sequencing (16)(17)(18)(19)(20)(21)(22). Several groups have explored the use of fetal-specific DNA polymorphisms, organ-specific DNA methylation (21), nucleosome footprinting (23), DNA fragmentation patterns (24), and tissuespecific RNA transcripts (19,20) to isolate the placental signal in the pool of circulating cell-free fetal nucleic acids and obtain changes of overall placental contribution.…”

mentioning

confidence: 99%

“…Previous studies have attempted to provide a comprehensive assessment of maternal plasma nucleic acids by microarray analysis, massively parallel transcriptomic, or methylomic sequencing (16)(17)(18)(19)(20)(21)(22). Several groups have explored the use of fetal-specific DNA polymorphisms, organ-specific DNA methylation (21), nucleosome footprinting (23), DNA fragmentation patterns (24), and tissuespecific RNA transcripts (19,20) to isolate the placental signal in the pool of circulating cell-free fetal nucleic acids and obtain changes of overall placental contribution. Nevertheless, these…”

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confidence: 99%

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Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics

Tsang

Vong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

259

267

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The human placenta is a dynamic and heterogeneous organ critical in the establishment of the fetomaternal interface and the maintenance of gestational well-being. It is also the major source of cell-free fetal nucleic acids in the maternal circulation. Placental dysfunction contributes to significant complications, such as preeclampsia, a potentially lethal hypertensive disorder during pregnancy. Previous studies have identified significant changes in the expression profiles of preeclamptic placentas using whole-tissue analysis. Moreover, studies have shown increased levels of targeted RNA transcripts, overall and placental contributions in maternal cell-free nucleic acids during pregnancy progression and gestational complications, but it remains infeasible to noninvasively delineate placental cellular dynamics and dysfunction at the cellular level using maternal cell-free nucleic acid analysis. In this study, we addressed this issue by first dissecting the cellular heterogeneity of the human placenta and defined individual cell-type-specific gene signatures by analyzing more than 24,000 nonmarker selected cells from full-term and early preeclamptic placentas using large-scale microfluidic single-cell transcriptomic technology. Our dataset identified diverse cellular subtypes in the human placenta and enabled reconstruction of the trophoblast differentiation trajectory. Through integrative analysis with maternal plasma cell-free RNA, we resolved the longitudinal cellular dynamics of hematopoietic and placental cells in pregnancy progression. Furthermore, we were able to noninvasively uncover the cellular dysfunction of extravillous trophoblasts in early preeclamptic placentas. Our work showed the potential of integrating transcriptomic information derived from single cells into the interpretation of cell-free plasma RNA, enabling the noninvasive elucidation of cellular dynamics in complex pathological conditions. single-cell transcriptomics | cell-free RNA | noninvasive prenatal testing | placenta | preeclampsia

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Section: Noninvasive Elucidation Of Placental Cellular Dynamics Durinmentioning

confidence: 95%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics

Tsang

Vong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

259

267

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“…Researchers have shown that such an approach is possible 12,13 . In 2014, for example, Quake's team examined blood samples from pregnant women using RNA-seq, in combination with other methods, to detect RNAs that probably originated in the fetus and placenta 12 .…”

Section: Full Transcriptmentioning

confidence: 99%

“…In 2014, for example, Quake's team examined blood samples from pregnant women using RNA-seq, in combination with other methods, to detect RNAs that probably originated in the fetus and placenta 12 . They could track the ebbs and flows of transcripts through all three trimesters, including the activity of genes that are crucial for normal brain development.…”

Section: Full Transcriptmentioning

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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Whole‐Genome Promoter Profiling of Plasma DNA Exhibits Diagnostic Value for Placenta‐Origin Pregnancy Complications

et al. 2020

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Placenta‐origin pregnancy complications, including preeclampsia (PE), gestational diabetes mellitus (GDM), fetal growth restriction (FGR), and macrosomia (MA) are common occurrences in pregnancy, resulting in significant morbidity and mortality for both mother and fetus. However, despite their frequency, there are no reliable methods for the early diagnosis of these complications. Since cfDNA is mainly derived from placental trophoblasts and maternal hematopoietic cells, it might have information for gene expression which can be used for disease prediction. Here, low coverage whole‐genome sequencing on plasma DNA from 2,199 pregnancies is performed based on retrospective cohorts of 3,200 pregnant women. Read depth in the promoter regions is examined to define read‐depth distribution patterns of promoters for pregnancy complications and controls. Using machine learning methods, classifiers for predicting pregnancy complications are developed. Using these classifiers, complications are successfully predicted with an accuracy of 80.3%, 78.9%, 72.1%, and 83.0% for MA, FGR, GDM, and PE, respectively. The findings suggest that promoter profiling of cfDNA may be used as a biological biomarker for predicting pregnancy complications at early gestational age.

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Noninvasive in vivo monitoring of tissue-specific global gene expression in humans

Cited by 276 publications

References 57 publications

Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics

Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics

Secrets of life in a spoonful of blood

Whole‐Genome Promoter Profiling of Plasma DNA Exhibits Diagnostic Value for Placenta‐Origin Pregnancy Complications

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