title: Molecular analyses of neurogenic defects in a human pluripotent stem cell model of fragile X syndrome.
abstract: New research suggests that common pathways are altered in many neurodevelopmental disorders including autism spectrum disorder; however, little is known about early molecular events that contribute to the pathology of these diseases. The study of monogenic, neurodevelopmental disorders with a high incidence of autistic behaviours, such as fragile X syndrome, has the potential to identify genes and pathways that are dysregulated in autism spectrum disorder as well as fragile X syndrome. In vitro generation of human disease-relevant cell types provides the ability to investigate aspects of disease that are impossible to study in patients or animal models. Differentiation of human pluripotent stem cells recapitulates development of the neocortex, an area affected in both fragile X syndrome and autism spectrum disorder. We have generated induced human pluripotent stem cells from several individuals clinically diagnosed with fragile X syndrome and autism spectrum disorder. When differentiated to dorsal forebrain cell fates, our fragile X syndrome human pluripotent stem cell lines exhibited reproducible aberrant neurogenic phenotypes. Using global gene expression and DNA methylation profiling, we have analysed the early stages of neurogenesis in fragile X syndrome human pluripotent stem cells. We discovered aberrant DNA methylation patterns at specific genomic regions in fragile X syndrome cells, and identified dysregulated gene- and network-level correlates of fragile X syndrome that are associated with developmental signalling, cell migration, and neuronal maturation. Integration of our gene expression and epigenetic analysis identified altered epigenetic-mediated transcriptional regulation of a distinct set of genes in fragile X syndrome. These fragile X syndrome-aberrant networks are significantly enriched for genes associated with autism spectrum disorder, giving support to the idea that underlying similarities exist among these neurodevelopmental diseases.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.|Center for Regenerative Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Boland
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.|Center for Regenerative Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Kristopher L
authors.initials: KL
authors.lastname: Nazor
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.|Center for Regenerative Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Ha T
authors.initials: HT
authors.lastname: Tran
authors.affiliation: BioCircuits Institute, University of California San Diego, La Jolla, CA, USA.|MTA-ELTE NAP-B Neuronal Cell Biology Group, Eötvös Lóránd University, Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Szücs
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.|Center for Regenerative Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Candace L
authors.initials: CL
authors.lastname: Lynch
authors.affiliation: CIRM Bridges to Stem Cells Program, California State University Channel Islands, Camarillo, CA, USA.
authors.forename: Ryder
authors.initials: R
authors.lastname: Paredes
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, USA.|MIND Institute, University of California Davis, Sacramento, CA, USA.
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Pietro Paolo
authors.initials: PP
authors.lastname: Sanna
authors.affiliation: MIND Institute, University of California Davis, Sacramento, CA, USA.|Department of Pediatrics, University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Randi J
authors.initials: RJ
authors.lastname: Hagerman
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.|Center for Regenerative Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Jeanne F
authors.initials: JF
authors.lastname: Loring
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D019175:DNA Methylation / Q000235:genetics; D005333:Fetus; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology*; D005786:Gene Expression Regulation / Q000235:genetics*; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D055495:Neurogenesis; D039904:Pluripotent Stem Cells / Q000502:physiology*; D014162:Transfection; D018911:Trinucleotide Repeats / Q000235:genetics
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human
keywords: autism spectrum disorder; brain development; fragile X syndrome; neurogenesis; stem cells