scholarly journals 16p11.2 microdeletion imparts transcriptional alterations in human iPSC-derived models of early neural development

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Julien G Roth ◽  
Kristin L Muench ◽  
Aditya Asokan ◽  
Victoria M Mallett ◽  
Hui Gai ◽  
...  
Keyword(s):  
Cell Lines ◽  
Neural Development ◽  
Developmental Disorders ◽  
Neural Progenitor Cells ◽  
Expression Patterns ◽  
Clinical Information ◽  
Copy Number Variations ◽  
Chromosomal Locus ◽  
Transcriptional Alterations ◽  
Induced Pluripotent

Microdeletions and microduplications of the 16p11.2 chromosomal locus are associated with syndromic neurodevelopmental disorders and reciprocal physiological conditions such as macro/microcephaly and high/low body mass index. To facilitate cellular and molecular investigations into these phenotypes, 65 clones of human induced pluripotent stem cells (hiPSCs) were generated from 13 individuals with 16p11.2 copy number variations (CNVs). To ensure these cell lines were suitable for downstream mechanistic investigations, a customizable bioinformatic strategy for the detection of random integration and expression of reprogramming vectors was developed and leveraged towards identifying a subset of ‘footprint’-free hiPSC clones. Transcriptomic profiling of cortical neural progenitor cells derived from these hiPSCs identified alterations in gene expression patterns which precede morphological abnormalities reported at later neurodevelopmental stages. Interpreting clinical information—available with the cell lines by request from the Simons Foundation Autism Research Initiative—with this transcriptional data revealed disruptions in gene programs related to both nervous system function and cellular metabolism. As demonstrated by these analyses, this publicly available resource has the potential to serve as a powerful medium for probing the etiology of developmental disorders associated with 16p11.2 CNVs.

scholarly journals Copy Number Variation at 16p11.2 Imparts Transcriptional Alterations in Neural Development in an hiPSC-derived Model of Corticogenesis

2020 ◽  
Author(s):  
Julien G. Roth ◽  
Kristin L. Muench ◽  
Aditya Asokan ◽  
Victoria M. Mallett ◽  
Hui Gai ◽  
...  
Keyword(s):  
Neural Development ◽  
Copy Number ◽  
Developmental Disorders ◽  
Neural Progenitor Cells ◽  
Copy Number Variations ◽  
Chromosomal Locus ◽  
Research Initiative ◽  
Transcriptional Alterations ◽  
Number Variation ◽  
Induced Pluripotent

ABSTRACTMicrodeletions and microduplications of the 16p11.2 chromosomal locus are associated with syndromic neurodevelopmental disorders and reciprocal physiological conditions such as macro/microcephaly and high/low body mass index. To facilitate cellular and molecular investigations of these phenotypes, 65 clones of human induced pluripotent stem cells (hiPSCs) were generated from 13 individuals with 16p11.2 copy number variations (CNVs). Cortical neural progenitor cells derived from these hiPSCs were profiled using RNA-Seq, which identified alterations in radial glial gene expression that precede morphological abnormalities reported at later neurodevelopmental stages. Moreover, a customizable bioinformatic strategy for the detection of random integration and expression of reprogramming vectors was developed and leveraged towards identifying a subset of “footprint”-free hiPSC clones that are available by request from the Simons Foundation Autism Research Initiative. This publicly available resource of 65 human hiPSC clones can serve as a powerful medium for probing the etiology of developmental disorders associated with 16p11.2 CNVs.

scholarly journals Molecular Characterization of Putative Chordoma Cell Lines

Sarcoma ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-14 ◽  
Author(s):  
Silke Brüderlein ◽  
Joshua B. Sommer ◽  
Paul S. Meltzer ◽  
Sufeng Li ◽  
Takuya Osada ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Line ◽  
Cell Lines ◽  
Copy Number ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Cancer Cell Line ◽  
Copy Number Variations ◽  
Genetic Changes

Immortal tumor cell lines are an important model system for cancer research, however, misidentification and cross-contamination of cell lines are a common problem. Seven chordoma cell lines are reported in the literature, but none has been characterized in detail. We analyzed gene expression patterns and genomic copy number variations in five putative chordoma cell lines (U-CH1, CCL3, CCL4, GB60, and CM319). We also created a new chordoma cell line, U-CH2, and provided genotypes for cell lines for identity confirmation. Our analyses revealed that CCL3, CCL4, and GB60 are not chordoma cell lines, and that CM319 is a cancer cell line possibly derived from chordoma, but lacking expression of key chordoma biomarkers. U-CH1 and U-CH2 both have gene expression profiles, copy number aberrations, and morphology consistent with chordoma tumors. These cell lines also harbor genetic changes, such as loss of p16, MTAP, or PTEN, that make them potentially useful models for studying mechanisms of chordoma pathogenesis and for evaluating targeted therapies.

scholarly journals Human iPSC-derived cerebral organoids model features of Leigh Syndrome and reveal abnormal corticogenesis

2020 ◽  
Author(s):  
Alejandra I. Romero-Morales ◽  
Anuj Rastogi ◽  
Hoor Temuri ◽  
Megan L. Rasmussen ◽  
Gregory Scott McElroy ◽  
...  
Keyword(s):  
Cell Lines ◽  
Neural Progenitor Cells ◽  
Three Dimensional ◽  
Leigh Syndrome ◽  
Mitochondrial Respiratory Chain ◽  
Model Systems ◽  
Phenotypic Characterization ◽  
Mitochondrial Morphology ◽  
Induced Pluripotent ◽  
Model Features

SummaryLeigh syndrome (LS) is a rare, inherited neuro-metabolic disorder that presents with bilateral brain lesions. This disease is caused by defects in the mitochondrial respiratory chain and associated nuclear-encoded proteins. We generated induced pluripotent stem cells (iPSCs) from three widely available LS fibroblast lines and identified, through whole exome and mitochondrial sequencing, unreported mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and dihydrolipoyl dehydrogenase (GM01503, DLD). LS derived cell lines were viable and able to differentiate into key progenitor populations, but we identified several abnormalities in three-dimensional differentiation models of brain development. The DLD-mutant line showed decreased neural rosette (NR) formation, and there were differences in NR lumen area in all three LS lines compared to control. LS-derived cerebral organoids showed defects in neural epithelial bud generation and reduced size when grown for 100 days. Loss of cortical architecture and markers were detected at days 30 and 100. The MT-ATP6/PDH line produced organoid neural progenitor cells with an abnormal mitochondrial morphology characterized by fragmentation and disorganization, and demonstrated increased generation of astrocytes. These studies aim to provide a comprehensive phenotypic characterization of available patient-derived cell lines that could be used as LS model systems.

Analysis of the Differential Expression Patterns of Sumoylation Enzymes E1, E2 and E3 in Ocular Cell Lines

2019 ◽  
Vol 18 (8) ◽  
pp. 509-515 ◽  
Author(s):  
Qian Nie ◽  
Jie Xie ◽  
Xiaodong Gong ◽  
Zhongwen Luo ◽  
Ling Wang ◽  
...  
Keyword(s):  
Differential Expression ◽  
Cell Lines ◽  
Expression Patterns

scholarly journals Generation of three heterozygous KCNH2 mutation-carrying human induced pluripotent stem cell lines for modeling LQT2 syndrome

2021 ◽  
pp. 102402
Author(s):  
Gema Mondéjar-Parreño ◽  
James W.S. Jahng ◽  
Nadjet Belbachir ◽  
Blake C. Wu ◽  
Xiaolan Zhang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Lines ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Stem Cell Lines ◽  
Induced Pluripotent

scholarly journals MED12-Related (Neuro)Developmental Disorders: A Question of Causality

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 663
Author(s):  
Stijn van de Plassche ◽  
Arjan PM de Brouwer
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Expression Patterns ◽  
Mediator Complex ◽  
Gene Expression Patterns ◽  
Facial Dysmorphism ◽  
Regulation Of Transcription ◽  
Feeding Difficulties ◽  
Missense Variants ◽  
Pathogenic Variants

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

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