title: MiR-135b is a direct PAX6 target and specifies human neuroectoderm by inhibiting TGF-β/BMP signaling.
abstract: Several transcription factors (TFs) have been implicated in neuroectoderm (NE) development, and recently, the TF PAX6 was shown to be critical for human NE specification. However, microRNA networks regulating human NE development have been poorly documented. We hypothesized that microRNAs activated by PAX6 should promote NE development. Using a genomics approach, we identified PAX6 binding sites and active enhancers genome-wide in an in vitro model of human NE development that was based on neural differentiation of human embryonic stem cells (hESC). PAX6 binding to active enhancers was found in the proximity of several microRNAs, including hsa-miR-135b. MiR-135b was activated during NE development, and ectopic expression of miR-135b in hESC promoted differentiation toward NE. MiR-135b promotes neural conversion by targeting components of the TGF-β and BMP signaling pathways, thereby inhibiting differentiation into alternate developmental lineages. Our results demonstrate a novel TF-miRNA module that is activated during human neuroectoderm development and promotes the irreversible fate specification of human pluripotent cells toward the neural lineage.
authors.affiliation: Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore City, Singapore.
authors.forename: Akshay
authors.initials: A
authors.lastname: Bhinge
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore City, Singapore.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Poschmann
authors.affiliation: Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore City, Singapore.
authors.forename: Seema C
authors.initials: SC
authors.lastname: Namboori
authors.affiliation: Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore City, Singapore.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Tian
authors.affiliation: Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore City, Singapore.
authors.forename: Sharon
authors.initials: S
authors.lastname: Jia Hui Loh
authors.affiliation: Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore City, Singapore.
authors.forename: Anna
authors.initials: A
authors.lastname: Traczyk
authors.affiliation: Computational and Systems Biology, Genome Institute of Singapore, Singapore City, Singapore.
authors.forename: Shyam
authors.initials: S
authors.lastname: Prabhakar
authors.affiliation: Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore City, Singapore Department of Biological Sciences, National University of Singapore, Singapore City, Singapore School of Biological Sciences Nanyang Technological University, Singapore City, Singapore stantonl@gis.a-star.edu.sg.
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Stanton
mesh_terms: D001665:Binding Sites; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D054258:Neural Plate; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; C544965:MIRN135 microRNA, human; D035683:MicroRNAs; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta
keywords: BMP; PAX6; TGF‐β; hsa‐miR‐135b; human embryonic stem cells; microRNA; neuroectoderm; transcription factor