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Kim K.-Y.,Yale University | Jung Y.W.,Yale University | Jung Y.W.,CHA Medical University | Sullivan G.J.,University of Oslo | And 3 more authors.
Trends in Molecular Medicine

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in reciprocal social interaction and communication, as well as the manifestation of stereotyped behaviors. Despite much effort, ASDs are not yet fully understood. Advanced genetics and genomics technologies have recently identified novel ASD genes, and approaches using genetically engineered murine models or postmortem human brain have facilitated understanding ASD. Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) provides unprecedented opportunities in generating human disease models. Here, we present an overview of applying iPSCs in developing cellular models for understanding ASD. We also discuss future perspectives in the use of iPSCs as a source of cell therapy and as a screening platform for identifying small molecules with efficacy for alleviating ASD. © 2012. Source

Aanes H.,BasAM | Winata C.L.,Genome Institute of Singapore | Lin C.H.,Genome Institute of Singapore | Chen J.P.,Genome Institute of Singapore | And 11 more authors.
Genome Research

Maternally deposited mRNAs direct early development before the initiation of zygotic transcription during mid-blastula transition (MBT). To study mechanisms regulating this developmental event in zebrafish, we applied mRNA deep sequencing technology and generated comprehensive information and valuable resources on transcriptome dynamics during early embryonic (egg to early gastrulation) stages. Genome-wide transcriptome analysis documented at least 8000 maternal genes and identified the earliest cohort of zygotic transcripts. We determined expression levels of maternal and zygotic transcripts with the highest resolution possible using mRNA-seq and clustered them based on their expression pattern. We unravel delayed polyadenylation in a large cohort of maternal transcripts prior to the MBT for the first time in zebrafish. Blocking polyadenylation of these transcripts confirms their role in regulating development from the MBT onward. Our study also identified a large number of novel transcribed regions in annotated and unannotated regions of the genome, which will facilitate reannotation of the zebrafish genome. We also identified splice variants with an estimated frequency of 50%-60%. Taken together, our data constitute a useful genomic information and valuable transcriptome resource for gene discovery and for understanding the mechanisms of early embryogenesis in zebrafish. © 2011 by Cold Spring Harbor Laboratory Press. Source

Siller R.,University of Oslo | Greenhough S.,University of Oslo | Naumovska E.,University of Oslo | Sullivan G.J.,University of Oslo | Sullivan G.J.,Norwegian Center for Stem Cell Research
Stem Cell Reports

The differentiation of pluripotent stem cells to hepatocytes is well established, yet current methods suffer from several drawbacks. These include a lack of definition and reproducibility, which in part stems from continued reliance on recombinant growth factors. This has remained a stumbling block for the translation of the technology into industry and the clinic for reasons associated with cost and quality. We have devised a growth-factor-free protocol that relies on small molecules to differentiate human pluripotent stem cells toward a hepatic phenotype. The procedure can efficiently direct both human embryonic stem cells and induced pluripotent stem cells to hepatocyte-like cells. The final population of cells demonstrates marker expression at the transcriptional and protein levels, as well as key hepatic functions such as serum protein production, glycogen storage, and cytochrome P450 activity. © 2015 The Authors. Source

Siller R.,University of Oslo | Greenhough S.,University of Oslo | Park I.-H.,Yale University | Sullivan G.J.,University of Oslo | Sullivan G.J.,Norwegian Center for Stem Cell Research
Current Gene Therapy

Recent progress in the field of cellular reprogramming has opened up the doors to a new era of disease modeling, as pluripotent stem cells representing a myriad of genetic diseases can now be produced from patient tissue. These cells can be expanded and differentiated to produce a potentially limitless supply of the affected cell type, which can then be used as a tool to improve understanding of disease mechanisms and test therapeutic interventions. This process requires high levels of scrutiny and validation at every stage, but international standards for the characterisation of pluripotent cells and their progeny have yet to be established. Here we discuss the current state of the art with regard to modelling diseases affecting the ectodermal, mesodermal and endodermal lineages, focusing on studies which have demonstrated a disease phenotype in the tissue of interest. We also discuss the utility of pluripotent cell technology for the modelling of cancer and infectious disease. Finally, we spell out the technical and scientific challenges which must be addressed if the field is to deliver on its potential and produce improved patient outcomes in the clinic. © 2013 Bentham Science Publishers. Source

Barrand S.,University of Oslo | Barrand S.,Norwegian Center for Stem Cell Research | Collas P.,University of Oslo | Collas P.,Norwegian Center for Stem Cell Research
Biochemical and Biophysical Research Communications

Oct4, Nanog and Sox2 constitute a core of transcription factors controlling pluripotency. Differentiation and reprogramming studies have unraveled a few epigenetic modifications associated in relation to the expression state of OCT4, NANOG and SOX2. There is, however, no comprehensive map of chromatin states on these genes in human primary cells at different stages of differentiation. We report here a profile of DNA methylation and of 10 histone modifications on regulatory regions of OCT4, NANOG and SOX2 in embryonal carcinoma cells, mesenchymal stem cells and fibroblasts. Bisulfite sequencing reveals correlation between promoter CpG methylation and repression of OCT4, but not NANOG or SOX2, suggesting distinct repression mechanisms. Whereas none of these genes, even when inactive, harbor repressive trimethylated H3K9, CpG hypomethylated NANOG and SOX2, but not CpG methylated OCT4, are enriched in repressive H3K27me3. H3K79me1 and H3K79me3 tend to parallel each other and are linked to repression. Moreover, we highlight an inverse relationship between H3K27me3 occupancy on promoters and H3K36me3 occupancy on coding regions of OCT4, NANOG and SOX2, suggesting a cross-talk between K27 and K36 methylation. Establishment of distinct repression mechanisms for pluripotency-associated genes may constitute a safeguard system to prevent promiscuous reactivation during development or differentiation. © 2009 Elsevier Inc. All rights reserved. Source

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