Large, Diverse Population Cohorts of hiPSCs and Derived Hepatocyte-like Cells Reveal Functional Genetic Variation at Blood Lipid-Associated Loci

Pashos, Evanthia; Park, Yo Son; Wang, Xiao; Raghavan, Avanthi; Yang, Wenli; Abbey, Deepti; Peters, Derek T; Arbelaez, Juan David; Hernandez, Mayda; Kuperwasser, Nicolas; Li, Wenjun; Lian, Zhaorui; Liu, Ying; Lv, Wenjian; Lytle-Gabbin, Stacey L.; Marchadier, Dawn; Rogov, Peter; Shi, Jianting; Slovik, Katherine J.; Stylianou, Ioannis M.; Wang, Li; Yan, Ruilan; Zhang, Xiaolan; Kathiresan, Sekar; Duncan, Stephen A.; Mikkelsen, Tarjei S.; Morrisey, Edward E.; Rader, Daniel J.; Brown, Christopher D.; Musunuru, Kiran

doi:10.1016/j.stem.2017.03.017

Cited by 138 publications

(153 citation statements)

References 44 publications

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“…While iPSCs have been used to model a number of human diseases (Yagi et al 2011;Choi et al 2013;Liang et al 2013;Miller et al 2013;Aflaki et al 2014;Pashos et al 2017;Cayo et al 2017), there is a limited amount of work demonstrating their ability to model regulatory phenotypes Alasoo et al 2017). iPSC-CMs recapitulate gene expression patterns observed in primary heart tissue obtained from the GTEx Consortium, and eQTLs identified in iPSC-CMs are also enriched among eQTLs identified in primary heart tissue (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Impact of regulatory variation across human iPSCs and differentiated cells

et al. 2017

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Induced pluripotent stem cells (iPSCs) are an essential tool for studying cellular differentiation and cell types that are otherwise difficult to access. We investigated the use of iPSCs and iPSC-derived cells to study the impact of genetic variation on gene regulation across different cell types and as models for studies of complex disease. To do so, we established a panel of iPSCs from 58 well-studied Yoruba lymphoblastoid cell lines (LCLs); 14 of these lines were further differentiated into cardiomyocytes. We characterized regulatory variation across individuals and cell types by measuring gene expression levels, chromatin accessibility, and DNA methylation. Our analysis focused on a comparison of inter-individual regulatory variation across cell types. While most cell-type-specific regulatory quantitative trait loci (QTLs) lie in chromatin that is open only in the affected cell types, we found that 20% of cell-type-specific regulatory QTLs are in shared open chromatin. This observation motivated us to develop a deep neural network to predict open chromatin regions from DNA sequence alone. Using this approach, we were able to use the sequences of segregating haplotypes to predict the effects of common SNPs on cell-type-specific chromatin accessibility.

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Section: Discussionmentioning

confidence: 99%

Impact of regulatory variation across human iPSCs and differentiated cells

et al. 2017

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“…The unique advantage of this approach is that in vitro differentiated somatic cells not only serve as discovery platform for QTLs but at the same time provide an experimental system to perform functional cellular genomic experiments. Pashos and colleagues used CRISPR/Cas genome editing to confirm a functional effect of novel risk variants on gene expression (Pashos et al, 2017). Comparing in vitro derived sensory neurons with primary dorsal root ganglia however reveals experimental variation of in vitro derived cells as major limitation of this approach.…”

Section: Hpsc Models Of Complex Diseases - Population Genetics Approachmentioning

confidence: 99%

Stem Cells, Genome Editing, and the Path to Translational Medicine

Soldner

Jaenisch

2018

Cell

112

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Summary The derivation of human embryonic stem cells (hESCs) and the stunning discovery that somatic cells can be reprogrammed into human induced pluripotent stem cells (hiPSCs) holds the promise to revolutionize biomedical research and regenerative medicine. In this review, we focus on disorders of the central nervous system and explore how advances in human pluripotent stem cells (hPSCs) coincide with evolutions in genome engineering and genomic technologies to provide realistic opportunities to tackle some of the most devastating complex disorders.

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“…This effort required the generation of thousands of iPSC lines from control patients and those with genetically complex disorders 41, 42 . Two of the groups within the consortium focused on using iPSC–derived hepatocytes 4143 . Both groups established that hepatocytes produced from iPSCs could successfully address the role of genetic variations on the regulation of blood lipid levels.…”

Section: Using Ipsc-derived Hepatocytes To Model Complex Genetic Varimentioning

confidence: 99%

“…It is also important to realize that hepatocyte function varies depending on its relative position within the liver lobule 50 . While the production of hepatocyte-like cells is highly efficient, the resulting cells are not identical to hepatocytes that are freshly isolated from a donor liver 16, 43, 51 . Differences include the expression of CYP450 enzymes, which could impact the identification of drugs that require metabolic activation and could also complicate drug toxicity studies.…”

Section: Closing Remarksmentioning

confidence: 99%

Modeling Inborn Errors of Hepatic Metabolism Using Induced Pluripotent Stem Cells

Pournasr

Duncan

2017

ATVB

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Inborn errors of hepatic metabolism are due to deficiencies commonly within a single enzyme as a consequence of heritable mutations in the genome. Individually such diseases are rare, but collectively they are common. Advances in genome wide association studies (GWAS) and DNA sequencing have helped researchers identify the underlying genetic basis of such diseases. Unfortunately, cellular and animal models that accurately recapitulate these inborn errors of hepatic metabolism in the laboratory have been lacking. Recently investigators have exploited molecular techniques to generate induced pluripotent stem cells (iPSCs) from patients’ somatic cells. iPSCs can differentiate into a wide variety of cell types including hepatocytes thereby offering an innovative approach to unravel the mechanisms underlying inborn errors of hepatic metabolism. Moreover, such cell models could potentially provide a platform for the discovery of therapeutics. In this mini-review, we present a brief overview of the state-of-the-art in using pluripotent stem cells for such studies.

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Large, Diverse Population Cohorts of hiPSCs and Derived Hepatocyte-like Cells Reveal Functional Genetic Variation at Blood Lipid-Associated Loci

Cited by 138 publications

References 44 publications

Impact of regulatory variation across human iPSCs and differentiated cells

Impact of regulatory variation across human iPSCs and differentiated cells

Stem Cells, Genome Editing, and the Path to Translational Medicine

Modeling Inborn Errors of Hepatic Metabolism Using Induced Pluripotent Stem Cells

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