Large-Scale Profiling Reveals the Influence of Genetic Variation on Gene Expression in Human Induced Pluripotent Stem Cells.

Abstract:

:In this study, we used whole-genome sequencing and gene expression profiling of 215 human induced pluripotent stem cell (iPSC) lines from different donors to identify genetic variants associated with RNA expression for 5,746 genes. We were able to predict causal variants for these expression quantitative trait loci (eQTLs) that disrupt transcription factor binding and validated a subset of them experimentally. We also identified copy-number variant (CNV) eQTLs, including some that appear to affect gene expression by altering the copy number of intergenic regulatory regions. In addition, we were able to identify effects on gene expression of rare genic CNVs and regulatory single-nucleotide variants and found that reactivation of gene expression on the X chromosome depends on gene chromosomal position. Our work highlights the value of iPSCs for genetic association analyses and provides a unique resource for investigating the genetic regulation of gene expression in pluripotent cells.

journal_name

Cell Stem Cell

journal_title

Cell stem cell

authors

DeBoever C,Li H,Jakubosky D,Benaglio P,Reyna J,Olson KM,Huang H,Biggs W,Sandoval E,D'Antonio M,Jepsen K,Matsui H,Arias A,Ren B,Nariai N,Smith EN,D'Antonio-Chronowska A,Farley EK,Frazer KA

doi

10.1016/j.stem.2017.03.009

subject

Has Abstract

pub_date

2017-04-06 00:00:00

pages

533-546.e7

issue

4

eissn

1934-5909

issn

1875-9777

pii

S1934-5909(17)30080-2

journal_volume

20

pub_type

杂志文章
  • Out of Many, One: Computational Reconstruction of Mouse Skin using Single-Cell Transcriptomics.

    abstract::Mammalian skin is a complex and heterogeneous tissue with several distinct compartments and stem cell populations. Joost et al. (2016) now use single-cell RNaseq to comprehensively reconstruct this complexity, revealing spatial and pseudotemporal differences between transcriptional programs in distinct compartments an...

    journal_title:Cell stem cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.stem.2016.09.009

    authors: Chen JC,Christiano AM

    更新日期:2016-10-06 00:00:00

  • Cyclosporine H Overcomes Innate Immune Restrictions to Improve Lentiviral Transduction and Gene Editing In Human Hematopoietic Stem Cells.

    abstract::Innate immune factors may restrict hematopoietic stem cell (HSC) genetic engineering and contribute to broad individual variability in gene therapy outcomes. Here, we show that HSCs harbor an early, constitutively active innate immune block to lentiviral transduction that can be efficiently overcome by cyclosporine H ...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2018.10.008

    authors: Petrillo C,Thorne LG,Unali G,Schiroli G,Giordano AMS,Piras F,Cuccovillo I,Petit SJ,Ahsan F,Noursadeghi M,Clare S,Genovese P,Gentner B,Naldini L,Towers GJ,Kajaste-Rudnitski A

    更新日期:2018-12-06 00:00:00

  • Importing human pluripotent stem cell lines derived at another institution: tailoring review to ethical concerns.

    abstract::Stem cell researchers commonly use human pluripotent stem cell lines derived by other investigators. Researchers may use lines derived elsewhere, provided that their derivation met consensus core standards. Some types of derivation raise heightened levels of ethical concern and require greater scrutiny. To maintain pu...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2009.01.013

    authors: Lo B,Parham L,Broom C,Cedars M,Gates E,Giudice L,Halme DG,Hershon W,Kriegstein A,Kwok PY,Oberman M,Roberts C,Wagner R

    更新日期:2009-02-06 00:00:00

  • Interspecies nuclear transfer: implications for embryonic stem cell biology.

    abstract::Accessibility of human oocytes for research poses a serious ethical challenge to society. This fact categorically holds true when pursuing some of the most promising areas of research, such as somatic cell nuclear transfer and embryonic stem cell studies. One approach to overcoming this limitation is to use an oocyte ...

    journal_title:Cell stem cell

    pub_type: 杂志文章,评审

    doi:10.1016/j.stem.2007.10.009

    authors: Beyhan Z,Iager AE,Cibelli JB

    更新日期:2007-11-01 00:00:00

  • Multiple epigenetic modifiers induce aggressive viral extinction in extraembryonic endoderm stem cells.

    abstract::To prevent insertional mutagenesis arising from retroviral reactivation, cells of embryonic origin possess a unique capacity to silence retroviruses. Given the distinct modes of X chromosome inactivation between embryonic and extraembryonic lineages, we investigated paradigms of viral extinction. We show that trophect...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2010.03.014

    authors: Golding MC,Zhang L,Mann MR

    更新日期:2010-05-07 00:00:00

  • Wnt-related molecules and signaling pathway equilibrium in hematopoiesis.

    abstract::There is near consensus that Wnt family molecules establish important gradients within niches where hematopoietic stem cells (HSC) reside. We review recent papers suggesting that a delicate balance is required between competing Wnt ligands and corresponding signaling pathways to maintain HSC integrity. Some steps in t...

    journal_title:Cell stem cell

    pub_type: 杂志文章,评审

    doi:10.1016/j.stem.2008.12.004

    authors: Malhotra S,Kincade PW

    更新日期:2009-01-09 00:00:00

  • Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons.

    abstract::We have recently demonstrated that reactive glial cells can be directly reprogrammed into functional neurons by a single neural transcription factor, NeuroD1. Here we report that a combination of small molecules can also reprogram human astrocytes in culture into fully functional neurons. We demonstrate that sequentia...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2015.09.012

    authors: Zhang L,Yin JC,Yeh H,Ma NX,Lee G,Chen XA,Wang Y,Lin L,Chen L,Jin P,Wu GY,Chen G

    更新日期:2015-12-03 00:00:00

  • Putting Two Heads Together to Build a Better Brain.

    abstract::3D organoids enable in vitro human brain development models, but they have not yet recapitulated some essential features of brain circuit formation. Recently, several studies appearing in Nature, Nature Methods, and Cell Stem Cell generated fused organoid models of inhibitory and excitatory neuron development, which c...

    journal_title:Cell stem cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.stem.2017.08.017

    authors: Mich JK,Close JL,Levi BP

    更新日期:2017-09-07 00:00:00

  • Bringing a Leukemic Stem Cell Gene Signature into Clinics: Are We There Yet?

    abstract::Prognostic markers that capture leukemia stem cell (LSC) activity can be useful for the risk stratification of acute myeloid leukemia (AML) patients. In a recent issue of Nature, Ng et al. (2016) develop a prognostic score based on a 17-gene expression signature of LSCs to predict outcome in AML patients. ...

    journal_title:Cell stem cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.stem.2017.02.010

    authors: Richard-Carpentier G,Sauvageau G

    更新日期:2017-03-02 00:00:00

  • Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity.

    abstract::Several cell populations have been reported to possess intestinal stem cell (ISC) activity during homeostasis and injury-induced regeneration. Here, we explored inter-relationships between putative mouse ISC populations by comparative RNA-sequencing (RNA-seq). The transcriptomes of multiple cycling ISC populations clo...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2017.06.014

    authors: Yan KS,Gevaert O,Zheng GXY,Anchang B,Probert CS,Larkin KA,Davies PS,Cheng ZF,Kaddis JS,Han A,Roelf K,Calderon RI,Cynn E,Hu X,Mandleywala K,Wilhelmy J,Grimes SM,Corney DC,Boutet SC,Terry JM,Belgrader P,Ziraldo SB

    更新日期:2017-07-06 00:00:00

  • Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation.

    abstract::It has been proposed that human embryonic stem cells could be used to provide an inexhaustible supply of differentiated cell types for the study of disease processes. Although methods for differentiating embryonic stem cells into specific cell types have become increasingly sophisticated, the utility of the resulting ...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2008.09.017

    authors: Di Giorgio FP,Boulting GL,Bobrowicz S,Eggan KC

    更新日期:2008-12-04 00:00:00

  • Naive versus Primed: It's Now Three-Dimensional.

    abstract::We are only beginning to understand the higher-order chromatin structure of pluripotent stem cells and its relevance to cell fate. Three recent studies used different approaches to reconstruct the 3D chromatin landscape of naive and primed pluripotent cells, unveiling common features as well as differences between the...

    journal_title:Cell stem cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.stem.2016.01.014

    authors: Wei Z,Lu W

    更新日期:2016-02-04 00:00:00

  • Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming.

    abstract::Cellular reprogramming converts differentiated cells into induced pluripotent stem cells (iPSCs). However, this process is typically very inefficient, complicating mechanistic studies. We identified and molecularly characterized rare, early intermediates poised to reprogram with up to 95% efficiency, without perturbin...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2018.06.013

    authors: Schwarz BA,Cetinbas M,Clement K,Walsh RM,Cheloufi S,Gu H,Langkabel J,Kamiya A,Schorle H,Meissner A,Sadreyev RI,Hochedlinger K

    更新日期:2018-08-02 00:00:00

  • Dosage Counts: Correcting Trisomy-21-Related Phenotypes in Human Organoids and Xenografts.

    abstract::Studies in mice suggest that Olig2 gene dosage alters cerebral cortical interneuron development and contributes to trisomy-21/Down-syndrome-related intellectual disability. Xu et al. (2019) extend these studies through the remarkable use of cerebral organoid and human iPSC/mouse brain chimera experimental systems that...

    journal_title:Cell stem cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.stem.2019.05.009

    authors: Manley WF,Anderson SA

    更新日期:2019-06-06 00:00:00

  • ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation.

    abstract::The Adenomatous Polyposis Coli (APC) gene is mutated in the majority of colorectal cancers (CRCs). Loss of APC leads to constitutively active WNT signaling, hyperproliferation, and tumorigenesis. Identification of pathways that facilitate tumorigenesis after APC loss is important for therapeutic development. Here, we ...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2013.04.006

    authors: Myant KB,Cammareri P,McGhee EJ,Ridgway RA,Huels DJ,Cordero JB,Schwitalla S,Kalna G,Ogg EL,Athineos D,Timpson P,Vidal M,Murray GI,Greten FR,Anderson KI,Sansom OJ

    更新日期:2013-06-06 00:00:00

  • Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification.

    abstract::During embryonic development, multipotent cardiovascular progenitor cells are specified from early mesoderm. Using mouse ESCs in which gene expression can be temporally regulated, we have found that transient expression of Mesp1 dramatically accelerates and enhances multipotent cardiovascular progenitor specification ...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2008.06.009

    authors: Bondue A,Lapouge G,Paulissen C,Semeraro C,Iacovino M,Kyba M,Blanpain C

    更新日期:2008-07-03 00:00:00

  • Engineering stem cell expansion.

    abstract::In this issue of Cell Stem Cell, Csaszar et al. (2012) develop a culture method that overcomes current limitations in ex vivo hematopoietic stem/progenitor cell expansion by continuously diluting inhibitory signaling factors and maintaining stem cell density. This approach enhances the generation of precursors with po...

    journal_title:Cell stem cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.stem.2012.01.012

    authors: Bernstein ID,Delaney C

    更新日期:2012-02-03 00:00:00

  • CIRM Alpha Stem Cell Clinics: Collaboratively Addressing Regenerative Medicine Challenges.

    abstract::The California Institute for Regenerative Medicine (CIRM) Alpha Stem Cell Clinic (ASCC) Network was launched in 2015 to address a compelling unmet medical need for rigorous, FDA-regulated, stem cell-related clinical trials for patients with challenging, incurable diseases. Here, we describe our multi-center experience...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2018.05.007

    authors: Jamieson CHM,Millan MT,Creasey AA,Lomax G,Donohoe ME,Walters MC,Abedi M,Bota DA,Zaia JA,Adams JS

    更新日期:2018-06-01 00:00:00

  • Transient maternal IL-6 mediates long-lasting changes in neural stem cell pools by deregulating an endogenous self-renewal pathway.

    abstract::The mechanisms that regulate the establishment of adult stem cell pools during normal and perturbed mammalian development are still largely unknown. Here, we asked whether a maternal cytokine surge, which occurs during human maternal infections and has been implicated in cognitive disorders, might have long-lasting co...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2013.10.002

    authors: Gallagher D,Norman AA,Woodard CL,Yang G,Gauthier-Fisher A,Fujitani M,Vessey JP,Cancino GI,Sachewsky N,Woltjen K,Fatt MP,Morshead CM,Kaplan DR,Miller FD

    更新日期:2013-11-07 00:00:00

  • Translational control: a new dimension in embryonic stem cell network analysis.

    abstract::Systems biology studies have revealed transcriptional networks and proteomic signatures critical for embryonic stem cell (ESC) function. In this issue of Cell Stem Cell, Sampath et al. (2008) demonstrate that translation is also differentially controlled in undifferentiated versus differentiated ESCs. ...

    journal_title:Cell stem cell

    pub_type: 评论,杂志文章

    doi:10.1016/j.stem.2008.04.009

    authors: Chang WY,Stanford WL

    更新日期:2008-05-08 00:00:00

  • RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia.

    abstract::N6-methyladenosine (m6A), the most abundant internal modification in mRNA, has been implicated in tumorigenesis. As an m6A demethylase, ALKBH5 has been shown to promote the development of breast cancer and brain tumors. However, in acute myeloid leukemia (AML), ALKBH5 was reported to be frequently deleted, implying a ...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2020.04.009

    authors: Shen C,Sheng Y,Zhu AC,Robinson S,Jiang X,Dong L,Chen H,Su R,Yin Z,Li W,Deng X,Chen Y,Hu YC,Weng H,Huang H,Prince E,Cogle CR,Sun M,Zhang B,Chen CW,Marcucci G,He C,Qian Z,Chen J

    更新日期:2020-07-02 00:00:00

  • Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression.

    abstract::Tumors contain hostile inflammatory signals generated by aberrant proliferation, necrosis, and hypoxia. These signals are sensed and acted upon acutely by the Toll-like receptors (TLRs) to halt proliferation and activate an immune response. Despite the presence of TLR ligands within the microenvironment, tumors progre...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2016.12.001

    authors: Alvarado AG,Thiagarajan PS,Mulkearns-Hubert EE,Silver DJ,Hale JS,Alban TJ,Turaga SM,Jarrar A,Reizes O,Longworth MS,Vogelbaum MA,Lathia JD

    更新日期:2017-04-06 00:00:00

  • Genome Editing in hPSCs Reveals GATA6 Haploinsufficiency and a Genetic Interaction with GATA4 in Human Pancreatic Development.

    abstract::Human disease phenotypes associated with haploinsufficient gene requirements are often not recapitulated well in animal models. Here, we have investigated the association between human GATA6 haploinsufficiency and a wide range of clinical phenotypes that include neonatal and adult-onset diabetes using CRISPR (clustere...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2017.01.001

    authors: Shi ZD,Lee K,Yang D,Amin S,Verma N,Li QV,Zhu Z,Soh CL,Kumar R,Evans T,Chen S,Huangfu D

    更新日期:2017-05-04 00:00:00

  • Distinct self-renewal and differentiation phases in the niche of infrequently dividing hair follicle stem cells.

    abstract::In homeostasis of adult vertebrate tissues, stem cells are thought to self-renew by infrequent and asymmetric divisions that generate another stem cell daughter and a progenitor daughter cell committed to differentiate. This model is based largely on in vivo invertebrate or in vitro mammal studies. Here, we examine th...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2009.06.004

    authors: Zhang YV,Cheong J,Ciapurin N,McDermitt DJ,Tumbar T

    更新日期:2009-09-04 00:00:00

  • FOXO3-Engineered Human ESC-Derived Vascular Cells Promote Vascular Protection and Regeneration.

    abstract::FOXO3 is an evolutionarily conserved transcription factor that has been linked to longevity. Here we wanted to find out whether human vascular cells could be functionally enhanced by engineering them to express an activated form of FOXO3. This was accomplished via genome editing at two nucleotides in human embryonic s...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2018.12.002

    authors: Yan P,Li Q,Wang L,Lu P,Suzuki K,Liu Z,Lei J,Li W,He X,Wang S,Ding J,Chan P,Zhang W,Song M,Izpisua Belmonte JC,Qu J,Tang F,Liu GH

    更新日期:2019-03-07 00:00:00

  • p57(Kip2) and p27(Kip1) cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70.

    abstract::Cell cycle regulators play critical roles in the balance between hematopoietic stem cell (HSC) dormancy and proliferation. In this study, we report that cell cycle entry proceeded normally in HSCs null for cyclin-dependent kinase (CDK) inhibitor p57 due to compensatory upregulation of p27. HSCs null for both p57 and p...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2011.07.003

    authors: Zou P,Yoshihara H,Hosokawa K,Tai I,Shinmyozu K,Tsukahara F,Maru Y,Nakayama K,Nakayama KI,Suda T

    更新日期:2011-09-02 00:00:00

  • Single-Cell Transcriptomic Analyses of Cell Fate Transitions during Human Cardiac Reprogramming.

    abstract::Direct cellular reprogramming provides a powerful platform to study cell plasticity and dissect mechanisms underlying cell fate determination. Here, we report a single-cell transcriptomic study of human cardiac (hiCM) reprogramming that utilizes an analysis pipeline incorporating current data normalization methods, mu...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2019.05.020

    authors: Zhou Y,Liu Z,Welch JD,Gao X,Wang L,Garbutt T,Keepers B,Ma H,Prins JF,Shen W,Liu J,Qian L

    更新日期:2019-07-03 00:00:00

  • Erosion of dosage compensation impacts human iPSC disease modeling.

    abstract::Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear whether such variability impacts their utility for disease modeling. Here, we show that although low-passage female hiPSCs retain the inactive X chromosome of the somatic cell they are...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2012.02.014

    authors: Mekhoubad S,Bock C,de Boer AS,Kiskinis E,Meissner A,Eggan K

    更新日期:2012-05-04 00:00:00

  • Directed differentiation of human embryonic stem cells into functional retinal pigment epithelium cells.

    abstract::Dysfunction and loss of retinal pigment epithelium (RPE) leads to degeneration of photoreceptors in age-related macular degeneration and subtypes of retinitis pigmentosa. Human embryonic stem cells (hESCs) may serve as an unlimited source of RPE cells for transplantation in these blinding conditions. Here we show the ...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2009.07.002

    authors: Idelson M,Alper R,Obolensky A,Ben-Shushan E,Hemo I,Yachimovich-Cohen N,Khaner H,Smith Y,Wiser O,Gropp M,Cohen MA,Even-Ram S,Berman-Zaken Y,Matzrafi L,Rechavi G,Banin E,Reubinoff B

    更新日期:2009-10-02 00:00:00

  • Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro.

    abstract::The study of gastric epithelial homeostasis and cancer has been hampered by the lack of stem cell markers and in vitro culture methods. The Wnt target gene Lgr5 marks stem cells in the small intestine, colon, and hair follicle. Here, we investigated Lgr5 expression in the stomach and assessed the stem cell potential o...

    journal_title:Cell stem cell

    pub_type: 杂志文章

    doi:10.1016/j.stem.2009.11.013

    authors: Barker N,Huch M,Kujala P,van de Wetering M,Snippert HJ,van Es JH,Sato T,Stange DE,Begthel H,van den Born M,Danenberg E,van den Brink S,Korving J,Abo A,Peters PJ,Wright N,Poulsom R,Clevers H

    更新日期:2010-01-08 00:00:00