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  1. Article ; Online: SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

    Matteo D’Antonio / Jennifer P. Nguyen / Timothy D. Arthur / Hiroko Matsui / Agnieszka D’Antonio-Chronowska / Kelly A. Frazer

    Cell Reports, Vol 39, Iss 11, Pp 110968- (2022)

    2022  

    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

    Matteo D’Antonio / Jennifer P. Nguyen / Timothy D. Arthur / Hiroko Matsui / Agnieszka D’Antonio-Chronowska / Kelly A. Frazer

    Cell Reports, Vol 37, Iss 7, Pp 110020- (2021)

    2021  

    Abstract: Summary: Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease ... ...

    Abstract Summary: Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types.
    Keywords COVID-19 ; SARS-CoV-2 ; GWAS ; eQTL ; colocalization ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Two iPSC lines generated from the bone marrow of a relapsed/refractory AML patient display normal karyotypes and myeloid differentiation potential

    Amanda E. Yamasaki / Nicholas E. King / Hiroko Matsui / Kristen Jepsen / Athanasia D. Panopoulos

    Stem Cell Research, Vol 41, Iss , Pp - (2019)

    2019  

    Abstract: Using iPSCs to study cancer has been complicated by the fact that many cancer cells are difficult to reprogram, which has been attributed to the genomic abnormalities present. Acute Myeloid Leukemia (AML) is a complex disease that presents with various ... ...

    Abstract Using iPSCs to study cancer has been complicated by the fact that many cancer cells are difficult to reprogram, which has been attributed to the genomic abnormalities present. Acute Myeloid Leukemia (AML) is a complex disease that presents with various types of genomic aberrations that affect prognosis. Here we reprogrammed CD34+ cells from an AML patient containing a rare der(7)t(7;13) translocation associated with poor prognosis, who had relapsed and was refractory to current treatments. The generated AML-iPSCs displayed normal karyotypes and myeloid differentiation potential. These findings have implications for modeling and treating AML disease. Keywords: Acute Myeloid Leukemia, Bone marrow cells, Disease modeling, Reprogramming, Induced pluripotent stem cells
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2019-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk

    Jennifer P. Nguyen / Timothy D. Arthur / Kyohei Fujita / Bianca M. Salgado / Margaret K. R. Donovan / iPSCORE Consortium / Hiroko Matsui / Ji Hyun Kim / Agnieszka D’Antonio-Chronowska / Matteo D’Antonio / Kelly A. Frazer

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 22

    Abstract: Abstract The impact of genetic regulatory variation active in early pancreatic development on adult pancreatic disease and traits is not well understood. Here, we generate a panel of 107 fetal-like iPSC-derived pancreatic progenitor cells (iPSC-PPCs) ... ...

    Abstract Abstract The impact of genetic regulatory variation active in early pancreatic development on adult pancreatic disease and traits is not well understood. Here, we generate a panel of 107 fetal-like iPSC-derived pancreatic progenitor cells (iPSC-PPCs) from whole genome-sequenced individuals and identify 4065 genes and 4016 isoforms whose expression and/or alternative splicing are affected by regulatory variation. We integrate eQTLs identified in adult islets and whole pancreas samples, which reveal 1805 eQTL associations that are unique to the fetal-like iPSC-PPCs and 1043 eQTLs that exhibit regulatory plasticity across the fetal-like and adult pancreas tissues. Colocalization with GWAS risk loci for pancreatic diseases and traits show that some putative causal regulatory variants are active only in the fetal-like iPSC-PPCs and likely influence disease by modulating expression of disease-associated genes in early development, while others with regulatory plasticity likely exert their effects in both the fetal and adult pancreas by modulating expression of different disease genes in the two developmental stages.
    Keywords Science ; Q
    Subject code 610
    Language English
    Publishing date 2023-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: In heart failure reactivation of RNA-binding proteins is associated with the expression of 1,523 fetal-specific isoforms.

    Matteo D'Antonio / Jennifer P Nguyen / Timothy D Arthur / Hiroko Matsui / Margaret K R Donovan / Agnieszka D'Antonio-Chronowska / Kelly A Frazer

    PLoS Computational Biology, Vol 18, Iss 2, p e

    2022  Volume 1009918

    Abstract: Reactivation of fetal-specific genes and isoforms occurs during heart failure. However, the underlying molecular mechanisms and the extent to which the fetal program switch occurs remains unclear. Limitations hindering transcriptome-wide analyses of ... ...

    Abstract Reactivation of fetal-specific genes and isoforms occurs during heart failure. However, the underlying molecular mechanisms and the extent to which the fetal program switch occurs remains unclear. Limitations hindering transcriptome-wide analyses of alternative splicing differences (i.e. isoform switching) in cardiovascular system (CVS) tissues between fetal, healthy adult and heart failure have included both cellular heterogeneity across bulk RNA-seq samples and limited availability of fetal tissue for research. To overcome these limitations, we have deconvoluted the cellular compositions of 996 RNA-seq samples representing heart failure, healthy adult (heart and arteria), and fetal-like (iPSC-derived cardiovascular progenitor cells) CVS tissues. Comparison of the expression profiles revealed that reactivation of fetal-specific RNA-binding proteins (RBPs), and the accompanied re-expression of 1,523 fetal-specific isoforms, contribute to the transcriptome differences between heart failure and healthy adult heart. Of note, isoforms for 20 different RBPs were among those that reverted in heart failure to the fetal-like expression pattern. We determined that, compared with adult-specific isoforms, fetal-specific isoforms encode proteins that tend to have more functions, are more likely to harbor RBP binding sites, have canonical sequences at their splice sites, and contain typical upstream polypyrimidine tracts. Our study suggests that compared with healthy adult, fetal cardiac tissue requires stricter transcriptional regulation, and that during heart failure reversion to this stricter transcriptional regulation occurs. Furthermore, we provide a resource of cardiac developmental stage-specific and heart failure-associated genes and isoforms, which are largely unexplored and can be exploited to investigate novel therapeutics for heart failure.
    Keywords Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: An iPSC line derived from a human acute myeloid leukemia cell line (HL-60-iPSC) retains leukemic abnormalities and displays myeloid differentiation defects

    Amanda E. Yamasaki / Jane N. Warshaw / Beverly L. Kyalwazi / Hiroko Matsui / Kristen Jepsen / Athanasia D. Panopoulos

    Stem Cell Research, Vol 49, Iss , Pp 102096- (2020)

    2020  

    Abstract: Cancer-derived iPSCs have provided valuable insight into oncogenesis, but human cancer cells can often be difficult to reprogram, especially in cases of complex genetic abnormalities. Here we report, to our knowledge, the first successful generation of ... ...

    Abstract Cancer-derived iPSCs have provided valuable insight into oncogenesis, but human cancer cells can often be difficult to reprogram, especially in cases of complex genetic abnormalities. Here we report, to our knowledge, the first successful generation of an iPSC line from a human immortalized acute myeloid leukemia (AML) cell line, the cell line HL-60. This iPSC line retains a majority of the leukemic genotype and displays defects in myeloid differentiation, thus providing a tool for modeling and studying AML.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Subtle changes in chromatin loop contact propensity are associated with differential gene regulation and expression

    William W. Greenwald / He Li / Paola Benaglio / David Jakubosky / Hiroko Matsui / Anthony Schmitt / Siddarth Selvaraj / Matteo D’Antonio / Agnieszka D’Antonio-Chronowska / Erin N. Smith / Kelly A. Frazer

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 17

    Abstract: It is currently unclear how quantitative changes in chromatin loop propensity contribute to differential gene regulation. Here, the authors use phased Hi-C, RNA-seq, and ChIP-seq to show that subtle changes in loop propensity associate with differential ... ...

    Abstract It is currently unclear how quantitative changes in chromatin loop propensity contribute to differential gene regulation. Here, the authors use phased Hi-C, RNA-seq, and ChIP-seq to show that subtle changes in loop propensity associate with differential gene regulation across cell types and haplotypes.
    Keywords Science ; Q
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Subtle changes in chromatin loop contact propensity are associated with differential gene regulation and expression

    William W. Greenwald / He Li / Paola Benaglio / David Jakubosky / Hiroko Matsui / Anthony Schmitt / Siddarth Selvaraj / Matteo D’Antonio / Agnieszka D’Antonio-Chronowska / Erin N. Smith / Kelly A. Frazer

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 17

    Abstract: It is currently unclear how quantitative changes in chromatin loop propensity contribute to differential gene regulation. Here, the authors use phased Hi-C, RNA-seq, and ChIP-seq to show that subtle changes in loop propensity associate with differential ... ...

    Abstract It is currently unclear how quantitative changes in chromatin loop propensity contribute to differential gene regulation. Here, the authors use phased Hi-C, RNA-seq, and ChIP-seq to show that subtle changes in loop propensity associate with differential gene regulation across cell types and haplotypes.
    Keywords Science ; Q
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Systematic genetic analysis of the MHC region reveals mechanistic underpinnings of HLA type associations with disease

    Matteo D'Antonio / Joaquin Reyna / David Jakubosky / Margaret KR Donovan / Marc-Jan Bonder / Hiroko Matsui / Oliver Stegle / Naoki Nariai / Agnieszka D'Antonio-Chronowska / Kelly A Frazer

    eLife, Vol

    2019  Volume 8

    Abstract: The MHC region is highly associated with autoimmune and infectious diseases. Here we conduct an in-depth interrogation of associations between genetic variation, gene expression and disease. We create a comprehensive map of regulatory variation in the ... ...

    Abstract The MHC region is highly associated with autoimmune and infectious diseases. Here we conduct an in-depth interrogation of associations between genetic variation, gene expression and disease. We create a comprehensive map of regulatory variation in the MHC region using WGS from 419 individuals to call eight-digit HLA types and RNA-seq data from matched iPSCs. Building on this regulatory map, we explored GWAS signals for 4083 traits, detecting colocalization for 180 disease loci with eQTLs. We show that eQTL analyses taking HLA type haplotypes into account have substantially greater power compared with only using single variants. We examined the association between the 8.1 ancestral haplotype and delayed colonization in Cystic Fibrosis, postulating that downregulation of RNF5 expression is the likely causal mechanism. Our study provides insights into the genetic architecture of the MHC region and pinpoints disease associations that are due to differential expression of HLA genes and non-HLA genes.
    Keywords major histocompatibility complex ; eQTLs ; gene expression ; HLA types ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2019-11-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Human iPSC-Derived Retinal Pigment Epithelium

    Erin N. Smith / Agnieszka D'Antonio-Chronowska / William W. Greenwald / Victor Borja / Lana R. Aguiar / Robert Pogue / Hiroko Matsui / Paola Benaglio / Shyamanga Borooah / Matteo D'Antonio / Radha Ayyagari / Kelly A. Frazer

    Stem Cell Reports, Vol 12, Iss 6, Pp 1342-

    A Model System for Prioritizing and Functionally Characterizing Causal Variants at AMD Risk Loci

    2019  Volume 1353

    Abstract: Summary: We evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated ...

    Abstract Summary: We evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they have morphological and molecular characteristics similar to those of native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observed high similarity in gene expression and enriched transcription factor motif profiles between iPSC-RPE and human fetal RPE. We performed fine mapping of AMD risk loci by integrating molecular data from the iPSC-RPE, adult retina, and adult RPE, which identified rs943080 as the probable causal variant at VEGFA. We show that rs943080 is associated with altered chromatin accessibility of a distal ATAC-seq peak, decreased overall gene expression of VEGFA, and allele-specific expression of a non-coding transcript. Our study thus provides a potential mechanism underlying the association of the VEGFA locus with AMD. : Smith, D'Antonio-Chronowska, and colleagues integrate newly generated epigenetic and transcriptomic data from iPSC-derived retinal pigment epithelium with data from adult samples to prioritize potential causal variants associated with age-related macular degeneration. They prioritize rs943080 at the VEGFA locus and show that the risk allele may reduce VEGFA gene expression by altering activity of a distal regulatory region. Keywords: induced pluripotent stem cells, retinal pigment epithelium, age-related macular degeneration, VEGFA, chromatin accessibility, fine mapping, regulatory variants, genome-wide association, iPSC-RPE
    Keywords Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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