scholarly journals Allele-specific open chromatin in human iPSC neurons elucidates functional non-coding disease variants

2019 ◽  
Author(s):  
Siwei Zhang ◽  
Hanwen Zhang ◽  
Min Qiao ◽  
Yifan Zhou ◽  
Siming Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Induced Pluripotent Stem Cell ◽  
Chromatin Accessibility ◽  
Adult Brain ◽  
Open Chromatin ◽  
Brain Disorders ◽  
Functional Interpretation ◽  
Allele Specific ◽  
Induced Pluripotent

AbstractFunctional interpretation of noncoding disease variants, which likely regulate gene expression, has been challenging. Chromatin accessibility strongly influences gene expression during neurodevelopment; however, to what extent genetic variants can alter chromatin accessibility in the context of brain disorders/traits is unknown. Using human induced pluripotent stem cell (iPSC)-derived neurons as a neurodevelopmental model, we identified abundant open-chromatin regions absent in adult brain samples and thousands of genetic variants exhibiting allele-specific open-chromatin (ASoC). ASoC variants are overrepresented in brain enhancers, transcription-factor-binding sites, and quantitative-trait-loci associated with gene expression, histone modification, and DNA methylation. Notably, compared to open chromatin regions and other commonly used functional annotations, neuronal ASoC variants showed much stronger enrichments of risk variants for various brain disorders/traits. Our study provides the first snapshot of the neuronal ASoC landscape and a powerful framework for prioritizing functional disease variants.One Sentence SummaryAllele-specific open chromatin informs functional disease variants

scholarly journals Allele-specific open chromatin in human iPSC neurons elucidates functional disease variants

Science ◽  
2020 ◽  
Vol 369 (6503) ◽  
pp. 561-565 ◽  
Author(s):  
Siwei Zhang ◽  
Hanwen Zhang ◽  
Yifan Zhou ◽  
Min Qiao ◽  
Siming Zhao ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Target Genes ◽  
Disease Risk ◽  
Induced Pluripotent Stem Cell ◽  
Open Chromatin ◽  
Regulatory Sequences ◽  
Functional Interpretation ◽  
Neuropsychiatric Disease ◽  
Risk Variants ◽  
Allele Specific

Most neuropsychiatric disease risk variants are in noncoding sequences and lack functional interpretation. Because regulatory sequences often reside in open chromatin, we reasoned that neuropsychiatric disease risk variants may affect chromatin accessibility during neurodevelopment. Using human induced pluripotent stem cell (iPSC)–derived neurons that model developing brains, we identified thousands of genetic variants exhibiting allele-specific open chromatin (ASoC). These neuronal ASoCs were partially driven by altered transcription factor binding, overrepresented in brain gene enhancers and expression quantitative trait loci, and frequently associated with distal genes through chromatin contacts. ASoCs were enriched for genetic variants associated with brain disorders, enabling identification of functional schizophrenia risk variants and their cis-target genes. This study highlights ASoC as a functional mechanism of noncoding neuropsychiatric risk variants, providing a powerful framework for identifying disease causal variants and genes.

scholarly journals Unique and assay specific features of NOMe-, ATAC- and DNase I-seq data

2019 ◽  
Vol 47 (20) ◽  
pp. 10580-10596 ◽  
Author(s):  
Karl J V Nordström ◽  
Florian Schmidt ◽  
Nina Gasparoni ◽  
Abdulrahman Salhab ◽  
Gilles Gasparoni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Experimental Design ◽  
Chromatin Accessibility ◽  
Dnase I ◽  
Open Chromatin ◽  
Functional Interpretation ◽  
Genome Wide ◽  
Show Evidence

Abstract Chromatin accessibility maps are important for the functional interpretation of the genome. Here, we systematically analysed assay specific differences between DNase I-seq, ATAC-seq and NOMe-seq in a side by side experimental and bioinformatic setup. We observe that most prominent nucleosome depleted regions (NDRs, e.g. in promoters) are roboustly called by all three or at least two assays. However, we also find a high proportion of assay specific NDRs that are often ‘called’ by only one of the assays. We show evidence that these assay specific NDRs are indeed genuine open chromatin sites and contribute important information for accurate gene expression prediction. While technically ATAC-seq and DNase I-seq provide a superb high NDR calling rate for relatively low sequencing costs in comparison to NOMe-seq, NOMe-seq singles out for its genome-wide coverage allowing to not only detect NDRs but also endogenous DNA methylation and as we show here genome wide segmentation into heterochromatic B domains and local phasing of nucleosomes outside of NDRs. In summary, our comparisons strongly suggest to consider assay specific differences for the experimental design and for generalized and comparative functional interpretations.

scholarly journals Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Michelle C Ward ◽  
Nicholas E Banovich ◽  
Abhishek Sarkar ◽  
Matthew Stephens ◽  
Yoav Gilad
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Induced Pluripotent Stem Cell ◽  
Chromatin Accessibility ◽  
Regulatory Changes ◽  
Life Threatening ◽  
Vitro Model ◽  
Culturing Conditions ◽  
Induced Pluripotent

One life-threatening outcome of cardiovascular disease is myocardial infarction, where cardiomyocytes are deprived of oxygen. To study inter-individual differences in response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We measured gene expression levels, chromatin accessibility, and methylation levels in four culturing conditions that correspond to normoxia, hypoxia, and short- or long-term re-oxygenation. We characterized thousands of gene regulatory changes as the cells transition between conditions. Using available genotypes, we identified 1,573 genes with a cis expression quantitative locus (eQTL) in at least one condition, as well as 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of genes with dynamic eQTLs is associated with complex traits and disease. Our data demonstrate how dynamic genetic effects on gene expression, which are likely relevant for disease, can be uncovered under stress.

scholarly journals Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes

2020 ◽  
Author(s):  
Michelle C. Ward ◽  
Nicholas E. Banovich ◽  
Abhishek Sarkar ◽  
Matthew Stephens ◽  
Yoav Gilad
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Induced Pluripotent Stem Cell ◽  
Chromatin Accessibility ◽  
Regulatory Changes ◽  
Life Threatening ◽  
Culturing Conditions ◽  
Induced Pluripotent

AbstractOne life-threatening outcome of cardiovascular disease is myocardial infarction, where cardiomyocytes are deprived of oxygen. To study inter-individual differences in response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We measured gene expression levels, chromatin accessibility, and methylation levels in four culturing conditions that correspond to normoxia, hypoxia and short or long-term re-oxygenation. We characterized thousands of gene regulatory changes as the cells transition between conditions. Using available genotypes, we identified 1,573 genes with a cis expression quantitative locus (eQTL) in at least one condition, as well as 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of genes with dynamic eQTLs is associated with complex traits and disease. Our data demonstrate how dynamic genetic effects on gene expression, which are likely relevant for disease, can be uncovered under stress.

scholarly journals Unique and assay specific features of NOMe-, ATAC- and DNase I-seq data

2019 ◽  
Author(s):  
Karl JV Nordström ◽  
Florian Schmidt ◽  
Nina Gasparoni ◽  
Abdulrahman Salhab ◽  
Gilles Gasparoni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Chromatin Accessibility ◽  
Dnase I ◽  
Open Chromatin ◽  
Functional Interpretation ◽  
Genome Wide ◽  
Show Evidence

AbstractChromatin accessibility maps are important for the functional interpretation of the genome. Here, we systematically analysed assay specific differences between DNase I-Seq, ATAC-Seq and NOMe-Seq in a side by side experimental and bioinformatic setup. We observe that most prominent nucleosome depleted regions (NDRs, e.g. in promoters) are roboustly called by all three or at least two assays. However we also find a high proportion of assay specific NDRs that are often “called” by only one of the assays. We show evidence that these assay specific NDRs are indeed genuine open chromatin sites and contribute important information for accurate gene expression prediction. While technically ATAC-Seq and DNAse I-Seq provide a high NDR calling rate for relatively low sequencing costs in comparison to NOMe-Seq, NOMe-Seq singles out as it provides a multitude of information: it allows to not only detect NDRs but also endogenous DNA methylation, genome wide segmentation into heterochromatic A/B domains and local phasing of nucleosomes outside of NDRs. In summary our comparison strongly suggest to consider assay specific differences for the experimental desgin and for generalized and comparative functional interpretations.

scholarly journals Human Induced Pluripotent Stem Cell-derived Hepatocyte-like Cells Provide Insights on Parenteral Nutrition Associated Cholestasis in the Immature Liver

2021 ◽  
Author(s):  
T. Hang Nghiem-Rao ◽  
Courtney Pfeifer ◽  
Michelle Asuncion ◽  
Joshua Nord ◽  
Daniel Schill ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Bile Acid ◽  
Parenteral Nutrition ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Computational Techniques ◽  
Adult Liver ◽  
Induced Pluripotent ◽  
The Impact

Abstract Parenteral nutrition-associated cholestasis (PNAC) significantly limits the safety of intravenous parenteral nutrition (PN). Critically ill infants are highly vulnerable to PNAC-related morbidity and mortality, however the impact of hepatic immaturity on PNAC is poorly understood. We examined developmental differences between fetal/infant and adult livers, and used human induced pluripotent stem cell-derived hepatocyte-like cells (iHLC) to gain insights into the contribution of development to altered sterol metabolism and PNAC. We used RNA-sequencing and computational techniques to compare gene expression patterns in human fetal/infant livers, adult liver, and iHLC. We identified distinct gene expression profiles between the human feta/infant livers compared to adult liver, and close resemblance of iHLC to human developing livers. Compared to adult, both developing livers and iHLC had significant downregulation of xenobiotic, bile acid, and fatty acid metabolism; and lower expression of the sterol metabolizing gene ABCG8. When challenged with stigmasterol, a plant sterol found in intravenous soy lipids, lipid accumulation was significantly higher in iHLC compared to adult-derived HepG2 cells. Our findings provide insights into altered bile acid and lipid metabolizing processes in the immature human liver, and support the use of iHLC as a relevant model system of developing liver to study lipid metabolism and PNAC.

scholarly journals Batch effects and the effective design of single-cell gene expression studies

2016 ◽  
Author(s):  
Po-Yuan Tung ◽  
John D. Blischak ◽  
Chiaowen Joyce Hsiao ◽  
David A. Knowles ◽  
Jonathan E. Burnett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Induced Pluripotent Stem Cell ◽  
Expression Levels ◽  
Amplification Bias ◽  
Expression Studies ◽  
Cell Gene Expression ◽  
Gene Expression Studies ◽  
Induced Pluripotent ◽  
Gene Expression Levels

AbstractSingle cell RNA sequencing (scRNA-seq) can be used to characterize variation in gene expression levels at high resolution. However, the sources of experimental noise in scRNA-seq are not yet well understood. We investigated the technical variation associated with sample processing using the single cell Fluidigm C1 platform. To do so, we processed three C1 replicates from three human induced pluripotent stem cell (iPSC) lines. We added unique molecular identifiers (UMIs) to all samples, to account for amplification bias. We found that the major source of variation in the gene expression data was driven by genotype, but we also observed substantial variation between the technical replicates. We observed that the conversion of reads to molecules using the UMIs was impacted by both biological and technical variation, indicating that UMI counts are not an unbiased estimator of gene expression levels. Based on our results, we suggest a framework for effective scRNA-seq studies.

scholarly journals A computational model of induced pluripotent stem-cell derived cardiomyocytes for high throughput risk stratification of KCNQ1 genetic variants

2020 ◽  
Vol 16 (8) ◽  
pp. e1008109 ◽  
Author(s):  
Divya C. Kernik ◽  
Pei-Chi Yang ◽  
Junko Kurokawa ◽  
Joseph C. Wu ◽  
Colleen E. Clancy
Keyword(s):  
Stem Cell ◽  
Risk Stratification ◽  
Computational Model ◽  
High Throughput ◽  
Genetic Variants ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Induced Pluripotent

scholarly journals Reporter-Based Isolation of Induced Pluripotent Stem Cell– and Embryonic Stem Cell–Derived Cardiac Progenitors Reveals Limited Gene Expression Variance

2010 ◽  
Vol 107 (3) ◽  
pp. 340-347 ◽  
Author(s):  
Linda W. van Laake ◽  
Li Qian ◽  
Paul Cheng ◽  
Yu Huang ◽  
Edward C. Hsiao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Pluripotent Stem Cell ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Cardiac Progenitors ◽  
Induced Pluripotent ◽  
Expression Variance
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