title: miR-124, -128, and -137 Orchestrate Neural Differentiation by Acting on Overlapping Gene Sets Containing a Highly Connected Transcription Factor Network.
abstract: The ventricular-subventricular zone harbors neural stem cells (NSCs) that can differentiate into neurons, astrocytes, and oligodendrocytes. This process requires loss of stem cell properties and gain of characteristics associated with differentiated cells. miRNAs function as important drivers of this transition; miR-124, -128, and -137 are among the most relevant ones and have been shown to share commonalities and act as proneurogenic regulators. We conducted biological and genomic analyses to dissect their target repertoire during neurogenesis and tested the hypothesis that they act cooperatively to promote differentiation. To map their target genes, we transfected NSCs with antagomiRs and analyzed differences in their mRNA profile throughout differentiation with respect to controls. This strategy led to the identification of 910 targets for miR-124, 216 for miR-128, and 652 for miR-137. The target sets show extensive overlap. Inspection by gene ontology and network analysis indicated that transcription factors are a major component of these miRNAs target sets. Moreover, several of these transcription factors form a highly interconnected network. Sp1 was determined to be the main node of this network and was further investigated. Our data suggest that miR-124, -128, and -137 act synergistically to regulate Sp1 expression. Sp1 levels are dramatically reduced as cells differentiate and silencing of its expression reduced neuronal production and affected NSC viability and proliferation. In summary, our results show that miRNAs can act cooperatively and synergistically to regulate complex biological processes like neurogenesis and that transcription factors are heavily targeted to branch out their regulatory effect.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.|Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Márcia C T
authors.initials: MC
authors.lastname: Santos
authors.affiliation: Department of Computer Science, Virginia Tech, Blacksburg, Virginia, USA.|Department of Statistics, Virginia Tech, Blacksburg, Virginia, USA.
authors.forename: Allison N
authors.initials: AN
authors.lastname: Tegge
authors.affiliation: Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.|Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil.
authors.forename: Bruna R
authors.initials: BR
authors.lastname: Correa
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Swetha
authors.initials: S
authors.lastname: Mahesula
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.|Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Luana Q
authors.initials: LQ
authors.lastname: Kohnke
authors.affiliation: Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Qiao
authors.affiliation: Department of Statistics, Virginia Tech, Blacksburg, Virginia, USA.
authors.forename: Marco A R
authors.initials: MA
authors.lastname: Ferreira
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Erzsebet
authors.initials: E
authors.lastname: Kokovay
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.|Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Luiz O F
authors.initials: LO
authors.lastname: Penalva
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D016678:Genome; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D017423:Sequence Analysis, RNA; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014162:Transfection
chemical_list: C551799:MIRN137 microRNA, mouse; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; C550324:Mirn128 microRNA, mouse; D016376:Oligonucleotides, Antisense; D016329:Sp1 Transcription Factor
keywords: Differentiation; Neural stem cell; Neurogenesis; Sp1; Transcription factors; miR-128; miR-137; miRNA; mir-124