miR-124,-128, and-137 Orchestrate Neural Differentiation by Acting on Overlapping Gene Sets Containing a Highly Connected Transcription Factor Network

Author(s)

Santos, Marcia C. T. ^{[1, 2]} ; Tegge, Allison N. ^{[3, 4]} ; Correa, Bruna R. ^{[5, 2]} ; Mahesula, Swetha ^[1] ; Kohnke, Luana Q. ^{[1, 2]} ; Qiao, Mei ^[2] ; Ferreira, Marco A. R. ^[4] ; Kokovay, Erzsebet ^[1] ; Penalva, Luiz O. F. ^{[1, 2]}

Affiliation

^[1] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 - USA

^[2] Univ Texas Hlth Sci Ctr San Antonio, Childrens Canc Res Inst, San Antonio, TX 78229 - USA

^[3] Virginia Tech, Dept Comp Sci, Blacksburg, VA - USA

^[4] Virginia Tech, Dept Stat, Blacksburg, VA - USA

^[5] Hosp Sirio Libanes, Ctr Oncol Mol, Sao Paulo - Brazil

• Document type: Journal article
• Source: Stem Cells; v. 34, n. 1, p. 220-232, JAN 2016.
• Web of Science Citations: 34

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. (AU)

• FAPESP's process: 11/51588-2 - Functional characterization of the LIN28 protein in tumorigenesis of the central nervous system
• Grantee: Márcia Cristina Teixeira dos Santos
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 12/22950-8 - Functional characterization of RNA binding proteins Lin28 and Msi1 in neurogenesis
• Grantee: Márcia Cristina Teixeira dos Santos
• Support type: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 13/25483-4 - Identification and functional analysis of RNA binding proteins associated with the development of glioblastoma multiform
• Grantee: Bruna Renata Silva Corrêa
• Support type: Scholarships abroad - Research Internship - Doctorate