title: Integrated transcriptome analysis of human iPS cells derived from a fragile X syndrome patient during neuronal differentiation.
abstract: Fragile X syndrome (FXS) patients carry the expansion of over 200 CGG repeats at the promoter of fragile X mental retardation 1 (FMR1), leading to decreased or absent expression of its encoded fragile X mental retardation protein (FMRP). However, the global transcriptional alteration by FMRP deficiency has not been well characterized at single nucleotide resolution, i.e., RNA-seq. Here, we performed in-vitro neuronal differentiation of human induced pluripotent stem (iPS) cells that were derived from fibroblasts of a FXS patient (FXS-iPSC). We then performed RNA-seq and examined the transcriptional misregulation at each intermediate stage during in-vitro differentiation of FXS-iPSC into neurons. After thoroughly analyzing the transcriptomic data and integrating them with those from other platforms, we found up-regulation of many genes encoding TFs for neuronal differentiation (WNT1, BMP4, POU3F4, TFAP2C, and PAX3), down-regulation of potassium channels (KCNA1, KCNC3, KCNG2, KCNIP4, KCNJ3, KCNK9, and KCNT1) and altered temporal regulation of SHANK1 and NNAT in FXS-iPSC derived neurons, indicating impaired neuronal differentiation and function in FXS patients. In conclusion, we demonstrated that the FMRP deficiency in FXS patients has significant impact on the gene expression patterns during development, which will help to discover potential targeting candidates for the cure of FXS symptoms.
authors.affiliation: Tongji Stem Cell Research Center, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: Tongji University, School of Life Sciences and Technology, Shanghai, 200092, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Tongji Stem Cell Research Center, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Tongji Stem Cell Research Center, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Tongji University, School of Life Sciences and Technology, Shanghai, 200092, China.
authors.forename: Cizhong
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Tongji University, School of Life Sciences and Technology, Shanghai, 200092, China. xianminzhu@hotmail.com.
authors.forename: Xianmin
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Tongji University, School of Life Sciences and Technology, Shanghai, 200092, China. gfan@mednet.ucla.edu.|Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. gfan@mednet.ucla.edu.
authors.forename: Guoping
authors.initials: G
authors.lastname: Fan
authors.affiliation: Tongji Stem Cell Research Center, Tongji University School of Medicine, Shanghai, 200092, China. xuezg@tongji.edu.cn.|Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai, 200065, China. xuezg@tongji.edu.cn.|Tongji University Suzhou Institute, Suzhou, 215101, China. xuezg@tongji.edu.cn.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Xue
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D002478:Cells, Cultured; D016000:Cluster Analysis; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods*; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA / Q000379:methods
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human
keywords: fragile X syndrome; induced pluripotent stem cells; neuronal differentiation; transcriptome